ADVANCES IN LUNG CANCER TREATMENTS

ADVANCES IN LUNG CANCER TREATMENTS Joan H. Schiller, MD Deputy Director of Clinical Research; Chief of Hematology/Oncology Inova Schar Cancer Institute; Fairfax, VA Chair of the Scientific Steering Committee, LCRF

A very special thank you to our partners

Hope through advances in lung cancer treatments Lung cancer continues to be the single largest cancer killer of men and women in the US 1 Research remains very much underfunded BUT, there is HOPE Important advances are being made in lung cancer diagnosis and treatment 1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer Society; 2016. 1. American Cancer Society. Cancer Facts & Figures 2018.

Research is the driver of change in the treatment of lung cancer Basis for changing clinical practice and improving outcomes: FDA approvals New drugs New ways to use existing drugs Removal of approval of drugs or specific uses of drugs Changes to the National Comprehensive Cancer Network (NCCN) Guidelines Help determine clinical practice, ie, how patients are treated Usually quickly updated in response to FDA approvals FDA approvals, NCCN guidelines, and other recommendations are driven by research

We are making progress: Key FDA approvals Chemotherapy 1990 2000 2010 2018 Targeted therapies FDA approvals of new drugs EGFR ROS1 ALK BRAF 2003 2010 2018 Immunotherapy T790M 2018 Lung Cancer Research Foundation 2015 2018 FDA.gov.

New research findings incorporated into NCCN guidelines Increase in frequency of updates of guidelines due to: New drugs Research on how best to use approved drugs New tumor testing techniques 1/2016 1/2017: Five updates for NSCLC In 2017, five updates by March 2017 Already in 2018, two versions issued for both NSCLC and small cell lung cancer (as of Jan 23)! 1,2 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Nonsmall Cell Lung Cancer. Version 2.2018. Published December 19, 2017. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Small Cell Lung Cancer. Version 2.2018. Published January 17, 2018.

Targeted therapies

Targeted therapies are specific for the particular protein or gene that is altered in the tumor 2017 Free to Breathe

Efficacy of an EGFR inhibitor (erlotinib) 6 FEB 2002 11 FEB 20029 Kim ES, et al. Personalized care for metastatic NSCLC: Practical application of research advances and emerging data. Educational Concepts Group, LLC; 2014.

Scientific story behind EGFR-targeted treatments An initial discovery Identification of EGFR overexpression in lung cancer 1. Ke EE, Wu YL. Trends Pharmacol Sci. 2016 Nov;37(11):887-903. 2. onclive.com/publications/oncology-live/2016/vol-17-no-3/egfr-inhibitors-continue-march-in-mutated-nsclc?p=4

Scientific story behind EGFR-targeted treatments Research continues to lead to new treatments and help refine how best to use treatments 1. Ke EE, Wu YL. Trends Pharmacol Sci. 2016 Nov;37(11):887-903. 2. onclive.com/publications/oncology-live/2016/vol-17-no-3/egfr-inhibitors-continue-march-in-mutated-nsclc?p=4

Currently approved EGFR-targeted therapies Uncommon mutations (S768I, L861Q, and/or G719X) Disease progression Tumor testing or liquid biopsy T790M 1. FDA.gov. 2. Melosky B, et al. Clin Lung Cancer. 2018;19(1):42-50. Osimertinib Afatinib/ Gilotrif Erlotinib/Tarceva Gefitinib/Iressa Osimertinib/Tagrisso

Anticipated change for EGFR-targeted therapies Uncommon mutations (S768I, L861Q, and/or G719X) Disease progression Tumor testing or liquid biopsy T790M Osimertinib moving to 1 st line Osimertinib 1. FDA.gov. 2. Melosky B, et al. Clin Lung Cancer. 2018;19(1):42-50.

What s new in EGFR-targeted therapies? FLAURA trial shows that osimertinib improved progression-free survival (PFS) vs erlotinib or gefitinib, in previouslyuntreated patients with locally-advanced or metastatic EGFR-mutated NSCLC September 2017 - NCCN guidelines include osimertinib as 1st-line treatment of patients with EGFR-mutated mnsclc based on FLAURA December 2017 - FDA accepts application of osimertinib as 1 st -line treatment based on FLAURA Osimertinib blocks EGFR-sensitizing and EGFR T790M-resistance mutations Source: NEJM Quick Takes 1. FDA.gov. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Non-small Cell Lung Cancer. Version 9.2017. Published September 28, 2017.

FLAURA trial results Soria JC, et al. N Engl J Med. 2018;378(2):113-125. Source: NEJM Quick Takes

What s next: EGFR-targeting drugs? More studies to see which EGFR-targeting drugs should be used first and in what order (ie, sequencing) eg, GioTag is a real-world study to look at sequential therapy in patients with EGFR mutation-positive NSCLC Many new drugs in clinical trials AP32788 and poziotinib for EGFR exon 20 mutant NSCLC and exon 20 mutant NSCLC Clinicaltrials.gov.

ALK inhibitors DB PET Pre- and post Crizotinib 12/2011 ALK=anaplastic lymphoma kinase

ALK inhibitors DB PET Pre- and post Crizotinib 12/2011 3/2012 ALK=anaplastic lymphoma kinase

Efficacy of an ALK inhibitor (crizotinib) Pre-Treatment Crizotinib x 12 weeks Kim ES, et al. Personalized care for metastatic NSCLC: Practical application of research advances and emerging data. Educational Concepts Group, LLC; 2014. 19

FDA approved ALK inhibitors Approved for 1 st line Alectinib/Alecensa Ceritinib/Zykadia Crizotinib/Xalkori Approved for 2 nd line Brigatinib/Alunbrig New in 2017 Brigatinib A new ALK inhibitor Alectinib Approval as front-line therapy, based on ALEX trial Alectinib improved PFS by 47% vs crizotinib ALEX and J-ALEX are practice-changing clinical trials ALK=anaplastic lymphoma kinase 1. FDA.gov. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Non-small Cell Lung Cancer. Version 2.2018. Published January 17, 2018.

Alectinib as 1st-line therapy: ALEX study Image available at: alecensa.com/hcp/clinical-overview/first-line-efficacy.html Peters S, et al. N Engl J Med. 2017;377:829-838.

Alectinib as 1st-line therapy: ALEX study Time to cause-specific CNS progression (percentage of patients with CNS as first site of progression) Image available at: alecensa.com/hcp/clinical-overview/first-line-efficacy.html Peters S, et al. N Engl J Med. 2017;377:829-838.

Other news of ALK inhibitors Brigatinib continues to be studied as a first-line treatment versus crizotinib (ATLA-1L trial) Shows promising activity against resistance mutations 1 ASCEND-8 trial of optimal dosing of ceritinib to minimize side effects 2 A lower dose (450 mg/day ceritinib) taken with food can result in fewer GI side effects than 750 mg/day taken while fasting FDA approved new dosing (December 2017) 1. Zhang S, et al. Clin Cancer Res. 2016;22(22):5527-5538. 2. Cho BC, et al. J Thorac Oncol. 2017;12(9):1357-1367.

ROS-1 inhibitors Crizotinib is approved for ROS-1 positive NSCLC Lorlatinib granted breakthrough therapy designation for use in patients with ALK-positive mnsclc (2017) Is a selective brain-penetrant ALK/ROS-1 inhibitor active against known resistance mutations Could be an option for patients who develop resistance after treatment with alectinib (ALK-positive NSCLC) Entrectinib granted orphan drug status for ROS-1 and ALK-positive lung cancer, and other rare cancers (2015) Designed to go across the blood-brain-barrier Ongoing studies to look at drugs to address brain metastasis 1. FDA.gov. 2. clinicaltrials.gov.

Available BRAF 600E inhibitors Dabrafenib/Tafinlar + Trametinib/Mekinist Treatment of patients with mnsclc expressing the BRAF V600E mutation First targeted treatment in the US specifically for BRAF V600E mutation-positive metastatic NSCLC June 2017 FDA approved the combination of dabrafenib and trametinib to treat patients whose tumors express the BRAF V600E mutation Patients with BRAF V600E mutation-positive metastatic NSCLC have responded less favorably to standard chemotherapy NCCN guidelines BRAF testing should be included as part of broad molecular profiling FDA.gov. mnsclc=metastatic non-small cell lung cancer

Other therapies Bevacizumab (Avastin ) and Ramucirumab (Cyramza ) Therapies that can stop angiogenesis, a process where the tumor makes new blood vessels Avastin is only used for patients who have nonsquamous NSCLC Necitumumab (Portrazza ) targets EGFR Necitumumab is only used for patients who have squamous NSCLC FDA.gov.

What s new in other treatments? IMpower150 trial Immunotherapy added to combo of chemo + bevacizumab (non-squamous NSCLC only) Promising early results* Atezolizumab + Carboplatin + Paclitaxel + Bevacizumab Median PFS, months Preliminary median overall survival*, months 8.3 19.2 Atezolizumab + Carboplatin + Paclitaxel N/A N/A Carboplatin + Paclitaxel + Bevacizumab 6.8 14.4 *Based on minimum 9.5 months of follow-up Reck M, et al, ESMO, 2017.

Advances in tumor testing NCCN guidelines include tumor testing for patients with adenocarcinoma for: EGFR mutations ALK gene rearrangements ROS-1 gene rearrangements BRAF V600E mutations PD-L1 testing might be done in patients considered for immunotherapy Studies continue to look at PD-L1 testing and other measures (eg, tumor mutation burden) Researchers hope tests will help identify which patients are likely to benefit from immunotherapy National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Small Cell Lung Cancer. Version 2.2018. Published January 17, 2018.

Advances in tumor testing: FDA approvals Liquid biopsy (test done on plasma) September 2016: Liquid biopsy for EGFR; osimertinib companion diagnostic for T790M June 2016: Liquid biopsy for EGFR; erlotinib companion diagnostic for exon 19 deletions or exon 21 (L858R) substitution mutations in EGFR Next-generation sequencing (NGS) November 2017: FoundationOne CDx (F1CDx) is the first approved NGS-based test; can detect mutations in 324 genes and two genomic signatures in solid tumors CMS proposed coverage (final policies in progress) 1. FDA.gov. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Small Cell Lung Cancer. Version 2.2018. Published January 17, 2018.

Immunotherapy

Immune Cells Types of WBCs Neutrophils Important in fighting bacteria Macrophages Important in fighting any foreign substance Lymphocytes The generals of the immune system Several different types of lymphocytes Tell other immune cells what to do B-lymphocytes: Make antibodies Joan s oversimplified version of immunity and cancer Lymphocytes Lymphocytes Lymphocytes Lymphocytes T-Lymphocytes or T cells are important in fighting any foreign substance, such as cancer cells

What s supposed to happen: T-lymphocytes (T cells) monitor the body for things that aren t supposed to be there *Joan s embarrassingly overly simplified version of the immune system

What s supposed to happen: When T-cells recognize cancer cells as foreign = PD-1 *Joan s embarrassingly overly simplified version of the immune system

And become activated, allowing the T-cells to attack the tumor = PD-1 *Joan s embarrassingly overly simplified version of the immune system

What sometimes happens: Cancer cells make checkpoint proteins such as PD-L1 to mask the T- cells, by binding to PD-1 on the T cells, = PD-1 = PDL1 *Joan s embarrassingly overly simplified version of the immune system

What sometimes happens: Cancer cells make checkpoint proteins such as PD-L1 to mask the T-cells, by binding to PD-1 on the T cells, = PD-1 = PDL1 *Joan s embarrassingly overly simplified version of the immune system

What sometimes happens: Thus rendering the cancer cell invisible to the T cell* = PD-1 = PDL1 *Joan s embarrassingly overly simplified version of the immune system

What to do??? Anti-PD-1 antibodies stop the PD-L1 from binding to the PD-1 on T-cells Nivolumab, Pembrolizumab = PD-1 = Anti PD-1 *Joan s embarrassingly overly simplified version of the immune system

Anti-PD-L1 antibodies also stop PD-L1 from Binding to PD-1 on T-cells Atezolizumab, Durvalumab = PD-1 = Anti PD-L1 *Joan s embarrassingly overly simplified version of the immune system

Thus allowing the T-cells to see the cancer cell and attack = PD-1 = Anti PD-L1 *Joan s embarrassingly overly simplified version of the immune system

Longer survival for nivolumab vs docetaxel 1-3 Checkmate 017: Squamous mnsclc (N=272) Checkmate 057: Non-Squamous mnsclc (N=582) 1. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Brahmer J, et al. N Engl J Med. 2015;373:123-135. 3. Borghaei H, et al. N Engl J Med. 73(17):1627-1639. Images available at: http://www.opdivohcp.bmscustomerconnect.com/metastatic-nsclc

CheckMate 057: 2 nd -line nivolumab vs docetaxel in non-squamous NSCLC Borghaei H, et al. N Engl J Med. 73(17):1627-1639.

Key advances October 2016 Immunotherapy moves to 1 st -line Pembrolizumab - first immunotherapy to be approved in first-line treatment for patients with NSCLC whose tumors have high PD-L1 expression with no EGFR or ALK aberrations May 2017 Immunotherapy combined with chemo Pembrolizumab - accelerated approval as first line treatment in combination with chemo (carboplatin + pemetrexed) for non-squamous NSCLC No PD-L1 testing required FDA.gov.

KEYNOTE 001: Pembrolizumab in chemo-naïve patients with NSCLC Survival of Patients Treated with Pembrolizumab by PD-L1 Expression PFS Higher PD-L1 expression Overall Survival Higher PD-L1 expression Garon EB et al. N Engl J Med 2015; 372(21):2018-2028.

Pembrolizumab + chemo in 1 st line Langer CJ, et al. Lancet Oncol. 2016;17(11):1497-1508.

FDA-approved immunotherapies Type Drug Use in first-line therapy? PD-1 inhibitor PD-L1 inhibitor Use with chemo? Use after chemo stops working? Requires PD-L1 testing? Nivolumab/ Opdivo No No Yes No Pembrolizumab/ Keytruda Yes Yes* Yes No** Yes Atezolizumab/ Tecentriq No No Yes No *Pembrolizumab is approved in combination with chemotherapy (pemetrexed and carboplatin) in patients with non-squamous NSCLC **When used with chemotherapy When used by itself for initial therapy (PD-L1 expression 50%) or after chemo stops working (PD-L1 expression 1%) These are not all of the FDA-approved indications FDA.gov.

Possible side effects of immunotherapy Part of the body Possible side effects Possible symptoms Lung Inflammation of the lungs (pneumonitis) Shortness of breath Cough Chest pain Intestine Inflammation of the colon (colitis) Diarrhea Pain in the stomach area Liver Inflammation of the liver (hepatitis) Dark urine Feeling less hungry Thyroid or other hormone glands Thyroid problems, such as underactive thyroid (hypothyroidism) Feeling cold Headaches Weight loss or gain Kidney Inflammation of the kidney (nephritis) Change in the amount or color of your urine Infusion reactions Skin or other organs Rash Eye problems Muscle problems Side effects related to IV administration Chills Fever These are not all the possible side effects of immunotherapy Rash or itching Rash Changes in eyesight Muscle pain or weakness Information obtained from Full Prescribing Information for approved immunotherapies available at FDA.gov.

Many more trials of immunotherapy Combinations Awaiting full results of KEYNOTE-189 trial of frontline pembrolizumab with pemetrexed (Alimta ) and either cisplatin or carboplatin New ways to use immunotherapy Neoadjuvant and adjuvant studies eg, LCMC 3 trial of atezolizumab before and after surgery New drugs under FDA review Durvalumab (Imfinzi ) after chemoradition in patients with stage 3 disease (Pacific trial) Studies of immunotherapy in small cell lung cancer (discussed in next sections)

PACIFIC trial may change clinical practice Active monitoring after chemoradiation was the standard of care for patients with locally advanced (Stage III) lung cancer whose tumors could not be removed by surgery PACIFIC trial looked at benefit of immunotherapy after chemoradiation Immunotherapy Patients with Stage III, locally advanced, unresectable NSCLC Chemoradiation treatment (CRT) Placebo Antonia SJ, et al. N Engl J Med. 2017;377(20):1919-1929.

Pacific Trial: PFS by BICR (Primary Endpoint; ITT) PFS probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Stratified hazard ratio, 0.52 (95% CI, 0.42 0.65) Two-sided P<0.0001 Durvalumab (N=476) Durvalumab 16.8 months Placebo 5.6 months Placebo (N=237) Median PFS (95% CI), months 16.8 (13.0 18.1) 5.6 (4.6 7.8) 12-month PFS rate (95% CI) 55.9% (51.0 60.4) 35.3% (29.0 41.7) 18-month PFS rate (95% CI) 44.2% (37.7 50.5) 27.0% (19.9 34.5) 0 3 6 9 18 12 15 2 1 Time from randomization (months) 2 4 2 7 Antonia SJ, et al. N Engl J Med. 2017;377(20):1919-1929. BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-free survival

Practical issues in immunotherapy How best to select patients likely to respond Biomarkers: Does the amount of PD-1 or PD-L1 in a tumor matter? Measure them or not? Logistical issues with obtaining biomarkers What about tumor mutation burden? Optimal dosing How long to give? Understanding hyperprogression Cost

Tumor mutation burden (TMB) TMB is a measure of mutations carried by a tumor Determined by the number of mutations in a specific area of genetic material, such as mutations: In a single cell In an entire tumor Per area of building blocks of DNA Potential marker of sensitivity to immunotherapy Higher TMB may mean more likely to respond to immunotherapy Hot off the press (2/2018): CheckMate-227 showed that TMB is a predictive biomarker that can identify people with NSCLC who may benefit from the nivolumab + ipilimumab combination Full results of the study to follow

Small cell lung cancer

New research holds promise for patients with small cell lung cancer (SCLC) Sabari JK, et al. Nat Rev Clin Oncol. 2017;14(9):549-561.

Potential benefit of immunotherapy in treatment of patients with SCLC Positive initial results from studies of nivolumab and pembrolizumab reported in 2015 1-4 NCCN guidelines include nivolumab +/- ipilimumab (Yervoy ) for treatment of patients with previously treated SCLC Based on Checkmate 032 trial 5 1. Antonia SJ, et al. J Clin Oncol. 2015; 33 (Suppl). Abstract 7503. 2. Ott PA, et al. J Clin Oncol. 2015;33 (Suppl). Abstract 7502. 3. Calvo E, et al. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3098. 4. Ott PA, et al. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 3285. 5. Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895. 55

Checkmate 032 trial Responses to immunotherapy did not seem to correlate with PD-L1 SCLC may have lower rate of PD-L1 expression than NSCLC Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895.

What s next for SCLC? Rova T is a DLL3-targeted antibody-drug conjugate with encouraging activity in SCLC Trininty trial is studying rova-t as third-line treatment Evidence indicates 80% of patients with SCLC are positive for DLL3 expression Lurbinectedin, is a new chemotherapy Atlantis trial of lurbinectedin + doxorubicin vs either topotecan or CAV (cyclophosphamide, doxorubicine, and vincristine) in patients with SCLC Tanaka K, et al. Lung Cancer. 2018;115:116-120.

Results with Rova-T Confirmed responses with Rova-T in the second-line and third-line setting of recurrent/ refractory SCLC Sabari JK, et al. Nat Rev Clin Oncol. 2017;14(9):549-561.

Guidelines updated based on new staging and techniques New staging system applied - January 2018 1 AJCC Cancer Staging Manual, Eight Edition, 2016 Management of nodules seen on scans 1 Updated guidelines to manage solid nodules on chest x-ray Updates to SCLC guidelines 2 Radiation therapy, eg, use of more advanced techniques Treatment of brain metastasis Adjuvant treatments and monitoring 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Non-small Cell Lung Cancer. Version 2.2018. Published January 17, 2018. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines In Oncology (NCCN guidelines ) Small Cell Lung Cancer. Version 2.2018. Published January 17, 2018.

CAR-T cell therapy

What s supposed to happen: T-cells recognize cancer cells as foreign But how do they do that? = PD-1 *This was one of Joan s many over-simplifications

What s supposed to happen: T-cells recognize cancer cells as foreign But how do they do that? = PD-1 *How they recognize the cancer cells was one of Joan s many over-simplifications

By recognizing proteins on the tumor cell as abnormal, or foreign. To do this, they need to have the proper receptor, like a hook and chain = PD-1 *This was one of Joan s many over-simplifications

T-cells need BOTH to see the cancer cell they need to have their PDL1 receptors open, AND they need to hook up to the cancer cell = PD-1 *This was one of Joan s many over-simplifications

But what happens if the T cells don t have the proper receptor? = PD-1 *This was one of Joan s many oversimplifications

CAR-T makes the proper receptor on the patient s T cells Image from MSKCC; available online at: mskcc.org/blog/car-t-cell-therapy-growing-area-research

CAR-T is an exciting new approach to treating cancer Cells are taken from the patient, filtered, and reprogramed to express the correct hook to target the cancer cell They are then grown and multiplied in the lab, and then returned to the patient Once returned to the patient, the cells can continue multiplying and could fight disease for months or years Two CAR-T cell therapies are FDA approved for blood cancers (2017) CAR=chimeric antigen receptor

Key take-aways Advances in treatments for lung cancer Happened through research! Incredible advances have been made But, more research is needed to improve survival!

Building a movement WE CANNOT DO IT WITHOUT YOU There is strength in numbers!! Participating in this conference is a first step.

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