NEWS LUNG CANCER. The Treatment of Patients with Oligometastatic Lung Cancer. Top Science in Lung Cancer Featured at WCLC 2018 INSIDE

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1 V3 / N5 / OCTOBER 2018 FOR THORACIC SPECIALISTS Read online at LungCancerNews.org & Visit IASLC.org LUNG CANCER NEWS INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNG CANCER INSIDE In Memorium: Dr. David J. Sugarbaker In Memorium: Dr. James D. Cox EGFR TKIs: A Marathon or a Sprint? The Vital and Evolving Role of Bronchoscopic Technologies Living in the Gray Zone : Entering a New Age in Radiation Therapy for Lung Cancer 2018 ASTRO Guideline for Palliative Thoracic Radiation Therapy for NSCLC After the Consultation: Social Media, Inter-Patient Communication, and Clinical Trials The IASLC Fight Against Lung Cancer in Peru and Latin America A Review of CancerSEEK CAR-T Cells for Lung Cancer: Q&A with Dr. Charu Aggarwal The IASLC Provides More Than Just Scientific Knowledge at Tangier Conference MEETING HIGHLIGHTS Top Science in Lung Cancer Featured at WCLC 2018 By Kara Nyberg, PhD The Presidential Symposium at the IASLC World Conference on Lung Cancer 2018 (WCLC) showcased the top five scientific abstracts highlighting progress in detecting and treating different forms of lung cancer and mesothelioma. These presentations featured four positive clinical trials that advance current treatment standards and one negative clinical trial that reinforces the benefits achieved with the current standard of care. CT Screening for Lung Cancer Harry J. de Koning, MD, PhD, professor at Erasmus MC, Rotterdam, the Netherlands, presented the 10-year results of the NELSON trial, a randomized, controlled, population-based study evaluating the ability of low-dose CT screening to reduce the incidence of lung cancer mortality, as compared with no screening, in high-risk individuals. More than 7,000 attendees gathered to hear about the practice-changing trials discussed during the Presidential Symposium. The 15,792 participants in the trial were winnowed from a pool of more than 606,000 people aged 50 to 74 in the Netherlands and Belgium. This select group, who had smoked more than 15 cigarettes per day for more than 25 years or more than 10 cigarettes per day for more than 30 years, and who were still smoking or had quit 10 years ago or less, underwent random assignment to CT screening (conducted at baseline and 1, 3, and 5.5 years) or to no screening. Indeterminate nodules identified during screening were rescanned 2 months after initial detection to estimate nodule volume doubling time and to prompt a referral, if appropriate. At 10 years after the start of the study, periodic CT screening reduced the rate of dying from lung cancer by 26% among high-risk men. Results were even more continued on page 6 EVOLVING STANDARDS OF CARE The Treatment of Patients with Oligometastatic Lung Cancer By Anne-Marie C. Dingemans, MD, PhD, and Lizza E.L. Hendriks, MD, PhD Patients with stage IV NSCLC are generally viewed as having incurable disease; however, for years, patients presenting with a solitary brain or adrenal metastasis have been treated with local ablative treatment (LAT) with curative intent, and multiple series have shown long-term overall survival (OS) in some of these patients. The concept of a clinically significant state of oligometastases was first described in 1995, 1 proposing that oligometastatic cancer has a different biology, and that these patients, therefore, could benefit from LAT. Long-term benefit of LAT in patients with up to three or five metastatic sites has been observed in several, mainly retrospective, series. 2 In 2012, De Ruysscher et al. 3 published the first prospective clinical trial in patients with NSCLC with synchronous oligometastases. In this Prof. Anne-Marie C. Dingemans single-arm phase II study, 40 patients with stage IV NSCLC and fewer than five metastases, amenable for LAT (radiotherapy or surgery), were enrolled. The 2- and 3-year survival rates were 23.3% and 17.5%, respectively, showing that some patients with oligometastatic NSCLC could benefit long-term from LAT. Although patients with up to four metastases were eligible, only 13% had more than one metastasis. In addition, 95% also received systemic chemotherapy. The study was unable to define predictive patient or tumor characteristics. In recent years, the concept of oligometastatic treatment has evolved. Growing interest has been pushed by the increasing number of available treatment strategies, as well as the widespread introduction of minimally invasive surgery and stereotactic radiotherapy. Several guidelines have described Dr. Lizza E.L. Hendriks oligometastatic NSCLC as a separate entity. For example, the European Society for Medical Oncology guideline states that patients with one to three synchronous metastases might have longterm disease-free survival when treated with systemic treatment and LAT. 4 In addition, in the last edition of the TNM (8th) staging system, patients with solitary metastasis (M1b) were identified as a separate prognostic group with a superior OS compared to patients with more widespread metastases (M1c). 5 However, data on the staging of these patients were lacking, and selection bias might have occurred, as some hospitals entered only a few patients. 6 Impressive Data but No Change to Daily Practice After years of retrospective data and single-arm trials reporting on oligometastatic NSCLC, the first randomized phase II trial was presented by Daniel Gomez, MD, at the 2016 American Society of Clinical Oncology Annual Meeting. Progression-free survival (PFS), the primary endpoint, was shown to be significantly superior when patients with oligometastatic NSCLC were treated with LAT compared to follow-up or maintenance therapy after treatment with at least four cycles of platinum-containing chemotherapy or 3 months of an EGFR TKI (EGFR mutation) or crizotinib (ALK rearrangement). Oligometastatic disease was defined as no progression after continued on page 8

2 FOR THE TREATMENT OF METASTATIC EGFRm NSCLC FIRST-LINE TAGRISSO DELIVERED AN UNPRECEDENTED 18.9 vs 10.2 months median PFS vs erlotinib/gefitinib in the FLAURA study Hazard ratio=0.46 (95% CI: 0.37, 0.57), P< Randomized, double-blind, active-controlled trial in 556 patients with metastatic EGFRm NSCLC who had not received prior systemic treatment for advanced disease. Patients were randomized 1:1 to either TAGRISSO (n=279; 80 mg orally, once daily) or EGFR TKI comparator (n=277; gefi tinib 250 mg or erlotinib 150 mg, once daily). Crossover was allowed for patients in the EGFR TKI comparator arm at confi rmed progression if positive for the EGFR T790M resistance mutation. Patients with CNS metastases not requiring steroids and with stable neurologic status were included in the study. The primary endpoint of the study was PFS based on investigator assessment (according to RECIST v.1.1). Secondary endpoints included OS, ORR, and DOR. 1,2 INDICATION TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. SELECT SAFETY INFORMATION There are no contraindications for TAGRISSO Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed Heart rate-corrected QT (QTc) interval prolongation occurred in TAGRISSO-treated patients. Of the 1142 TAGRISSO-treated patients in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. TAGRISSO is a registered trademark of the AstraZeneca group of companies AstraZeneca. All rights reserved. US /18

3 GROUNDBREAKING EFFICACY DOSING First-line TAGRISSO offers convenient, once-daily dosing, with or without food 1 ALL SUBGROUPS Delivered consistent PFS results across all subgroups, including patients with or without CNS metastases 2 First-line osimertinib (TAGRISSO) is a National Comprehensive Cancer Network (NCCN ) Category 1* option 3 *Category 1 means NCCN has uniform consensus based upon high-level evidence. 3 SELECT SAFETY INFORMATION Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Cardiomyopathy occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) 10% from baseline and to <50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose Most common adverse reactions ( 20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue and decreased appetite Abbreviations: CNS, central nervous system; DOR, duration of response; EGFRm, epidermal growth factor receptor mutation-positive; NSCLC, non-small cell lung cancer; ORR, overall response rates; OS, Overall Survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors; TKI, tyrosine kinase inhibitor. REFERENCES: 1. TAGRISSO [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2): Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for NSCLC V National Comprehensive Cancer Network, Inc All rights reserved. Accessed June 29, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. To view the most recent and complete version of the guideline, go online to NCCN.org. Please see Brief Summary of Prescribing Information on adjacent pages. LEARN MORE AT TagrissoHCP.com

4 TAGRISSO (osimertinib) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1) in the full Prescribing Information]. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the first-line treatment of metastatic EGFR-positive NSCLC with TAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in tumor or plasma specimens [see Clinical Studies (14) in the full Prescribing Information]. If this mutation is not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests for the detection of EGFR mutations is available at companiondiagnostics. Recommended Dosage Regimen The recommended dosage of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food. If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled. Administration to Patients Who Have Difficulty Swallowing Solids Disperse tablet in 60 ml (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 ml to 240 ml (4 to 8 ounces) of water and immediately drink. If administration via nasogastric tube is required, disperse the tablet as above in 15 ml of non-carbonated water, and then use an additional 15 ml of water to transfer any residues to the syringe. The resulting 30 ml liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 ml). Dosage Modifications Adverse Reactions Table 1. Recommended Dosage Modifications for TAGRISSO Target Organ Adverse Reaction a Dosage Modification Pulmonary Interstitial lung disease (ILD)/Pneumonitis Permanently discontinue TAGRISSO. Cardiac Other QTc interval greater than 500 msec on at least 2 separate ECGs b QTc interval prolongation with signs/ symptoms of life-threatening arrhythmia Symptomatic congestive heart failure Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose. Permanently discontinue TAGRISSO. Permanently discontinue TAGRISSO. Adverse reaction of Grade 3 or greater Withhold TAGRISSO for up to 3 weeks. severity If improvement to Grade 0-2 within 3 weeks Resume at 80 mg or 40 mg daily. If no improvement within 3 weeks Permanently discontinue TAGRISSO. a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). b ECGs = Electrocardiograms QTc = QT interval corrected for heart rate Drug Interactions Strong CYP3A4 Inducers If concurrent use is unavoidable, increase TAGRISSO dosage to 160 mg daily when coadministering with a strong CYP3A inducer. Resume TAGRISSO at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer [see Drug Interactions (7) and Clinical Pharmacology (12.3) in the full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Interstitial Lung Disease/Pneumonitis Interstitial lung disease (ILD)/pneumonitis occurred in 3.9% of the 1142 TAGRISSO-treated patients; 0.4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6) in the full Prescribing Information]. QTc Interval Prolongation Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec [see Clinical Pharmacology (12.2) in the full Prescribing Information]. No QTc-related arrhythmias were reported. Clinical trials of TAGRISSO did not enroll patients with baseline QTc of > 470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia [see Dosage and Administration (2.4) in the full Prescribing Information]. Cardiomyopathy Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the 1142 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) 10% from baseline and to less than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.4) in the full Prescribing Information]. Keratitis Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist. Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) in the full Prescribing Information] QTc Interval Prolongation [see Warnings and Precautions (5.2) in the full Prescribing Information] Cardiomyopathy [see Warnings and Precautions (5.3) in the full Prescribing Information] Keratitis [see Warnings and Precautions (5.4) in the full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions section reflect exposure to TAGRISSO in 1142 patients with EGFR mutation-positive NSCLC who received TAGRISSO at the recommended dose of 80 mg once daily in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)], two single arm trials [AURA Extension (n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see Warnings and Precautions (5) in the full Prescribing Information]. The data described below reflect exposure to TAGRISSO (80 mg daily) in 558 patients with EGFR mutationpositive, metastatic NSCLC in two randomized, active-controlled trials [FLAURA (n=279) and AURA3 (n=279)]. Patients with a history of interstitial lung disease, drug induced interstitial disease or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 msec on electrocardiogram were excluded from enrollment in these studies. Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months. The most common adverse reactions ( 20%) in patients treated with TAGRISSO were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis (29%), and decreased appetite (20%). Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions ( 1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%). Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA. FLAURA was not designed to demonstrate a statistically significant reduction in adverse reaction rates for TAGRISSO, or for the control arm, for any adverse reaction listed in Tables 2 and 3. Table 2. Adverse Reactions Occurring in 10% of Patients Receiving TAGRISSO in FLAURA* Adverse Reaction Any Grade (%) TAGRISSO (N=279) Grade 3 or higher (%) EGFR TKI comparator (gefitinib or erlotinib) (N=277) Any Grade (%) Grade 3 or higher (%) Gastrointestinal Disorders Diarrhea a Stomatitis Nausea Constipation Vomiting Skin Disorders Rash b Dry skin c Nail toxicity d Pruritus e Metabolism and Nutrition Disorders Decreased appetite Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Neurologic Disorders Headache Cardiac Disorders Prolonged QT Interval f General Disorders and Administration Site Conditions Fatigue g Pyrexia Infection and Infestation Disorders Upper Respiratory Tract Infection * NCI CTCAE v4.0 a One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator b Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion. c Includes dry skin, skin fissures, xerosis, eczema, xeroderma. d Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia. e Includes pruritus, pruritus generalized, eyelid pruritus. f The frequency of Prolonged QT Interval represents reported adverse events in the FLAURA study. Frequencies of QTc intervals of >500 ms or >60 ms are presented in Section 5.2. g Includes fatigue, asthenia.

5 TAGRISSO (osimertinib) tablets, for oral use 2 Table 3. Laboratory Abnormalities Worsening from Baseline in 20% of Patients in FLAURA Laboratory Abnormality a,b Change from Baseline All Grades (%) TAGRISSO (N=279) Change from Baseline to Grade 3 or Grade 4 (%) EGFR TKI comparator (gefitinib or erlotinib) (N=277) Change from Baseline All Grades (%) Change from Baseline to Grade 3 or Grade 4 (%) Hematology Lymphopenia Anemia Thrombocytopenia Neutropenia Chemistry Hyperglycemia c Hypermagnesemia Hyponatremia Increased AST Increased ALT Hypokalemia Hyperbilirubinemia a NCI CTCAE v4.0 b Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: and EGFR TKI comparator range: ) c Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191) DRUG INTERACTIONS Effect of Other Drugs on Osimertinib Strong CYP3A Inducers Coadministering TAGRISSO with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Decreased osimertinib exposure may lead to reduced efficacy. Avoid coadministering TAGRISSO with strong CYP3A inducers. Increase the TAGRISSO dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable [see Dosage and Administration (2.4) in the full Prescribing Information]. No dose adjustments are required when TAGRISSO is used with moderate and/or weak CYP3A inducers. Effect of Osimertinib on Other Drugs Coadministering TAGRISSO with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity. Monitor for adverse reactions of the BCRP substrate, unless otherwise instructed in its approved labeling, when coadministered with TAGRISSO. Drugs That Prolong the QTc Interval The effect of coadministering medicinal products known to prolong the QTc interval with TAGRISSO is unknown. When feasible, avoid concomitant administration of drugs known to prolong the QTc interval with known risk of Torsades de pointes. If not feasible to avoid concomitant administration of such drugs, conduct periodic ECG monitoring [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) in the full Prescribing Information], TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended clinical dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1 times the AUC observed at the recommended clinical dose of 80 mg once daily), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6. Lactation Risk Summary There are no data on the presence of osimertinib or its active metabolites in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1) in the full Prescribing Information]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose. Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Contraception TAGRISSO can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) in the full Prescribing Information]. Females Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1) in the full Prescribing Information]. Males Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1) in the full Prescribing Information]. Infertility Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible [see Nonclinical Toxicology (13.1) in the full Prescribing Information]. Pediatric Use The safety and effectiveness of TAGRISSO in pediatric patients have not been established. Geriatric Use Forty-three percent (43%) of the 1142 patients in FLAURA (n=279), AURA3 (n=279), AURA Extension (n=201), AURA2 (n=210), and AURA1, (n=173) were 65 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggests a higher incidence of Grade 3 and 4 adverse reactions (13.4% versus 9.3%) and more frequent dose modifications for adverse reactions (13.4% versus 7.6%) in patients 65 years or older as compared to those younger than 65 years. Renal Impairment No dose adjustment is recommended in patients with mild, [creatinine clearance (CLcr) ml/min, as estimated by the Cockcroft Gault method (C-G)], moderate, (CLcr ml/min) or severe (CLcr ml/min) renal impairment. There is no recommended dose of TAGRISSO for patients with end-stage renal disease [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 to 1.5 times ULN and any AST] or moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE TAGRISSO is a registered trademark of the AstraZeneca group of companies. AstraZeneca 2018 Rev. 04/18 US /18

6 6 IASLC LUNG CANCER NEWS / OCTOBER 2018 WCLC 2018 from page 1 favorable for high-risk women, who benefitted from 61%, 53%, and 39% reductions in the rates of lung cancer mortality at 8, 9, and 10 years, respectively, after the start of random assignment. Among the patients assigned to the screening arm, 86% complied with all four CT scans. Only 9.3% of participants required a follow-up CT scan within 2 months after a suspicious screening scan, which led to an overall referral rate of 2.2% and a lung cancer detection rate of 3.6%. Based on these findings, Dr. de Koning concluded, Volume CT lung cancer screening of high-risk former and current smokers results in low referral rates and a statistically significant reduction in lung cancer mortality in both genders. Durvalumab After Chemoradiotherapy in Stage III NSCLC Results of the randomized, double-blind, placebo-controlled, phase III PACIFIC trial previously generated considerable excitement by demonstrating that use of the PD-L1 inhibitor durvalumab in patients with unresectable stage III NSCLC whose disease did not progress following platinum-based chemoradiotherapy the standard of care dramatically prolonged median progression-free survival (PFS) by almost 1 year when compared with placebo (16.8 vs 5.6 months; stratified HR, 0.52; 95% CI, ; p < 0.001). These findings marked the first major advance for such patients in many years and were sufficient to garner durvalumab approval by the U.S. Food and Drug Administration. Scott J. Antonia, MD, PhD, of H. Lee Moffitt Cancer Center & Research Institute, presented updated findings from PACIFIC for overall survival (OS), the other primary endpoint, which proved equally impressive to the PFS results. Among the 713 randomly assigned patients (intent-to-treat population) who were followed for a median of 25.2 months, median OS has not yet been reached in the group that received durvalumab every 2 weeks for up to 1 year following chemoradiotherapy, whereas the median in the placebo group was 28.7 months (stratified HR, 0.68; 99.73% CI, ; p = ; Fig.1). All patient subgroups, except those with <1% PD-L1 tumor expression, showed a survival benefit with durvalumab. Results of the secondary endpoints bolstered the other primary endpoints. The time to distant metastasis or death (stratified HR, 0.53; 95% CI, ) and updated incidence of new lesions (22.5% in the durvalumab group and 33.8% in the placebo group) heavily favored durvalumab over placebo. Because PACIFIC is the first study to show a survival advantage following chemoradiotherapy in patients with unresectable stage III NSCLC, Dr. Antonia stated that use of durvalumab in the absence of disease progression constitutes the new standard of care for this patient population. Brigatinib in Advanced ALK-Positive NSCLC Brigatinib, a next-generation ALK inhibitor, stands poised to become a new firstline standard of care for patients with ALK-positive NSCLC and one favored over crizotinib based on results emerging from ALTA-1L, a randomized, openlabel, phase III trial comparing brigatinib and crizotinib in 275 patients with stage IIIB/IV ALK-positive, ALK-inhibitor naive NSCLC. Brigatinib overcomes some of the shortcomings associated with crizotinib by readily penetrating the central nervous system (CNS) and remaining active against ALK mutations that render tumor cells resistant to crizotinib. Brigatinib has Fig. 1. Overall Survival in PACIFIC* (ITT) No. of events/ No. of patients Median OS (95% CI) months also consistently demonstrated the longest reported median PFS (16+ months) of any licensed or investigational ALK inhibitor in the post-crizotinib setting, so a head-to-head comparison of brigatinib and crizotinib as initial targeted therapy seemed inevitable. D. Ross Camidge, MD, PhD, of University of Colorado Cancer Center, provided the first report from ALTA-1L, which was open to patients with asymptomatic brain metastases. Up to one prior systemic therapy regimen for locally advanced or metastatic disease was permitted, so long as it was not an ALK inhibitor. Based on a median follow-up of only 9 to 11 months, the trial met the primary endpoint by demonstrating that brigatinib reduced the risk of progression or death by 51% compared with crizotinib, according to assessment by a blinded independent review committee (HR 0.49, 95% CI ; p = ; Fig. 2, page 9). Although median PFS has not yet been reached for the brigatinib arm, 12-mo OS (95% CI) % 24-mo OS (95% CI) % Durvalumab 183/476 NR (34.7 NR) 83.1 ( ) 66.3 ( ) Placebo 116/ (22.9 NR) 75.3 ( ) 55.6 ( ) Reprinted with permission from The New England Journal of Medicine year PFS rates were 67% with brigatinib versus 43% with crizotinib. Brigatinib yielded more favorable PFS outcomes across all subgroups at this first interim analysis. However, the agent worked particularly well in patients with CNS disease at baseline. Among this subgroup of patients, the hazard ratio for PFS was 0.20 (95% CI, ) in favor of brigatinib. Similarly, the hazard ratio for intracranial PFS was 0.27 (95% CI, ). Brigatinib appeared to be well tolerated. Although 29% of patients required dose reductions (vs 21% of patients treated with crizotinib), these were predominantly protocol-mandated for asymptomatic laboratory abnormalities (eg, increases in creatine phosphokinase, lipase, amylase). The ALTA-1L data suggest that early-onset pneumonitis may be a unique side effect of brigatinib compared with other ALK inhibitors, but this event occurred infrequently (3%). continued on page 9 IN MEMORIUM Dr. David J. Sugarbaker David J. Sugarbaker, MD, an internationally known pioneer in the surgical management of malignant pleural mesothelioma and of complex thoracic cancers, passed away in August 2018 at the age of 66. Throughout his lifetime, Dr. Sugarbaker developed methods to perform intraoperative heated chemotherapy and refined extrapleural pneumonectomy techniques. Dr. Sugarbaker graduated top of his class with his medical degree from Cornell University Medical School in After his residency, he was appointed chief of the Division of Thoracic Surgery at Brigham and Women s Hospital in Boston, where he founded the first noncardiac division of thoracic surgery in the United States. In 1990, Dr. Sugarbaker performed the first lung transplant, and developed the first general thoracic surgical training program in Dr. Sugarbaker founded the International Mesothelioma Program in 2002, with the goal of finding a cure for the disease. He moved to Texas Medical Center in 2014, where he founded the new Division of General Thoracic Surgery, The Lung Institute, as well as the Mesothelioma Treatment Center. Dr. Sugarbaker wore numerous hats throughout the years at the American Association for Thoracic Surgery (AATS). The current president, David H. Adams, MD, said in a statement by the AATS that Through [Dr. Sugarbaker s] leadership and focused attention, he played a major role in transforming [the AATS] into the contemporary, international, and philanthropic organization that it is today. His mentorship of so many leaders in the association will have a lasting effect on the trajectory of the organization for years to come.

7 LUNGCANCERNEWS.ORG / OCTOBER IN MEMORIUM Dr. James D. Cox James D. Cox, MD, a leader in the radiation oncology community and pioneer of proton therapy, passed away in August, just a month after his 80th birthday. Dr. Cox s career path was peppered with illustrious mentors, directorships, society accolades, hundreds of peer-reviewed article publications, and an editorship of almost 2 decades. A native of Dayton, Ohio, Dr. Cox obtained his undergraduate degree from Kenyon College in Gambier, Ohio, and his medical degree from the University of Rochester Medical School. Dr. Cox spent his residency and a year of fellowship at Gustave Roussy, France, to study with Bernard Pierquin, MD, the king of brachytherapy, and other giants in the world of radiation oncology, including Andrée Dutreix, PhD, Maurice Tubiana, MD, PhD, and Daniel Chassagne, MD. Dr. Cox went on active duty in the U.S. Army upon his return from overseas and was stationed at Walter Reed Army Institute of Research from 1970 to When his commanding officer and head of the department of radiology at Walter Reed, John G. Maier, MD, retired, Dr. Cox became the head of the radiotherapy service there by default in his second year. Shortly after, at the age of 34, Dr. Cox became the head of the radiotherapy section in the department of radiology at Georgetown University. From there Dr. Cox took directorships with the Medical College of Wisconsin and Columbia University before becoming physician-in-chief at The University of Texas MD Anderson Cancer Center (MDACC) in During that time, he also chaired the Radiation Therapy Oncology Group (RTOG), where he oversaw the completion of several important randomized trials in carcinomas of the prostate and esophagus, as well as lung cancer, many of which were practice-changing at the time. Dr. Cox stepped down as physicianin-chief in In 1995, he became chairman of the department of radiation oncology and head of the division of radiation oncology at MDACC, which included experimental radiation oncology and radiation physics. During his time as chair, the department grew to include six accelerators and two simulators, and its staff grew from 17 to 55 physicians. Dozens of doctoral- and masterlevel physicists were also added. Since the inception of the Proton Therapy Center at MDACC in May of 2006, he and his colleagues developed a number of trailblazing studies in an extremely diverse patient population, with a residency program that includes many physician scientists. [Dr. Cox s] 10-year term as RTOG Group Chairman transformed the group into a modern multidisciplinary research organization, conducting and completing practice-changing phase III trials for patients with lung, head and neck, and prostate cancers, as well as for those with brain tumors, said Walter J. Curran, Jr., MD, group chairman and principal investigator of NRG Oncology (formerly RTOG). Dr. Cox served as the editor in chief of the International Journal of Radiation Oncology Biology Physics (known as the Red Journal) for 15 years. He was also the recipient of many honors and awards, including gold medals from the del Regato Foundation and ASTRO, the Robert Fowler Fellow of the Anti- Cancer Council of Victoria, Australia, and the 6th Isadore Lampe Lecturer. The newest IASCL lectureship, started in 2017, was named for Dr. Cox. Dr. Cox is survived by his wife, radiation oncologist Ritsuko Komaki, MD, his children Christoph and Lara, and five grandchildren: Lukas, Tristan, Livia, Aengus, and Pixie. EVOLVING STANDARDS OF CARE EGFR TKIs: A Marathon or Sprint? By Edgardo S. Santos Castillero, MD, FACP The approval of osimertinib in the frontline setting for patients with EGFRsensitizing mutations has immediately challenged the decision-making process for oncologists. Osimertinib, a thirdgeneration EGFR TKI, was initially developed as a specific therapy for EGFR T790M mutations, the most common mechanism of acquired resistance for first- and second-generation EGFR TKIs (i.e., gefitinib, erlotinib, afatinib, and dacomitinib). This mutation is present in 50% to 60% of patients at the time clinical resistance first manifests. In that scenario, osimertinib is the only available rescue drug for patients with this EGFR mutation at the time of first progression. On the other hand, when osimertinib is not used upfront, we preclude patients from receiving the EGFR TKI with the best progression-free survival (PFS) time to date (PFS 18.9 vs. standard TKI [gefitinib or erlotinib] 10.2 months, HR 0.46, 95% CI [037, 057]; p < 0.001). However, T790M mutations are not a universal mechanism of resistance; hence, there is no guarantee that patients with refractory EGFR mutant tumors will be exposed to this compound. Based on the molecular evolution of these tumors, sequencing EGFR TKIs and reserving osimertinib for use at the time of documented resistance may make more sense if we want to generate the best long-term outcomes. Consequently, the dilemmas and controversies that arise from this topic deserve some consideration. When we treat a patient with EGFR mutations and advanced disease, we hope to induce a prolonged duration of response to a TKI, so therapy in this scenario is more like a marathon than a sprint. Certainly, multiple factors help determine first-line treatment decisions including available therapeutic options that vary tremendously from one part of the world to another, toxicity profile, existing comorbid conditions, presence of brain metastases, and cost. Relevant Trials Pooled overall survival (OS) data from AURA and AURA 2 studies showed a median OS of 26.8 months for patients who had been treated with osimertinib. Patients enrolled in those studies had been previously treated with a TKI and developed T790M at progression. The AURA 3 trial results, which showed superior PFS for osimertinib versus chemotherapy in the second-line setting after progression on an EGFR TKI due to emergence of a T790M mutation, Dr. Edgardo S. Santos Castillero resulted in the approval of osimertinib. Unfortunately, OS data are not yet available from the AURA 3 trial, which is critical as all those patients in second line received osimertinib (sequencing from first- to thirdgeneration TKI). Meanwhile, FLAURA demonstrated an unprecedented PFS time for osimertinib versus first-generation TKIs, including erlotinib and gefitinib. Here too, however, OS data are not yet mature, although early assessments look promising (p = ). By the same token, ARCHER 1050, a phase III trial that compared dacomitinib (a second-generation EGFR TKI) to gefitinib in the first-line setting demonstrated superior PFS for dacomitinib, an agent that does not specifically target T790M mutations. This PFS was superior to those observed in other studies in the frontline setting, including IPASS (gefitinib vs. carboplatin/paclitaxel), EURTAC (erlotinib vs. physician s choice chemotherapy), and LUX-Lung 3 and 6 (afatinib vs. cisplatin/pemetrexed or cisplatin/gemcitabine, respectively). ARCHER 1050 and LUX Lung 7 (a phase IIb randomized trial of afatinib vs. gefitinib) both prove that second-generation TKIs have more efficacy than gefitinib (category 1 by the National Comprehensive Cancer Network s classification). Survival data from preplanned analyses of both LUX- Lung 3 and 6 clinical trials have been enumerated. For patients with EGFR exon 19 deletions OS was 33.3 months receiving afatinib in LUX-Lung 3 trial, compared to 21.1 months for chemotherapy (HR 0.54, 95% CI [ ], p = ); in LUX-Lung 6, OS was 31.4 months for patients whose tumors harbored EGFR exon 19 deletions receiving afatinib compared to 18.4 months for chemotherapy (HR 0 64, 95% CI [ ], p = 0.023). Conversely, there were no differences in OS by treatment group for patients with EGFR exon 21 (L858R) continued on page 10

8 8 IASLC LUNG CANCER NEWS / OCTOBER 2018 Oligometastatic Lung Cancer from page 1 this systemic treatment; a maximum of three remaining metastases were allowed with lymph nodes counting as one site. After random assignment of 49 of the planned 94 patients, the independent safety monitoring board recommended closing the study because of substantial efficacy improvement. The median PFS was 11.9 and 3.9 months in the LAT and the control group, respectively (HR 0.35, 95% CI [0.18, 0.66], p = ). 7 Since then, oligometastatic NSCLC has become a prominent topic at cancer conferences. One wonders whether additional evidence is needed, or whether this randomized phase II trial with PFS as the primary endpoint will change daily clinical practice. In the meantime, another randomized phase II study was recently published, assigning patients with EGFR/ALK negative NSCLC and up to six extracranial cancer sites (including primary) with no evidence of disease progression after four to six cycles of chemotherapy to either maintenance chemotherapy alone or to chemotherapy with LAT (radiotherapy) to all tumor sites. 8 The primary outcome was PFS. An unplanned interim analysis prompted by publication of the Gomez trial led investigators to stop this study. Twenty nine of the 36 planned patients, including 11 previously treated for brain metastases, were randomly assigned to a study arm, The median PFS was 9.7 months in the radiotherapy arm and 3.5 months in the control group (HR 0.30, 95% CI [0.11, 0.82]; p = 0.01). The phase III part of this study is ongoing (NCT ), and OS is the primary outcome measure. In addition to both randomized trials, data from a single-arm phase II study of pembrolizumab in oligometastatic NSCLC were presented at the 2017 IASLC World Conference on Lung Cancer by Joshua Bauml and colleagues at the University of Pennsylvania. 9 The treatment sequence was reversed compared to the previously described trials: 45 patients with up to four metastases and no progression after LAT to all known sites were treated with up to a year of pembrolizumab. The 1-year PFS was 68%. Although the PFS difference is impressive in both randomized phase II studies, some concerns must be registered before implementing this strategy in daily practice. Most importantly, the total number of patients enrolled in the two trials combined is very limited (78, including eight patients with EGFR mutation/alk rearrangement), and the majority had only one metastatic site. Knowing that assessment of local progression might be challenging in patients treated with radiotherapy, especially stereotactic ablative radiotherapy, OS data are needed to draw firm conclusions. Because patients were randomly assigned after first-line treatment, baseline characteristics were not known, and selection bias might have occurred. The question as to whether an induced oligometastatic state (after induction treatment) is the same as de novo presentation with oligometastatic disease at NSCLC diagnosis must be addressed. The hypothesis is that patients with true oligometastatic disease at presentation have less metastatic capacity; this might be different from those with more overt metastasis at diagnosis but with a few remaining after induction treatment. 10 Ongoing Trials: Standardizing Definitions and Staging A search on ClinicalTrials.gov showed that ongoing clinical trials all use different definitions of oligometastatic NSCLC and that they all require different staging procedures. In one of the ongoing studies, the SARON trial (NCT ), patients with oligometastatic NSCLC (defined as up to three metastases with mandatory FDG- PET and brain imaging) are registered before treatment initiation and are randomly assigned in the absence of disease progression after two chemotherapy cycles to two additional cycles of chemotherapy with or without radical radiotherapy to all INDUSTRY AND REGULATORY NEWS RET Inhibitor Wins Breakthrough Therapy Designation The U.S. Food and Drug Administration (FDA) has granted LOXO-292, an investigational new agent, Breakthrough Therapy Designation for treatment of patients with RET-positive NSCLC who require systemic therapy and have experienced disease progression following treatment with a platinum-based chemotherapy and an anti PD-1 PD-L1 therapy. The designation was based on the phase I/II LIBRETTO-001 trial (NCT ), an open-label, multi-center trial, which will be conducted in two parts: phase I (dose escalation) and phase II (dose expansion). The trial is currently enrolling patients. Patients are eligible if they have RET-fusion positive NSCLC that has progressed on or if they have proven intolerant to available standard therapies. Visit the Virtual Library at Free for attendees, $99 for members become a member today! Abstracts open to the public. tumor sites. The number of metastases and mediastinal lymph nodes are stratification factors. The primary outcome measure is OS. This trial, if it completes enrollment, may give the final answer as to whether local ablative treatment will improve OS in patients with oligometastatic NSCLC. In addition, OLIGO-CARE, a joint project of the European Organisation for Research and Treatment of Cancer (EORTC) and the European Society for Radiotherapy and Oncology (ESTRO), has been initiated. OLIGO-CARE is a pragmatic observational basket study to evaluate radical radiotherapy for patients with oligometastatic cancer. In conclusion, oligometastatic NSCLC will continue to be an important topic of discussion at upcoming international cancer conferences. Most trials focus on radical radiotherapy as the LAT modality, but optimally, trials should also include surgery as an option. However, despite initial promising results, important issues need to be addressed. To speak the same language, a uniform definition of oligometastatic NSCLC is needed. This definition might change as new insights emerge. The EORTC lung cancer group has started an initiative to develop a consensus definition of oligometastatic disease for synchronous NSCLC. In addition, to be treated appropriately, these patients must be accurately staged (i.e., FDG-PET and brain MRI/CT), as has been proposed by the EORTC imaging group. 11 But most importantly, future trials must address predictive factors because a selection tool is needed to identify those patients who are more likely to have long-term benefit from LAT. About the Authors: Prof. Dingemans is a pulmonologist in the Department of Pulmonology and GROW, School for Oncology and Development Biology, Maastricht University Medical Center, The Netherlands. Dr. Hendriks is a pulmonologist in the Department of Pulmonology and GROW, School for Oncology and Development Biology, Maastricht University Medical Center, The Netherlands. References: 1. Hellman S and Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1): Ashworth A, et al. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung Cancer. 2013;82(2): De Ruysscher D, et al. Radical treatment of nonsmall-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct ). J Thorac Oncol. 2012;7(10): Novello S, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v1-v Eberhardt WE, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2015;10(11): Hendriks LE, Dingemans AM, and De Ruysscher D. Proposals for the M-descriptors of the Eight TNM Classification for Non-Small Cell Lung Cancer: Are More Data Needed? J Thorac Oncol. 2016;11(3):e Gomez DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016; 17(12): Iyengar P, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e Bauml J, et al. OA Phase II Study of Pembrolizumab for Oligometastatic Non- Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT). J Thorac Oncol. 12(11):S1794-S Weichselbaum RR and Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8(6): desouza NM, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer. 2018;91:

9 LUNGCANCERNEWS.ORG / OCTOBER WCLC 2018 from page 6 Atezolizumab Plus Carboplatin and Etoposide in Extensive- Stage SCLC The first-line standard of care for treatment of extensive-stage SCLC has long been a platinum-etoposide combination. However, IMpower133 appears poised to establish a new standard in the first-line setting the first trial to do so in more than 30 years that pairs a platinum doublet with immunotherapy. Stephen V. Liu, MD, of Georgetown University, presented findings from this randomized, double-blind, placebo-controlled phase I/III trial that was conducted in 403 patients with untreated extensivestage SCLC, regardless of PD-L1 status. Participants received four 21-day cycles of carboplatin/etoposide combined with either atezolizumab or placebo as initial therapy, followed by maintenance therapy with atezolizumab or placebo until progressive disease or loss of clinical benefit. IMpower133 met both co-primary endpoints at median follow-up of 13.9 months. Median OS reached 12.3 months in the atezolizumab arm versus 10.3 months in the placebo arm (HR 0.70, 95% CI ; p = ), and median PFS reached 5.2 and 4.3 months, respectively (HR 0.77, 95% CI ; p = 0.017). These benefits persisted across nearly all key patient subgroups evaluated, including all tumor mutation burden subsets (ie, < 10, 10, < 16, and 16 mutations/ Mb; Fig. 3). The addition of atezolizumab to chemotherapy resulted in a slight increase in toxicity. Whereas grade 3/4 adverse events (67.2% vs 63.8%%) and serious Fig. 2. Primary Endpoint of ALTA-1L: BIRC-Assessed PFS Fig. 3. Overall Survival in Key Subgroups of IMpower133 adverse events (37.4% vs 34.7%) were roughly similar between the atezolizumab and placebo arms, the greatest difference between the respective groups pertained to immune-related adverse events (39.9% vs 24.5%) toxicities such as rash, hepatitis, and colitis, which occurred more frequently with atezolizumab, as expected. In addition, a greater proportion of patients assigned to the atezolizumab arm discontinued any study therapy compared with those in the placebo arm (11.1% vs 3.1%); withdrawal from atezolizumab was more prevalent than withdrawal from placebo (10.6% and 2.6%, respectively). Nintedanib Plus Pemetrexed and Cisplatin in Unresectable MPM Malignant pleural mesothelioma (MPM) is an uncommon cancer, but it is one increasing in frequency worldwide. Pemetrexed/cisplatin, the only approved regimen for the condition, provides a median OS duration of approximately 1 year. The randomized, double-blind, phase III LUME-Meso trial sought to INDUSTRY AND REGULATORY NEWS Reprinted with permission from The New England Journal of Medicine improve upon this benchmark by adding the multikinase inhibitor nintedanib to pemetrexed/cisplatin. Although initial signals from the phase II portion of the trial showed that the nintedanib-chemotherapy combination improved PFS over that of chemotherapy alone (9.4 vs 5.7 months; p = 0.017), with a trend toward improved OS, the phase III portion of the trial fell short in meeting the primary PFS endpoint. As Giorgio V. Scagliotti, MD, PhD, of University of Turin and San Luigi Hospital, Torino, Italy, explained during his presentation of the LUME-Meso data, the trial has since been discontinued. Median PFS among the 458 patients with previously untreated, unresected epithelioid MPM included in the study reached 6.8 months for patients who received nintedanib plus pemetrexed/ cisplatin and 7.0 months for patients who received placebo plus pemetrexed/ cisplatin (HR 1.01, 95% CI, ; p = 0.914; Fig. 4, online). An interim analysis of OS proved no more encouraging, with median values of 14.4 months and 16.1 months for nintedanib and placebo, respectively (HR, 1.12; 95% CI, ; p = 0.538). The safety profile of nintedanib was manageable and consistent with results observed in prior studies. Nintedanib did not compromise chemotherapy delivery or adversely affect patient quality of life. Although disappointing that the addition of nintedanib to chemotherapy did not improve survival, the field can be reassured that pemetrexed/cisplatin continues to be the standard of care for unresectable MPM. New Standard of Care in Japan for First-Line Management of EGFR Mutation Positive NSCLC The Japanese Ministry of Health, Labour, and Welfare approved osimertinib for first-line treatment of patients with inoperable or recurrent EGFR mutation positive NSCLC. Approval was based on superior progression-free Slide reproduced with permission of Dr. Camidge survival for osimertinib (18.9 months) compared with gefitinib or erlotinib (10.2 months), which was consistent across all subgroups, as found in the FLAURA trial. Osimertinib was also generally well tolerated, with grade 3 or higher adverse events occurring in 34% of patients (vs. 45% for gefitinib or erlotinib). Japan is the 40th country to approve osimertinib for this indication. LUNG CANCER NEWS EDITOR Corey J. Langer, MD, FACP ASSOCIATE EDITORS Fabrice Barlesi, MD, PhD, and Caicun Zhou, MD, PhD IASLC CEO Fred R. Hirsch, MD, PhD MANAGING EDITOR AND PUBLISHER Joy Curzio, Curzio Communications COPY EDITOR Alana Williams PRODUCTION DIRECTOR Doug Byrnes GRAPHIC DESIGNER Kelli Schmidt, KSchmidt Designs LLC IASLC Lung Cancer News is published bimonthly by the International Association for the Study of Lung Cancer (IASLC). IASLC Headquarters is located at East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Purpose and Audience: IASLC Lung Cancer News features news about lung cancer research, patient care, tobacco control, and expert commentary from lung cancer leaders. The target audience for this publication is physicians and other specialists involved in the research and treatment of patients with lung cancer and other thoracic oncologic disorders. Correspondence: Address correspondence to Corey J. Langer, MD, FACP, Editor, c/o curziocommunications@gmail.com. Change of Address: Postmaster send address changes to IASLC Lung Cancer News, c/o IASLC Headquarters, East Colfax Avenue, Unit 10, Aurora, CO, 80011, US. Subscription: To initiate or cancel a subscription to IASLC Lung Cancer News or to update your mailing address, please membership@iaslc.org or call Advertising: For information on advertising rates or reprints, contact Kevin Dunn, Cunningham Associates, , kdunn@cunnasso.com. All advertising is subject to acceptance by IASLC. IASLC is not responsible for the content of advertising and does not endorse any advertiser or its products or services. Disclaimer: The ideas and opinions expressed in IASLC Lung Cancer News do not necessarily reflect those of the International Association for the Study of Lung Cancer. The mention of any product, service, or therapy in this publication should not be construed as an endorsement, and the Association accepts no responsibility for any injury or damage to person or persons arising out of or related to any use of material contained in this publication or to any errors or omissions. IASLC MISSION To embrace the study of the etiology, epidemiology, prevention, diagnosis, treatment, and all other aspects of lung cancer and other thoracic malignancies; to provide education and information about lung cancer and other thoracic malignancies to IASLC members, to the medical community at large, and to the public; to use all available means to eliminate lung cancer and other thoracic malignancies as a health threat for the individual patient and throughout the world.

10 10 IASLC LUNG CANCER NEWS / OCTOBER 2018 EGFR TKIs from page 7 Table. Comparison Among the Five FDA-approved EGFR TKI Agents mutations in either trial. Importantly, patients treated on LUX-Lung 3 did not receive second-line osimertinib at the time of disease progression, since it was not available at that time. Under these circumstances, one wonders if the use of a second-generation EGFR TKI, such as afatinib or dacomitinib followed by osimertinib or other agents, at the time of disease progression might be a preferable route. That is why the data presented at the recent annual meeting of the American Society of Clinical Oncology (ASCO) in June 2018 are relevant to this discussion. Recent Data Presented at ASCO ARCHER-1050 showed that dacomitinib improved OS over gefitinib (34.1 vs months, p = ; HR 0.76, 95% CI [ ]). The nature of subsequent therapies given to these patients after dacomitinib progression (PFS1) is critical to this discussion. Of the 227 patients treated with dacomitinib, 27.8% subsequently received chemotherapy, 9.7% osimertinib, and 8.8% other TKI agents. Those patients exposed to osimertinib had an even better OS of 36.7 months. In September at the IASCL 19th World Conference on Lung Cancer, there were new data investigating the efficacy of dacomitinib at reduced doses because of its associated G3 toxicity (mainly dermatitis acneiform [13.7%], diarrhea [8.8%], paronychia [7.5%], and stomatitis [3.5%]). Dacomitinib was reduced from 45 mg daily to 30 mg (38.3% of the patients) or to 15 mg (27.8% of the patients) daily. PFS for those who received a reduced dose was 16.6 months vs 14.7 months for the ITT population. Interestingly, the group with the lowest dose (15 mg/day) had better PFS (31.2 months) than the groups receiving 30 mg/day (12.9 months) or 45 mg/day (9.1 months). Median OS has not yet been reached for the lowest-dose group, again demonstrating benefit over the other two doses (32.6 months for 30 mg/day and 22 months for 45 mg/day). As of the fall of 2018, it is not clear what the optimal EGFR treatment algorithm should be, with a median OS range between 33 to 37 months as the threshold. To make matters more complicated, another landmark randomized phase II study (JO25567) presented by a Japanese group combined erlotinib with bevacizumab (75 patients) vs. erlotinib alone (77 patients) for treatment-naive patients with actionable EGFR mutations. In this randomized phase II study, survival follow-up results were presented. Erlotinib/bevacizumab showed superior PFS over erlotinib monotherapy (16.4 Trial Comparator TKI Patients mpfs (months) PFS HR LUX-3 Cis/Pem Afatinib 345 **/***13.6 vs 6.9; p < LUX-6 Cis/Gem Afatinib vs 5.6; p < 0001 LUX-7 Gef Afatinib 319 *11 vs 10.9; p = FLAURA Gef/Erl Osimertinib 556 *18.9 vs 10.2; p < ARCHER 1050 Gef Dacomitinib 452 **14.7 vs 9.2; p < IPASS Carbo/Taxol Gefitinib 1217 & 9.5 vs 6.3; p < EURTAC Cis-Carbo/Doce-Gem Erlotinib vs 5.2; p < vs. 9.4 months, p = 0.005; HR 0.52, 95% CI [ ]). Although this trial was not powered to assess the OS benefit of erlotinib/bevacizumab combination, the median OS was 47.0 for erlotinib/bevacizumab and 47.4 months for single agent -erlotinib. Moreover, OS for patients with EGFR exon 19 deletions was 53.2 and 50.9 months, respectively, for those receiving erlotinib/bevacizumab and erlotinib. In patients with EGFR exon 21 (L858R) mutations, OS was 43.6 vs months, respectively, for the combination arm and for erlotinib alone. The authors also reported post-discontinuation therapy up to third line, specifying the agents used. In the combination and erlotinib arms, 52% and 55% of the patients, respectively, were able to receive fourth or later lines of treatment; in this clinical scenario, 11 patients in each group received osimertinib. Moreover, we see encouraging OS data in both the intentto-treat group as well as by mutation type. In addition, a phase III study comparing erlotinib plus bevacizumab to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations (NEJ 026) was also presented at this year s ASCO meeting. The primary endpoint of PFS was met; 16.9 vs months (HR 0.605, 95% CI, [ ]; p = ). OS, a secondary endpoint, was not mature. These two trials (JO25567 and NEJ 026) close the gap further between first- and third-generation TKIs in terms of PFS, which has been the endpoint for comparison among EGFR TKI agents until now. Specifically, the PFS results for combination erlotinib/bevacizumab in these two studies approaches that observed with osimertinib alone upfront but potentially preserves the option of administering osimertinib if T790M mutation emerges as a mechanism of resistance. Deciphering the Data This underscores the controversy. Should we treat all patients with EGFR exon 21 mos 0.47 **/***33.3 vs 21.1; p < **/***31.4 vs 18.4; p < vs 24.5; p = mutations or exon 19 deletions with osimertinib upfront, based on the PFS data of FLAURA as well as other factors such as improved central nervous system penetration (overall response rate 77% by blinded independent central review) and the lowest toxicity profile to date among all approved TKIs? Or should we treat patients with actionable EGFR mutations with second-generation TKIs and reserve osimertinib for the second line at progression (PFS1) if T790M emerges? From my perspective, patients with an EGFR exon 21 mutation or exon 19 deletion with brain metastases at presentation should be considered for first-line osimertinib. For those patients with an exon 19 deletion (which is more sensitive to EGFR TKIs than exon 21 defects) and no known brain lesions, the decision for physicians is more difficult and likely requires an individualized discussion with each patient. Moreover, how to handle disease progression on osimertinib is not very clear at this moment. Based on the FLAURA study, certain novel genomic abnormalities appear, but no standard effective treatments are available, especially for the C797S mutation and other variants in the same EGFR codon. As a result, most patients will need to proceed to chemotherapy alone or to the chemoimmunotherapy combination. With this in mind, observations from the IMpower 150 trial, presented at the 2018 American Association for Cancer Research Annual Meeting, are relevant. This study, which compared the E4599 platform (carboplatin/paclitaxel/bevacizumab; triplet regimen) to the same platform plus atezolizumab (quadruplet regimen), included patients who had TKI-refractory EGFR-mutant (+) tumors. The results showed significant improvement in both PFS and OS for the entire population, and the presence of EGFR mutation did not seem to alter OS HR PFS HR (95%) BM+ > G3 toxicity (%) 0.54 NR 49% 0.64 NR 36% ( ) 31 vs NR NR 0.47 ( ) 18 vs vs 26.8; p = NA 42 vs ^18.6 vs NR NR NR NR 46 * = investigator assessment; ** = blinded independent review committee (BIRC); *** = EGFR exon 19; & = EGFR-positive patients only; ^ = ITT population. Abbreviations: mpfs, median progression-free survival; HR, hazard ratio; mos, median overall survival; BM+, patients with brain metastases; G3, grade 3; cis, cisplatin; pem, pemetrexed; NR, not reported; Gem, gemcitabine; Gef, Gefitinib; Erl, erlotinib; NA, not applicable; Carbo, carboplatin; doce, docetaxel. the results. In fact, that group fared better than the overall intent-to-treat population; the hazard ratio for PFS benefit in those with actionable EGFR mutations was 0.41 compared to 0.61 for the entire population. The OS for the intent-to-treat wild type group was 19.2 vs 14.7 months in favor of the quadruplet vs the triplet regimen (HR 0.78, 95% CI ; p = ). The HR for OS in the EGFR/ ALK (+) patients only was Consequently, from my perspective, it is perfectly permissible if a clinician decides to use a sequential approach, particularly because we still lack longterm OS data from the FLAURA and AURA 3 trials, both of which involved the use of osimertinib. Data from these two trials are eagerly awaited and will help to clarify the final picture. The OS data from ARCHER 1050 established a higher bar, especially now with updated data for clinical efficacy (PFS and OS) at lower doses if dose reduction is necessary to manage grade 2 or higher toxicity. A more cautious approach, rather than a wholesale switch to osimertinib, would be to wait for these studies to mature. If an EGFR sequencing approach is chosen by the oncologist, the patient must be closely monitored for progression of disease, and at the first manifestation of disease progression, all possible detection methods for T790M should be undertaken, including tissue re-biopsy and/or liquid biopsy. When using TKI sequencing, patients must understand that there is only a 50% to 60% chance that T790M will be documented at the time of disease progression, in which case the default option is systemic chemotherapy with or without immunotherapy. At the same token, if osimertinib is chosen at frontline, at the time of recurrence, the default option will be systemic chemotherapy or chemoimmunotherapy. The extent to which osimertinib can increase the OS benchmark after afatinib continued on page 18

11 LUNGCANCERNEWS.ORG / OCTOBER EVOLVING STANDARDS OF CARE The Vital and Evolving Role of Bronchoscopic Technologies in Lung Cancer Management By Andrew R. Haas, MD, PhD Lung cancer remains the leading global cause of cancer-related mortality. 1 Due to the lack of symptoms at the time earlystage disease first manifests, the majority of patients still present with advancedstage disease. Optimal treatment and patient outcome is incumbent on thorough radiographic and invasive staging. In addition, the rapid acceleration in development and use of Dr. Andrew R. Haas targeted and immunotherapeutic agents as treatment options has obligated proceduralists to not only obtain a diagnosis and to ascertain nodal staging, but also to ensure adequate tissue acquisition to perform molecular and immunoprofiling analyses. The development of advanced bronchoscopic diagnostic technology in the past decade has enhanced the capacity for pulmonologists to biopsy primary lesions, provide minimally invasive nodal staging, and obtain adequate tissue for tumor profiling from small-volume tissue samples. Since the flexible bronchoscope was developed in 1966, there has been no greater technologic advance in diagnostic bronchoscopy than the introduction of curvilinear and radial endobronchial ultrasound (EBUS). More than a decade Fig. 1. of clinical trials has demonstrated that lymph node staging by EBUS is not only effective and safe, but it can supplant mediastinoscopy for nodal staging when performed correctly and thoroughly. With this mounting evidence in support of EBUS as an effective nodal staging modality, the third edition of the American College of Chest Physicians lung cancer guidelines added EBUS as the preferred method of initial lymph node staging in patients with suspected lung cancer and nodal involvement. 2 EBUS nodal staging should follow a standard systematic approach via EBUS visualization from N3 to N1 nodal stations; any lymph node with a short axis greater than 5 mm should be sampled. However, with the expanding portfolio of targeted and immunotherapeutic agents available for patients with unresectable malignancy, diagnostic and staging information alone from EBUS is no longer adequate. Additional material must be acquired to perform tumor molecular and immunoprofiling, and multiple studies have shown that biopsies obtained via EBUS needle aspiration, if sufficiently cellular, can be adequate to perform standard histologic, immunohistochemical, and molecular and immunoprofiling analyses. Rapid on-site evaluation (ROSE) is used at many centers to identify malignancy, and often, further nodal sampling is ceased once a tumor is detected. This practice should be reconsidered for two reasons: the eighth edition of the IASLC continued on page 15 IASLC Foundation Donations to the IASLC Foundation support the education of research fellows who are the next generation of lung cancer physicians and scientists. Use remittance envelope attached to support lung cancer research! Screening CT scan for a 72-year-old former smoker that demonstrates an 8-mm pulmonary nodule (left) with a subtle air bronchogram on a 1.0-mm thin-cut CT scan. Bronchoscopy was undertaken with radial EBUS (right) to identify the lesion (Note that scale for the EBUS). Transbronchial biopsy demonstrated adenocarcinoma, and the patient received a left-lower lobectomy, with confirmation of a stage IA lung adenocarcinoma.

12 12 IASLC LUNG CANCER NEWS / OCTOBER 2018 RADIATION ONCOLOGY Living in the Gray Zone : Entering a New Age in Radiation Therapy for Patients with Lung Cancer Patients with stage III or more advanced lung cancer tend to be older and less healthy than patients with other stage III cancers. Because of this, selection of optimal therapies for individual patients, including stereotactic body radiation therapy (SBRT), is more nuanced. With the advent of improvements in technology, more multidisciplinary approaches to decision making, and changing recommendations on fractionation, numerous factors influence radiation therapy selection and delivery often in the absence of an abundance of data. In addition, the rapid addition of immunotherapy in locally advanced NSCLC has resulted in even more questions and potential for rapid change in best practices. In the following interview, Kristin Higgins, MD, associate professor and medical Dr. Kristin Higgins director of radiation oncology of The Emory Clinic at Winship Cancer Institute s Clifton campus, explains her approaches to therapeutic decision making and provides an overview of the state of the art in radiation oncology technology. Multidisciplinary Care for Patients with Early-Stage Disease The current standard of care for earlystage NSCLC is surgical resection. However, many patients aren t optimal surgical candidates, whether it s because of damage to their lungs from years of smoking, risks associated with anesthesia, or potential perceived postoperative toxicities. These patients live in a gray zone of sorts. They are clearly not surgical candidates, and for them, the standard of care is sterotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR). There are often disagreements across subspecialties about nodule management for these patients because no trials that directly compare surgery with SBRT have met their accrual goals, many closing early or prematurely. The ongoing Veterans Affairs Lung Cancer or Stereotactic Radiotherapy (VALOR) trial within the Veterans Affairs system is comparing SBRT with surgery for a high-risk population, but this is not open to patients who do not have a military service history. In the meantime, we base our decisions for this high-risk population on the data we have available to us and on the best interest of the patient. More often, we re trying to involve the patient in a multidisciplinary discussion that involves the surgeon, the radiation oncologist, and the medical oncologist so that the patient can hear the pros and cons for each potential treatment scenario and can participate in decision making. I think this shared approach is a good way to determine appropriate therapy for each individual patient when there is no black or white answer. Treating Stage III Disease The average age of a patient at lung cancer diagnosis is 70, 1 which means that decisions regarding concurrent therapy should not be based solely on age. It s important that decision making about combined modality treatment is a thoughtful process that involves geriatricians in the evaluation of candidacy, especially because the management of the side effects from combined-modality therapy has so drastically improved over time. If you look at RTOG 0617 for example, the rates of high-grade pneumonitis and esophagitis were only approximately 7% in the standard-dose arm, 2 which was a decrease from the approximately 15% to 20% or higher rates observed in the first generation of combined modality trials for stage III lung cancer. 3 There is great interest in immunotherapy and combination immunotherapy/ radiation clinical trials for lung cancer, especially in the locally advanced setting. The standard of care has really shifted and now includes consolidated Fig. 1. Clinical Case: Stage IIIB NSCLC immunotherapy for stage III disease based on the positive PFS results of the phase III PACIFIC trial which, as presented at the 19th World Conference on Lung Cancer in September, also demonstrated a highly significant OS advantage. However, despite the emergence of immunotherapy in stage III NSCLC, a lot of questions remain. How do you approach immunotherapy in an elderly patient, for example, who may not be a candidate for combined- modality treatment? We ve seen exciting results with immunotherapy given in the consolidative setting, but can it be moved into the concurrent setting? What is the optimal radiation dose/fractionation regimen to use with immunotherapy? There are developing clinical trials designed to answer these and other emerging questions around immunotherapy and locally advanced NSCLC. Proton Therapy s Unproven Benefits Proton therapy is being more widely used in the management of many cancers throughout the United States, with more and more proton centers coming online. The randomized phase III NRG 1308 trial (NCT ) is evaluating proton versus photon therapy for unresectable stage II and III NSCLC. The study design has recently been revised to include co-primary endpoints of overall survival, development of grade 2 or greater cardiac toxicity, and grade 4 or greater lymphopenias. RTOG 0617 demonstrated that a higher dose of radiation led to decreased survival. Importantly, this study also showed that when the radiation dose to the heart increased, there was a greater risk of mortality. 2 The top panel of Figure 1 shows radiation dose distribution overlaying CT imaging of a patient with stage III NSCLC treated with 60 Gy VMAT technique, compared to the lower panel showing the same 60 Gy with proton technique. There is higher dose to the contralateral lung and heart, with a comparison DVH shown on the far right. With lung cancer, radiation dose to the heart is an obvious concern given the close proximity of lung tumors to cardiac structures. Using protons in stage III lung cancer makes a lot of sense from that standpoint because you can deliver an adequate dose to the tumor but decrease the bystander radiation dose to the heart, which cannot be done as well with standard photon techniques including intensity modulated radiation therapy (IMRT). Until we see the results of this trial, however, I think that proton therapy should still be used wisely in patients in a clinical trial, which is really the best way to explore this technology. Clinical Trials Versus the Real Word: Technology Must Be Biology Driven In radiation oncology, we are technologically driven. We try to use our technologies to make our therapy more precise and accurate, but it is important to remember that these costly improvements must be clinically meaningful. Applications of technologies must lead to improvements in meaningful outcomes for our patients, such as reduced side effects, improved quality of life, and, of course, improved survival. To tackle some of these challenges, next-generation linear accelerators are being developed. They are more costly than standard linear accelerators, but they offer features such as built-in MRI, which allows tumor imaging in real time as the radiation beam is being directed at the tumor. One such accelerator, marketed by ViewRay, has been approved by the U.S. Food and Drug Administration (FDA). There s also a next-generation machine, which is not yet FDA approved, that combines a linear accelerator with PET and can yield biologically guided radiation therapy, in which the photon beam is sent from the linear accelerator directly to the PET signal within the tumor. The use of these next-generation machines could be advantageous in that you can potentially dose escalate tumors that are near critical organs because you can see the organs in real time and adapt the radiation to the exact anatomy of the patient at the time of treatment. This is especially helpful in pancreatic cancers, for example, and these machines are being used in prospective clinical trials. For lung cancer, this newer technology would potentially allow us to better continued on page 13

13 LUNGCANCERNEWS.ORG / OCTOBER RADIATION ONCOLOGY 2018 ASTRO Guideline for Palliative Thoracic Radiation Therapy for NSCLC: The Balance Between Curative and Palliative Radiotherapy Shalini K. Vinod, MBBS, MD The standard of care for patients with inoperable stage III NSCLC is curative radiotherapy and concurrent chemotherapy. 1 However, there are numerous factors that may preclude this approach, including poor respiratory function and large tumor volume both of which are surrogates for unacceptable radiation Table. Comparison of Studies Evaluating Concurrent Chemotherapy and Palliative Radiotherapy versus Single-Modality Treatment in Stage III NSCLC Nawrocki et al. 5 Strom et al. 6 Trial design Phase II RCT Phase III RCT Primary endpoint Response rate Overall survival Patients (randomized)/patients (eligible for primary endpoint analysis) 99/ /188 Eligibility criteria Stage III NSCLC and ECOG 0-2 and 1 adverse factor: FEV1 40% Tumor diameter 8 cm Randomized arms 30Gy/10 fractions 3 cycles of cisplatin/ vinorelbine with concurrent RT 30 Gy in 10 fractions with cycle 3 Stage III NSCLC and 1 adverse factor: Tumor diameter 8 cm ECOG 2 Weight loss > 10% 4 cycles of carboplatin/ vinorelbine 4 cycles of carboplatin/ vinorelbine with concurrent RT 42 Gy in 15 fractions with cycle 2 Number of patients Response rate 27% 53% Median OS 9 months* 12.9 months* 9.7 months* 12.6 months* 2-year OS 6%* 24%* 7.4%* 27.7%* Symptoms/QOL 67% pain free 76% cough free 60% dyspnoea free # 85% pain free 82% cough free 70% dyspnoea free # Steady and significant decline in HRQOL Transient decline followed by stability in HRQOL Toxicity No neutropaenia* 11 (22%) neutropaenia* 23 (27%) toxicity related admissions* 5 (8%) Gd2+ oesophagitis* Grade-5 toxicity None* 6 (12%) early treatment deaths* 6 (6%) 4 (4%) Post-study treatment 27% chemotherapy 29% chemotherapy 58% RT* 44% chemotherapy* *statistically significant # statistical comparisons not performed 45 (54%) toxicity related admissions* 62 (69%) Gd2+ oesophagitis* 31% RT* 25% chemotherapy* Abbreviations: RCT, randomized controlled trial; FEV1, forced expiratory volume in one second; ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy; OS, overall survival; HRQOL, health-related quality of life. doses to normal lung tissue resulting in high risk of pulmonary toxicity. Other more subjective factors include Eastern Cooperative Oncology Group performance status (ECOG PS), comorbidities, and age. In practice, 57% to 61% of patients with stage III NSCLC are treated with palliative radiotherapy. 2,3 Patients not suitable for curative treatment usually receive single-modality palliative treatment given sequentially, with the order of treatment based on patient symptoms and disease burden. Until now, international guidelines have not specifically addressed palliative treatment of stage III NSCLC due to a paucity of evidence. The American Society for Radiation Oncology (ASTRO) has updated its palliative radiotherapy guideline to recommend palliative hypofractionated radiotherapy and concurrent chemotherapy for patients with stage III NSCLC who are deemed unsuitable for curative therapy. 4 Patients must be fit for chemotherapy, have an ECOG PS of 0 to 2, and a life expectancy of at least 3 months. This guideline change is largely based on the publication of two randomized controlled trials. 5,6 Both trials tested the efficacy of palliative hypofractionated radiotherapy and concurrent chemotherapy; however, the standard arms differed, with palliative radiotherapy featured in one 5 and palliative chemotherapy in the other (Table). 6 Supporting Data Nawrocki et al. conducted a phase II trial of patients with stage III NSCLC unsuitable for curative treatment on continued on page 16 Radiation Therapy from page 12 target tumors during the respiratory cycle and to more safely dose escalate or treat multiple sites of metastatic disease simultaneously. In addition to using trial data to prove that technologic improvements result in improved patient care, it is also important that we design radiation trials so that they are reflective of a real-world population. Future trials should be framed around the typical patient with lung cancer elderly and often with a comorbid conditions, such as heart disease or diabetes because, otherwise, we won t be able to translate our findings from clinical trials with stricter inclusion criteria into real-world care. Palliative Radiation SBRT The American Society for Radiation Oncology consensus guideline for palliative thoracic radiation therapy for NSCLC recommends a longer course of Gy delivered at Gy per day fractions if the patient has a preserved performance status in order to achieve durable tumor control; however, many patients have performance statuses that fluctuate. 4 There are clinical situations where shortened courses of one to five fractions are the best option in highly symptomatic patients. Additionally, when treating metastatic disease particularly bone metastases clinical trials have shown no difference in pain reduction with single fraction versus more prolonged treatment courses. The utilization of single-fraction treatments for palliation has been more slowly adopted in the United States, compared with Europe for example, for unclear reasons. I think we should base our decisions on individual patient presentations. We are using SBRT more frequently for patients with stage IV disease to try to improve progression-free survival based on multiple studies showing improvement in this endpoint. NRG LU002 (NCT ) is examining administration of SBRT to the primary and metastatic sites of disease after firstline chemotherapy or immunotherapy, using a hypofractionated approach. I think stage IV palliative radiation therapy is becoming more nuanced than palliative radiation therapy for other disease stages because we are using ablative fractionation regimens to achieve local control of the primary and distant disease sites, if they re limited, which has been a real change in the field for stage IV lung cancer. As our patients are living longer with more effective systemic therapies, there may be more of a role for radiation to local sites of disease. The data from NRG LU002 and other trials will help us make these determinations. Immunotherapy and Early-Stage Disease There are also trials being designed to examine whether immunotherapy after SBRT or SBRT alone is better for patients with early-stage disease who are not surgical candidates. These studies may help to further improve the outcomes of patients who are medically inoperable. Also, there are single institutions at large academic centers that are evaluating the optimal timing of immunotherapy, the optimal radiation therapy fractionation regimen, and biomarkers for the optimal selection of patients who receive immunotherapy with radiation. Overall, this is an amazingly exciting time for thoracic radiation oncologists. Through innovation and collaboration, we ve made quite a bit of progress in the treatment of lung cancer with radiation therapy, but the continued on page 15

14 14 IASLC LUNG CANCER NEWS / OCTOBER 2018 ADVOCACY & SURVIVORSHIP After the Consultation: Social Media, Inter-Patient Communication, and Clinical Trials By D. R. Camidge Between March 2017 and April 2018, nearly 20,000 new members signed up for the Lung Cancer Survivors Support Community on Inspire. At present, membership of this online community is over 90,000 individuals from more than 200 different countries. Physicians have always known that patients continue discussions with friends and relatives long after a clinic consultation has finished. However, with the global acceptance of social media, these ancillary conversations are now far more extensive than ever before. With more than 5 million words posted in this lung cancer community in 2017 alone, just what are they all talking about? On one level it s about support a community helping each other through the stresses of serious diseases such as lung cancer, said John Novack, director of communications for Inspire. However, it s also about connecting patients around therapeutic opportunities, including clinical trials. Inspire was set up as a private company in 2005 with Brian Loew, an internet entrepreneur, as the CEO. Seeing itself as a healthcare social network, Inspire manages multiple different disease-specific communities, with the Lung Cancer Survivors community representing one of its largest and oldest groups. Access is free, with full-time moderator support. Sometimes [support consists of] just helping out on basic technology issues, said Mr. Novack. But it s also to help ensure that different member perspectives in the community are equally valued and to quell potential brush fires among members as early as possible. A Vocal Minority According to Mr. Novack, only approximately 20% of members of any community on Inspire create discussion topics and comment on them; the rest of the community uses the platform as a resource. Of the members who do post, some may discuss their experiences with different doctors or hospitals, which worries some patient advocates. If only patients with outlier experiences post, others could end up being dissuaded from entering a clinical trial, said Marcia Horn, JD, the director of the International Cancer Advocacy Network and of the Exon20 group, both patient advocacy groups. According to Janet Freeman-Daily, INDUSTRY AND REGULATORY NEWS Alectinib Approved for ALK-Positive NSCLC in China The China National Drug Administration (CNDA) granted marketing authorization for alectinib as monotherapy for patients with ALK-positive advanced NSCLC. This authorization follows on the heels of U.S. Food and Drug Administration and European Medicines Agency approvals. Authorization was based on the phase III ALEX and ALESIA studies, as well as on two phase II studies assessing alectinib for treatment of patients with disease progression on or intolerance to crizotinib. Updated ALEX results were presented in June 2018 at the American Society of Clinical Oncology Annual Meeting and showed that progression-free survival more than tripled for patients who received alectinib vs. crizotinib (34.8 months vs months, respectively). Specifically regarding Asian patients with ALK-positive NSCLC, ALESIA found that alectinib reduced the risk of progression or death compared with crizotinib; these data will be submitted to the CNDA to complete a post-approval agreement. Results of ALESIA will be presented at an upcoming meeting. another prominent lung cancer advocate, group members will often police their own communities and encourage an individual to get a second opinion if there is a perception of inadequate care rather than criticizing the physician or center that provided the care. In addition, because the site is monitored at all times by members, moderators, and surveillance programs, any potential marketing or sales-related conversations are removed. This vigilance dissuades any potential internet snipers from masquerading as members in an attempt to promote or denigrate a product or institution. Commercialization of Patient Perspective Communities on Inspire are also directly linked to nonprofit advocacy partners, which help to promote the community and strengthen trust in the Inspire brand. Since August 2015, the American Lung Association has fufilled this role for the Lung Cancer Survivors community. Financial support for Inspire comes from paid advertising on the webpages and through other pharmaceutical industry collaborations, such as market research activities (e.g., roundtables) or surveys. Participating companies may seek to understand medical conditions or treatments in more detail, said Mr. Novack. However, members control privacy filters for their own accounts and can easily opt out. Biotech analysts, investors, or pharmaceutical companies seeking competitive intelligence on ongoing clinical trials have been known on rare occasions to lurk alongside members, resulting in members feeling a violated sense of trust. Concern about this issue sparked an article in The Wall Street Journal on the risks of social media participation by patients resulting in an unblinding during ongoing trials. 1 The issue continues to generate significant debate regarding the ability to restrict a patient from discussing individual experiences. Appropriately communicated positive experiences, if they are not misleading and are representative of the whole population, can accelerate breakthroughs. H. Jack West, MD, a medical oncologist and president of an expert-moderated online patient education community, the Global Resource for Advancing Cancer Education, told the IASLC Lung Cancer News that After the interim data on crizotinib for ALK-positive lung cancer came out, patient-to-patient discussion though social media probably helped a lot in completing accrual to the pivotal molecularly selected phase I trial. Equally, however, there are concerns that the early public posts of a patient with an atypical negative safety or efficacy experience in a trial could affect another patient s willingness to enroll in the same study, thereby undermining the opportunity to definitively answer a vital clinical research question. This is particularly worrying when one person s experiences can t be put into context, either because of the details of his/her individual case or just because data on the rest of the group in the trial are lacking, said Ms. Horn. It has been suggested that clinical trial consent forms should start to offer guidance to trial participants on what is or is not considered acceptable regarding social media participation. Although this may not be enforceable, such guidance could inform patients about the consequences of early posting, dissuading premature discussion. Posting delays could be requested or notifications to patients about when to initiate social media discussion about specific trial treatment and outcomes or any other key trial-related information, such as overall accrual or how other patients are doing, could be provided once these data enter the public domain. Limiting posts to a defined circle of trusted social media friends, with instructions to not repost, has also been suggested. Reference: 1. Marcus AD. Researchers Fret as Social Media Lift Veil on Drug Trials. Wall Street Journal Jul 30.

15 LUNGCANCERNEWS.ORG / OCTOBER Bronchoscopic Technologies from page 11 lung cancer staging guidelines 3 breaks the nodal status into subcategories of singleversus multiple-station disease; and tissue acquisition from more than one potentially involved site may improve the probability of having adequate material for all necessary tumor analyses. Repeat sampling of different areas within an involved node should also be considered to provide better material for analyses, especially if radiography or EBUS suggests the nodes are necrotic. An interesting ROSE application may be to semiquantitatively assess the degree of sample cellularity to guide decisions regarding sample adequacy for all tissue analyses. Navigation Platforms Suspected peripheral lung cancers continue to pose challenges and limitations, but the development of radial EBUS and navigation platforms has improved the ability to approach some peripheral lesions for biopsy where access has been difficult. Navigation systems are based on two main platforms: electromagnetic (EMN) or virtual bronchoscopy. Although single-center series of diagnostic yield using navigational platforms has reported diagnostic rates as high as 80% to 90%, only one randomized control trial has been performed comparing EMN to radial EBUS to EMN and EBUS combined. This study showed nearly equivalent diagnostic yield for EMN and radial EBUS alone (59% vs. 69%, respectively), but combined EMN and EBUS had a diagnostic yield of 88%. 4 Therefore, in the absence of lesion selection bias, combined use of EMN and radial EBUS appears most effective to access and biopsy peripheral lesions. No study has been performed comparing EMN to virtual bronchoscopy. The limitation of navigational bronchoscopy and radial EBUS is the reliance on airway access for lesion localization and biopsy. If no airway is adjacent to or within a lesion, existing navigational platforms and radial EBUS cannot adequately access a lesion for biopsy. Multiple approaches are under early investigation to provide an out of airway transparenchymal approach to those nodules to improve diagnostic yield. Efficacy and safety of these approaches will be forthcoming. All patients should undergo thorough and complete EBUS nodal staging with consideration of either ROSE assessment of sample cellularity or acquisition of extra aspirations to maximize tissue available for analyses. Real-World Decisions How are bronchoscopists to use the new technologies at their disposal for the diagnosis, staging, and tumor profiling of lung cancer, particularly advanced-stage disease? All patients should undergo thorough and complete EBUS nodal staging with consideration of either ROSE assessment of sample cellularity or acquisition of extra aspirations to maximize tissue available for analyses. If the primary parenchymal lesion is easily accessible to transbronchial biopsy, consideration should be given to biopsy this lesion to maximize tissue for analysis, particularly PD-L1 immunohistochemistry, which is only validated on surgical pathology specimens. For suspected clinical stage 1A malignancy or suspicious solitary pulmonary nodules, advanced bronchoscopic techniques may not be the optimal first approach for a patient, and the respiratory physician must consider whether CT-guided needle aspiration or direct surgical resection would be a more prudent approach than using the latest bronchoscopic technologies. What Is on the Horizon? Bronchoscopic technology developments have all been inspired by the need to enhance minimally invasive diagnostic capabilities for nodal staging and peripheral nodule biopsy; however, bronchoscopists need to capitalize on the capacity of these technologies to deliver novel therapeutics directly to lymph nodes, masses, and/or nodules. Several bronchoscopic ablation devices for early-stage lung cancer are under development and in early-phase investigation. Investigations of these ablative devices must maintain clinical equipoise, as the safety and efficacy of stereotactic radiation creates a high standard to match. More importantly, with the expanding repertoire of targeted agents, viral and gene therapy vectors, adoptive cell therapies, and immunomodulating agents, respiratory physicians should work collaboratively with their thoracic oncology colleagues to design and to undertake novel trials of bronchoscopic-delivered therapies to further expand the armamentarium against lung cancer. About the Author: Dr. Haas is Associate Professor of Medicine, Director of the Interventional Pulmonary and Thoracic Oncology Program, and Bronchoscopy Director at the Hospital of the University of Pennsylvania. References: 1. Cancer. World Health Organization website. who. int/mediacentre/factsheets/fs297/en. Accessed February 12, Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e211S-50S. 3. Detterbeck FC, Boffa DJ, Kim AW, Tanoue LT. The Eighth Edition Lung Cancer Stage Classification. Chest. 2017;151(1): Eberhardt R, Anantham D, Ernst A, Feller- Kopman D, Herth F. Multimodality bronchoscopic diagnosis of peripheral lung lesions: A randomized controlled trial. Am J Respir Crit Care Med. 2007;176(1): GLOBAL INITIATIVES The IASLC Fight Against Lung Cancer in Peru and Latin America By Dr. Luis E. Raez, MD Dr. Luis E. Raez (bottom left), Dr. Fred Hirsch, and attendees of the 2018 Best of World Conference on Lung Cancer, Westin Lima Hotel, in February Peru is one of the largest Latin American countries, with a population of approximately 28 million people. Cancer is not yet a leading cause of mortality because of the young median age of the population and other factors like the high prevalence of infectious diseases; in addition, lung cancer is simply not as prevalent as it is in the United States. However, cancer remains a major public health issue in Peru: each year, 47,000 new cancer cases are diagnosed, with at least 25,000 deaths. As it stands, lung cancer is the third leading cause of cancer-related death in Peru, just below cervical and breast cancers. In addition, lung cancer is diagnosed in late stage in 85% of patients, and its incidence is not only related to tobacco smoking or radon but may additionally be linked to wood-burning stoves, which are still used for cooking in the Andean regions. There is no formal lung cancer screening program in the country, as is the case in most Latin American countries (as of April 2018, only Brazil and Uruguay have such programs), nor are there any plans or polices in place to implement such programs any time in the near future. My colleagues and I discussed this issue extensively in recently published review in Journal of Global Oncology. 1 In this paper, we also discussed particular challenges for the Latin American region, such as the high prevalence of granulomatous disease, which can complicate the interpretation of screening studies and potentially impair the efficacy of lowdose CT screening. Adequate diagnostic tools, such as genomic profiling for stage IV disease, are of limited availability and are performed only sporadically. In addition, the gene panels are very small, and most of the diagnostic companies that perform next-generation sequencing have not yet started conducting business in Latin America. For this reason, the implementation of targeted therapy is behind that of higher-income countries because genomic profiling is essential to identification of the proper targeted therapy. In addition, the new agents approved for targeted therapy by the U.S. Food and Drug Administration have experienced continued on page 19 Radiation Therapy from page 13 field awaits continued improvements. We are certainly on the right track and hope that we can continue to improve the lives of our patients with lung cancer. References: 1. American Cancer Society. Key Statistics for Lung Cancer. small-cell-lung-cancer/about/key-statistics.html. Accessed July 20, Bradley JD, Paulus R, Komaki R, et al. Standarddose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, twoby-two factorial phase 3 study. Lancet Oncol. 2015;16(2): Curran WJ, Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG J Natl Cancer Inst. 2011;103(19): Moeller B, Balagamwala EH, Chen A, et al. Palliative thoracic radiation therapy for nonsmall cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Practical Radiation Oncology. [Epub ahead of print April 2018].

16 16 IASLC LUNG CANCER NEWS / OCTOBER 2018 LUNG CANCER SCREENING A Review of CancerSEEK Blood test addresses possibility of detecting solid tumors through combination ctdna and protein biomarkers. By Pierre P. Massion, MD Early detection is key to disease management. For example, there are numerous data in hypertension, diabetes, coronary artery disease, and renal dysfunction showing strong correlation between early diagnosis and improved outcome. 1 Noninvasive means of early detection of cancer is around the corner. 2-4 Recent research has positioned the detection of genetic alterations in the circulating tumor DNA at the forefront of cancer management. Oncologists are already using liquid biopsies in the clinic to monitor disease and to guide personalized cancer care in advanced disease, but it is evident that such strategies can be extended to earlier stages. 5-7 The recent paper by Cohen et al. 8 addresses the possibility of detecting solid tumors more than 59% of the time at an early stage with a combination of ctdna and protein biomarkers. The approach proposed by the authors is simple and low in cost, potentially resulting in a stage shift, a significant time savings for diagnosis, and improved patient survival. Although hard outcomes are not yet achieved, this manuscript advances the field. Liquid Biopsies: Realizing the Potential CancerSEEK, the blood test reported on by Cohen et al., is a combination of genetic testing and protein chemistry. It uses a combination of genetic variants for cancer-related genes and eight proteins related to cancer diagnosis. Such a mixed platform is both a strength and a challenge for the generalizability of such combinations. Importantly, the authors used protein biomarkers to facilitate the localization of the cancer. The importance of localization addresses the problem of detecting tumors that have similar genetic oncogenic drivers yet originate in different organs. Also, the identification of the underlying tissue of origin may be of greater clinical relevance than initially realized when trying to localize an early, presumed sub-centimeter sized nodule. Whereas a blood biomarker is not likely to replace the use of standard imaging in the near future, it may better CancerSEEK uses a combination of genetic variants for cancer-related genes and eight proteins related to cancer diagnosis. target the imaging and help save cost. CancerSEEK has a sensitivity of 69% to 98% for ovarian, liver, stomach, pancreatic, and esophageal tumors with Dr. Pierre P. Massion an outstanding specificity of 99%, while also achieving a less than 1% false-positive rate. The genetic signature provides cancer specificity, but oncogenic drivers are not tissue specific. The protein signature provides reasonable tissue specificity for localization of the tumor. These are essential goals of a biomarker, which have been achieved for the most part. Sensitivity remains a continued on page ASTRO Guideline from page 13 the basis of FEV1 less than or equal to 40% and/or tumor diameter greater than 8 cm. 5 Random assignment was to radiotherapy alone or two cycles of chemotherapy followed by concurrent radiotherapy. Patients receiving chemoradiotherapy had a significantly better median and 2-year survival and a similar rate of symptom relief compared to radiotherapy alone. Toxicity was greater in the chemoradiotherapy arm, with six early deaths (12%) versus 0 (0%) in the radiotherapy arm. Strom et al. randomly assigned patients with stage III NSCLC unsuitable for curative treatment on the basis of one or more adverse prognostic factors (tumor size of 8 cm or greater, ECOG PS of 2 or greater, or weight loss of 10% or greater) to four cycles of chemotherapy or the same regimen with radiotherapy between cycles 2 and 3. 6 Overall survival was significantly better with chemoradiotherapy (Table). Treatment-related mortality was similar; however, there were more hospital admissions and esophagitis in the chemoradiotherapy arm. Neither study mandated PET staging, which could result in imbalances in otherwise unrecognized stage IV disease between arms. Differences in treatment on progression can also affect survival. Patients in the control arm of the study by Nawrocki et al. 5 were less likely to receive palliative chemotherapy upon disease progression. Considering that these patients were chemo naive, one would have expected the majority of them to receive chemotherapy upon progression; however, this did not occur due to poor performance status. Interestingly, the converse was true in the study by Strøm et al. 6, in which significantly more patients in the chemotherapy-alone arm received both further chemotherapy and radiotherapy. There is now evidence to support the use of concurrent chemotherapy and palliative radiotherapy in improving survival, symptoms, and quality of life in patients with stage III NSCLC who are unsuitable for curative treatment. Shalini K. Vinod, MBBS, MD Despite some differences in eligibility criteria, the improvement in median and 2-year survival seen with concurrent palliative chemoradiotherapy in both studies was remarkably similar. Remaining Questions and Challenges There is now evidence to support the use of concurrent chemotherapy and palliative radiotherapy in improving survival, symptoms, and quality of life in patients with stage III NSCLC who are unsuitable for curative treatment. However, the challenge remains in identifying patients who would be eligible for this approach without denying them the possibility of curative chemoradiotherapy. Curative radiotherapy in stage III NSCLC is underutilized, and this guideline should not be used as an excuse to treat patients palliatively. Tumor size alone should not be used as an indication for palliative treatment 7 unless a safe radiotherapy plan respecting normal tissue tolerances cannot be generated. Similarly, it may be safe to treat patients with poor pulmonary function if the tumor volume, hence radiotherapy field is small. Performance status is a clearer indication of the ability to tolerate curative treatment; however, the survival benefit seen in Strom et al. was not seen in the subgroup with an ECOG performance status of 2 or greater. Significant weight loss is associated with poor prognosis and is often a marker of systemic disease, which would not have necessarily been detected in these studies in the absence of PET staging. For patients with stage III NSCLC who are deemed unsuitable for curative treatment, concurrent chemotherapy and palliative radiotherapy is superior to either single modality alone. However, the optimal chemotherapy agents, radiotherapy doses, and scheduling are yet to be determined. Given the uncertainties in selecting patients for this treatment strategy, decisions are best made in the setting of a multidisciplinary team. About the Author: Professor Vinod is a radiation oncologist at Liverpool Hospital, Sydney, Australia, and a conjoint professor at the University of New South Wales. References: 1. Bradley JD, Paulus R, Komaki R, et al. Standarddose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, twoby-two factorial phase 3 study. Lancet Oncol. 2015;16(2): Vinod SK, Wai E, Alexander C, Tyldesley S, Murray N. Stage III non-small-cell lung cancer: population-based patterns of treatment in British Columbia, Canada. J Thorac Oncol. 2012;7(7): Vinod SK, Simonella L, Goldsbury D, Delaney GP, Armstrong B, O Connell DL. Underutilization of radiotherapy for lung cancer in New South Wales, Australia. Cancer. 2010;116(3): Moeller B, Balagamwala EH, Chen A, et al. Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. Pract Radiat Oncol. 2018; pii: S (18) Nawrocki S, Krzakowski M, Wasilewska-Tesluk E, et al. Concurrent Chemotherapy and Short Course Radiotherapy in Patients with Stage IIIA to IIIB Non-small Cell Lung Cancer Not Eligible for Radical Treatment: Results of a Randomized Phase II Study. J Thorac Oncol. 2010;5(8): Strøm HH, Bremnes RM, Sundstrøm SH, Helbekkmo N, Fløtten O, Aasebø U. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br J Cancer. 2013;109(6): Ball DL, Fisher RJ, Burmeister BH, et al. The complex relationship between lung tumor volume and survival in patients with non-small cell lung cancer treated by definitive radiotherapy: A prospective, observational prognostic factor study of the Trans-Tasman Radiation Oncology Group (TROG 99.05). Radiother Oncol. 2013;106(3):

17 LUNGCANCERNEWS.ORG / OCTOBER EVOLVING STANDARDS OF CARE CAR-T Cells for Lung Cancer: Q&A with Dr. Charu Aggarwal With complete remissions seen in up to 90% of patients with B-cell acute lymphoblastic leukemia (ALL), a breakthrough therapy designation in multiple myeloma, and a first-of-its-kind approval for children and young adults with ALL, CAR-T cells have transformed the treatment landscape for hematologic malignancies. Progress in solid tumors, however, has been considerably slower. Charu Aggarwal, MD, MPH, an assistant professor of medicine at the Hospital of the University of Pennsylvania, discusses the status of CAR-T cell research regarding thoracic solid tumors. Q: How do CAR-T cells work? A: CAR-T cells have been described as living drugs that capitalize on the body s own immune system to generate response against the tumor. The way they work is that they use the patient s own T cells, which are re-engineered, to drive an immune Dr. Charu Aggarwal response against a particular antigen, for example, on antigens specific to B cells in lymphoblastic leukemia or certain kinds of B- cell lymphomas. CAR-T cells are now being explored in solid tumors as well, including lung, breast, melanoma, and sarcoma. Q: What are the obstacles and barriers? A: Specifically for thoracic malignancies, there is no particular antigen that is distinct for tumors themselves, so finding a discrete antigen that we can actually target becomes challenging. There have been clinical trials using EGFR-based approaches, but these have not been successful because, for example, EGFR is expressed widely elsewhere in the body. As a result, an on target/off tumor effect can occur; we want to see on target/on tumor effect, so I think that s the biggest obstacle. In addition, as opposed to liquid tumors and other malignancies, patients with lung cancer generally have more comorbidities and are generally sicker, so they may not seek out this therapy unless they ve received multiple lines of treatment that have failed. This makes it challenging in terms of performance status and the residue of toxicities from the prior treatments. Q: How does one choose the antigen target? A: In our current CAR-T cell trial, we are targeting mesothelin as our antigen because it is relatively tumor specific. Mesothelin is highly expressed in mesothelioma and widely expressed in ovarian cancer. In fact, approximately 30% to 50% of patients with NSCLC express mesothelin at various levels, from 0% expression all the way to 100% expression. It s normally expressed on tumor and not typically on normal tissue, when it is expressed in lung cancer, so that is why we thought it would be a feasible target to evaluate. Certainly, there are other ongoing trials using mesothelin for mesothelioma and lung cancer. Q: Do you foresee a time where T cells can be trained on multiple antigen targets? Or might that lead to untoward toxicity? A: Certainly that s the eventual goal; however, it is still early days. Toxicity will be the limiting factor here. Q: Will the addition of other immunotherapeutics such as checkpoint inhibitors yield a synergistic effect with CAR-T cells? A: Definitely. There s ongoing research in hematologic tumors, where PD-L1 therapies are being introduced in the post-car-t cell setting. However, we are a long way from using that in solid tumors right now, but we are lucky either way because we do use PD-L1 therapies for solid tumors, particularly NSCLC, so it s easier for us to study the effects of PD-L1 therapies in patients who are going to receive CAR-T cells. However, a clinical trial that s combining checkpoint inhibitors with CAR-T cells from the beginning in solid tumors is not ongoing, to the best of my knowledge. Q: Can the healthcare system afford the cost? A: It s certainly expensive, and it s certainly something we worry about with healthcare costs rising in general. As is the case with other therapies, costs will have to be balanced with the degree of benefit and improvement in outcomes parameters. CancerSEEK from page 16 bigger problem for early-stage disease. The paucity of DNA molecules shed by small tumors and the limit of quantitation of the protein analytes are big challenges to overcome. For the protein biomarker, the signal-to-noise discrimination highly depends on the analytic strength of the method. Detection of single mutations in ctdna requires a large volume of plasma, which pushes the scientific community to discover other genetic or epigenetic alterations to increase the likelihood of success. Challenges The study design is probably the weakest point of the paper. The biomarker is not tested in the clinical context of its intended use but rather in a casecontrol study. In the journey of biomarker development, this study positions the biomarker in phase two of five phases (from discovery to cancer control). Validation of the performance metrics in independent cohorts and in clinically meaningful settings at multiple institutions, demonstrating the added value to current standards, and ultimately demonstrating a reduction in cancer-related mortality or improved cancer control 9 are the most challenging, time-consuming, and costly investigations. The authors interrogated the plasma of a relatively small number of healthy controls without matched controls for inflammatory lesions that could mimic the disease process. With 805 cancers tested and 200 controls, the false-positive rate is probably underestimated, primarily because of the protein component of the assay, where inflammatory disease is known to decrease the specificity. A given biomarker is unlikely to fit multiple clinical scenarios but should be tested in the context where it is predicted to be most helpful. For example, candidate biomarkers could be tested in patients presenting for evaluation of indeterminate pulmonary nodules of intermediate risk (pretest probability of cancer 15% to 80%) to complement low-dose chest CT screening. Given the exquisite specificity of CancerSEEK and the expected strong positive diagnostic likelihood ratios, the test may offer a high post-test probability of cancer and significantly enhance the patient/ provider management of the nodule. Finally, these noninvasive strategies call for novel biomarker-driven diagnostic trials in which patients are enrolled prospectively in the clinical setting and, based on testing, offered customized diagnostics and therapy. These trials are urgently needed in the early detection of cancer to move strong candidate biomarkers closer to clinical utility. About the Author: Dr. Massion is Cornelius Vanderbilt Chair in Medicine and Professor of Medicine in the Division of Allergy, Pulmonary, and Critical Care Medicine, and director of the Cancer Early Detection and Prevention Initiative at Vanderbilt Ingram Cancer Center. References: 1. U.S. Preventative Services Task Force website. uspreventiveservicestaskforce.org. Accessed March 27, Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5): Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403). 4. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5): Thompson JC, Yee SS, Troxel AB, et al. Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA. Clin Cancer Res. 2016;22(23): Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017;7(12): Blakely CM, Watkins TBK, Wu W, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017;49(12): Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multianalyte blood test. Science. 2018;359(6378): Pepe MS, Etzioni R, Feng Z, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93(14):

18 18 IASLC LUNG CANCER NEWS / OCTOBER 2018 Names and News After 11 years at NYU Langone Health, Jessica S. Donington, MD, MSCR, has moved to the University of Chicago Medicine as professor of surgery and chief of the Section of Thoracic Surgery. In addition to her clinical practice, Dr. Donington is an avid researcher and respected leader in her field. Her research focus is in the discovery of novel biomarkers for early detection and treatment of lung cancer and clinical trials that incorporate surgery into multimodality care plans for locally advanced and metastatic lung cancer. Dr. Donington is a past president of Women in Thoracic Surgery and the New York Society for Thoracic Surgery and serves on the editorial boards for the Journal of Thoracic Oncology and the Annals of Thoracic Surgery. Raymond Osarogiagbon, MBBS, FACP, has been selected as a member-elect to the Fleischner Society. Founded in 1969, the Fleischner Society is a collegial, multidisciplinary international thoracic imaging society dedicated to promoting education and research directed to innovative patient care. Dr. Osarogiagbon is director of the Multidisciplinary Thoracic Oncology Program at the Baptist Cancer Center, in Memphis, and director of the Thoracic Oncology Research (ThOR) Group of the Baptist Cancer Center. He also is the principal investigator of two major ongoing regional projects: a U.S. National Institutes of Health R01-funded regional quality-improvement project titled Dissemination and implementation of a corrective intervention to improve mediastinal lymph node examination in resected lung cancer (R01 CA ) and the Patient Centered Outcomes Research Institute-funded comparative effectiveness study of multidisciplinary versus serial care for lung cancer titled Building a Multidisciplinary Bridge Across the Quality Chasm in Thoracic Oncology (IH ). Dr. Osarogiagbon is a research professor at the University of Memphis School of Public Health and a member of several professional societies including the International Association for the Study of Lung Cancer, American Society of Clinical Oncology, and the American Society of Hematology. Vassiliki A. Papadimitrakopoulou, MD, is the recipient of the 2018 Addario Lectureship Award presented by The Bonnie J. Addario Lung Cancer Foundation for her groundbreaking clinical research in immunotherapy. Dr. Papadimitrakopoulou is the Jay and Lori Eisenberg Distinguished Professor of Medicine at The University of Texas MD Anderson Cancer Center, where she serves as the section chief of Thoracic Medical Oncology in the department of Thoracic/Head and Neck Medical Oncology. Dr. Papadimitrakopoulou is co-principal investigator for the Master Lung Protocol (Lung-MAP) trial, the first of its kind to use a comprehensive genomics-driven approach to squamous cell lung cancer. She serves as a member of the IASLC Publications Committee. Antoinette Wozniak, MD, moved to Hillman Cancer Center at University of Pittsburgh Medical Center in September 2018, where she is now a professor of medicine, leader of the Lung Cancer Disease Team, and associate director of clinical research. She was previously with the Karmanos Cancer Institute for more than 25 years. GLOBAL INITIATIVES EGFR TKIs from page 10 The IASLC Provides More Than Just Scientific Knowledge at Tangier Conference By Anna Wrona, MD, PhD The IASLC Africa Conference on Lung Cancer 2018 in Tangier, Morocco, held last spring, provided participants with unique expert perspectives in lung cancer epidemiology, diagnostics, and treatment. This meeting created a collegial environment for open discussion among its international participants. The program offered a number of substantive and directly applicable discussions beginning with the first day s roundtable discussion on opportunities and challenges associated with clinical trials in Africa and on treatment-related best practices regarding the surgical management of early lung cancer, optimal combination of chemoradiotherapy in locally-advanced lung cancer, immunotherapy application, and lung cancer screening. The plenary session focused on practical approaches to improve networking and cooperation among Middle East and North Africa Countries. The second day s program featured for discussion of clinically relevant topics such as the epidemiologic landscape of lung cancer in Africa, tobacco control The IASLC s first conference in Africa was robust in content, diverse in speakers, and received very favorably by attendees. issues, practice implications regarding the 8th edition of TNM classification, molecular targeted therapies, immunotherapies, the intricacies of lung cancer staging procedures with PET/CT and mediastinal lymph nodes evaluation with endobronchial ultrasound, and oligometastatic lung cancer in the context of optimal local ablative therapies (surgery, stereotactic radiotherapy) exploitation. (For more on oligometastatic lung cancer, read the article on page 1.) Multidisciplinary case-based discussions about precise indications for surgical treatment of early lung cancer compared with the benefits of sterotactic radiotherapy provided holistic approaches to real-life questions. The conference also allowed for discussion of more sensitive topics such as pharmacoeconomic limitations and limited drug access, with potential solutions suggested by and provided to members of the pharmaceutical industry, advocacy groups, the medical and academic community, and even the African governments. Bridges were also built between Moroccan Foundation Lalla Salma for Cancer Prevention and Treatment and the IASLC Foundation. As a conference attendee, it is apparent that the knowledge and expertise that the IASLC brings to such an event is important; the creation of a forum to exchange experiences, concerns, and ideas is invaluable. Friendships have been made, collaborations developed, and steps for diagnostic and therapeutic improvement solidified; however, there is more work to be done. About the Author: Dr. Wrona works as a consulting radiation oncologist and academic in the Department of Oncology and Radiotherapy at the Medical University of Gdansk, Poland. failure is unknown; for dacomitinib, that figure is 36.7 months. At the very least, afatinib followed by additional treatment at progression offers a 33-month median survival (at a minimum) for patients with exon 19 deletion. The extent to which osimertinib can increase the OS benchmark after afatinib failure is unknown; for dacomitinib, that figure is 36.7 months For the time being, both approaches seem acceptable, particularly while we await final OS data from FLAURA, AURA 3, and other studies. Based on data from the IMpower 150 trial, immunotherapy combined with chemotherapy and an antiangiogenic agent may result in unprecedented OS rates and would constitute a very reasonable therapeutic option once a patient s tumor becomes TKI refractory, regardless of whether osimertinib is used in the first or second line. About the Author: Dr. Santos Castillero is a thoracic oncologist at the Center for Hematology- Oncology and is a clinical associate professor at Florida Atlantic University. He is also chair of the IASLC Publications Committee.

19 LUNGCANCERNEWS.ORG / OCTOBER 2018 Peru and Latin America from page 15 delayed approval in Peru for months, if not years, as is the case in most of Latin America. The same problems exist for immunotherapy, where approval delays limit access. The first three immunotherapy agents nivolumab, pembrolizumab, and atezolizumab are now available in just a few countries, such as Peru, whcih is ahead of many other Latin American countries regarding standard treatment in the second-line setting and beyond. It is imperative that we create policies to make these therapies available to the majority of patients with lung cancer, who are being treated in the public healthcare systems; the benefits of these more novel treatments are currently confined to the private sector, where the use of targeted therapy and immunotherapy is concentrated. IASLC-LATAM Initiatives My colleagues and I have published several articles including, most recently, an article in Lung Cancer,2 outlining the challenges of managing lung cancer care in Peru and Latin America. In that regard, with the help of the IASLC, we have been trying to expand education and awareness at several levels to prepare the region to face these challenges. In this regard, the IASLC Latin American Group (IASLC-LATAM) has successfully organized regular IASLC Latin-American Cancer Meetings (LALCA). These meetings were initially held every 2 years, but as of this year, they will be held annually starting with Córdoba, Argentina. With the support of the IASLC CEO Fred R. Hirsch, MD, PhD, I have served as the meeting chair of several Best of World Lung Cancer Meetings in Lima, Peru successively for 3 years. The last meeting, held in early February 2018, was chaired by myself, along with the local chairs Carlos Vallejos, MD, and Luis Mas, MD. The meeting featured 18 speakers, including eight international speakers. Among them were Dr. Hirsch, IASLC-LATAM Board Member Clarissa Mathias, MD, and other IASLC speakers from the United States, Brazil, Chile, and Colombia. More than 180 physicians from Peru and other Latin American LUNG CANCER 19 countries attended, where they had the opportunity to meet with members of the IASLC and were invited to join the organization. Under the sponsorship of the IASLC, other smaller, regional, multidisciplinary meetings are being organized. For example, the Peruvian Association for Bronchology and Interventional Pulmonology organized two seminars on bronchoscopy ultrasound and navigational bronchoscopy in Lima, Peru in Two IASCL members, Pedro Garcia-Mantilla, MD, FCCP, a pulmonologist from Guillermo Almenara Hospital in Lima, Peru, and Francisco Tarrazzi, MD, from Memorial Cancer Institute, Miami-Florida, were among the faculty, and Dr. Garcia-Mantilla chaired both events. This meeting included a lesson on endobronchial ultrasound that was actually conducted with real patients who were previously classified as difficult cases with unstaged disease and who did not previously have access to these technologies. Finally, thanks to the initiative of Christian Rolfo, MD, PhD, MBA, from the IASLC Education Committee, the IASLC LATAM Group has been able to conduct the IASLC School of Oncology, which has focused on training earlycareer oncologists in Chile, Costa Rica, and Peru for the past 3 years. These IASLC initiatives and others are crucial for cancer care specialists and patients in Peru and other countries. With continued support and continuing education, the IASLC-LATAM group will continue to confront the many challenges that exist in the battle against lung cancer in the years to come, with the goal of improving patient care and outcomes. About the Author: Dr. Raez is chair of the IASLCLatin American (LATAM) Group and chief of hematology/oncology and medical director of Memorial Cancer Institute at Memorial Healthcare System in Miami-Florida. References: 1. Raez LE, Nogueira A, Santos ES, et al. Challenges in Lung Cancer Screening in Latin America. J Glob Oncol. 2018;4: Raez LE, Cardona AF, Santos ES, et al. The burden of lung cancer in Latin-America and challenges in the access to genomic profiling, immunotherapy and targeted treatments. Lung Cancer. 2018;119:7-13. Read the December issue of the IASLC Lung Cancer News to learn about the top science presented at the IASLC Latin America Conference on Lung Cancer. Video interviews with the IASLC CEO Dr. Fred Hirsch, as well as with top Latin American medical oncologists and IASLC members, about news and challenges in the region are available on IASLC.org under the Conferences & Events tab. NEWS I N T E R N AT I O N A L A S S O C I AT I O N F O R T H E S T U D Y O F L U N G C A N C E R I A S LC Meetings Schedule IASLC 19th Lung Cancer Targeted Therapies Meeting February 20-23, 2019 Santa Monica, California #LCTT19 IASLC Small Cell Lung Cancer Meeting 2019 April 3-5, 2019 New York, New York #SCLC European Lung Cancer Congress April 10-13, 2019 Geneva, Switzerland #ELCC19 IASLC Mesothelioma Meeting 2019 July 10-12, 2019 New York, New York #MESO19 IASLC 20th World Conference on Lung Cancer September 7-10, 2019 Barcelona, Spain #WCLC2019 IASLC North America Conference on Lung Cancer 2019 October 9-12, 2019 Chicago, Illinois #NACLC19 IASLC Latin America Conference on Lung Cancer 2019 October 18-19, 2019 Mexico City, Mexico #LACLC19

20 *MSI status will be reported for samples determined to have high microsatellite instability Foundation Medicine, Inc. MKT