PAVING THE PATH TO PRECISION MEDICINE IN NSCLC

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1 PAVING THE PATH TO PRECISION MEDICINE IN NSCLC Using Biomarkers to Determine Treatment Course

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes. All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s). The information in this slide deck is intended as reference material and should not replace clinical judgment or updated recommendations that may supersede those provided here. CEC makes no warranty, express or implied, regarding the information provided. CEC assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review or any applicable manufacturer s product information, and comparison with recommendations of other authorities. Usage Rights: This slide deck is provided for educational purposes and individual slides may be used for personal, non commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. Special Thanks! Supported through an independent educational grant from AstraZeneca Presented by Creative Educational Concepts, Inc. (CEC)

3 Learning Objectives 1) Review the molecular pathology of advanced non small cell lung cancer (NSCLC) and identify clinically relevant molecular mutations that impact treatment selection. 2) Examine strategies to coordinate care in the community setting to improve adherence to guideline recommended molecular testing in NSCLC and discuss the utility of newer technologies, such as ctdna liquid biopsy, in clinical practice. 3) Evaluate targeted treatment options for actionable and acquired mutations in NSCLC, such as EGFR/T790M, and assess the safety and efficacy of these targeted therapies. 4) Using a case based approach, examine how to best incorporate molecular testing to optimize targeted therapy selection in EGFRmutated NSCLC at initiation of therapy and upon disease progression.

4 Lung Cancer Percent of Cases by Stage 5% 16% 100% 80% 5 Year Relative Survival 57% 22% Percent 60% 40% 20% 0% 55.2% 28.0% 4.3% 7.4% Localized (16%) Confined to Primary Site Regional (22%) Spread to Regional Lymph Nodes Distant (57%) Cancer Has Metastasized Unknown (5%) Unstaged Stage

5 Lung Cancer Classification Lung Cancer Small Cell Lung Cancer 15% Non Small Cell Lung Cancer 85% Squamous 30% Non squamous 70% Gridelli C, et al. Nat Rev Dis Primers Large Cell Carcinoma (10%) Large cell Neuroendocrine Carcinoma Adenocarcinoma (90%) Mixed subtypes Lepidic (non mucinous or mucinous) Acinar Papillary Micropapillary Solid

6 SQUAMOUS CELL CARCINOMA SMALL CELL CARCINOMA Kenfield SA, et al. Tob Control

7 Evolution of Genomic Alterations in Lung Adenocarcinoma No known genotype No known genotype Lindeman NI, et al. Arch Path Lab Med

8 Why Genotype at the Time of Diagnosis? Helpful to confirm the diagnosis/provide the full diagnosis Helpful for prognostication Most important: can determine first line therapy in some cases (especially EGFR, ALK, ROS1, BRAF V600E); can provide additional options for salvage therapies in other cases NCCN Guidelines Non Small Cell Lung Cancer. Version

9 2018 Targeted Therapies in the United States EGFR mutation Erlotinib* Gefitinib* Afatinib* Osimertinib* ROS1 rearrangement Crizotinib Ceritinib HER2 (ERBB2) mutations Ado trastuzumab emtansine ALK rearrangement Crizotinib* Ceritinib Alectinib* Brigatinib (second line) BRAF mutation Dabrafanib + trametinib* MET amplification or MET exon 14 mutation Crizotinib RET rearrangement Cabozantinib Vandetinib *FDA approved in the first line setting. NCCN Guidelines Non Small Cell Lung Cancer. Version

10 Testing Methodologies No such thing as a perfect test Many different testing approaches Targeted mutation testing Fluorescence in situ hybridization (FISH) Next generation sequencing (NGS) Others Every testing methodology has advantages and limitations The two major test features that describe these advantages and limitations are Clinical sensitivity Analytical sensitivity

11 Think of Needles and Haystacks Clinical Sensitivity How many of the possible changes does the test detect? Analytic Sensitivity How sensitively can the test detect a rare change in a background of normal? These two features are nearly always inversely related. Advantage: A test with excellent clinical sensitivity can detect a wide range of alterations. Limitation: False negatives are mostly attributable to requiring a high level of any given mutation (requires a high proportion of tumor cells in the sample). Advantage: A test with excellent analytic sensitivity can detect an alteration even when present at very low level. Limitation: False negatives are mostly attributable to an alteration not being part of test design (you can t get an answer to Looking for a needle in a haystack - The test can identify only a couple of colors something of needles, you but don t can test). pick them out even when they are very rare Slide courtesy of Dara L. Aisner, MD, PhD.

12 Why Is This Important? Tumor samples consist of a mixture of tumor and non tumor If the sample has a high proportion of non tumor AND a testing method with poor analytic sensitivity is used, there is increased risk for false negatives Conversely, if a highly targeted test is used and a patient has a rare alteration, it may not be detected

13 Tumor Enrichment Tumor enrichment can overcome assay analytic sensitivity limitations No enrichment all material in the specimen is included for testing Macrodissection a broad area is isolated Microdissection tumor cells are selectively isolated under a microscope

14 Many laboratories performing molecular testing utilize macrodissection... far fewer use microdissection Lung adenocarcinoma before and after manual microdissection Slide courtesy of Dara L. Aisner, MD, PhD.

15 Examples of Methods & Analytic Sensitivity Method Analytic Sensitivity Can be used for Clinical Sensitivity Sanger Sequencing Lowest (~15%) Highly enriched tumor samples Usually entire exons or regions of exons queried Single Base Extension (SNaPshot, MassArray) Moderate (~5%) Moderately enriched samples Usually highly targeted to individual alterations Real Time PCR Highest (1% 2%) Samples in which enrichment is not feasible Highly targeted to individual alterations Next Generation Sequencing Moderate (5% 10%) Moderately enriched samples Usually entire exons or regions of exons Bottom line: Be familiar with the methodology employed by a laboratory, and whether it is paired with tumor enrichment.

16 What is Next Generation Sequencing? NGS is NOT a test it is a platform Allows the evaluation of multiple regions simultaneously How in the world does this work?

17 How Does NGS Work? Each one of these blocks represents an unique stretch of a patient s DNA Called a cluster DNA is freed from the tumor sample and selectively amplified Then, the clusters are spread across a flow cell to make each occupy a unique 2 dimensional coordinate Flow Cell Slide courtesy of Dara L. Aisner, MD, PhD.

18 How Does NGS Work? Each flow cell is visualized by optical equipment to detect events at each cluster Nucleotide bases (A, T, G, C) are added the optics determine which base is added at each cluster Typically, there are millions (10M 30M) of base reads on a single flow cell The view of the flow cell from above Each dot represents one cluster Different colors represent different nucleotide bases (A, T, G, C) Slide courtesy of Dara L. Aisner, MD, PhD.

19 Lots of Data Data comes out looking like this This portion is the actual sequence data Next steps are bioinformatics, which is part of the reason NGS is more expensive than older tools Slide courtesy of Dara L. Aisner, MD, PhD.

20 Bioinformatics of NGS Data Major Steps 1) Assess the quality of the data Poor quality NGS data is less reliable 2) Align the sequence with the reference Human genome is reference for tumor NGS 3) Map the aligned sequence What gene or where in the chromosomes? 4) Variant call What is different between the reference sequence and the patient sequence? 5) Variant annotation What is known about this specific alteration?

21 NGS is a Platform Each cluster is a unique stretch of a patient s DNA Exactly which pieces of DNA are evaluated in the test is dependent on the NGS assay design Slide courtesy of Dara L. Aisner, MD, PhD.

22 Some Examples of NGS What is being sequenced/ genotyped? Size of read (how much data is generated) Targeted NGS Panels User defined, but typically specific genes Ranges 0.1Mb 3Mb Whole Exome Sequencing All exons in all genes ~20,000 genes ~350K exons 60Mb Whole Genome Sequencing All exons and introns (noncoding regions) in all genes 3.2Gb RNASeq Messenger RNAs (gives data about gene expression) Ranges 20Mb 60Mb Cost $ $$ $$$$$ $$

23 Clinical Considerations for Ordering Genotyping

24 Care Coordination Making Biomarker Testing Happen Multi disciplinary conversations help to streamline processes Interventional radiology, pulmonology acquiring enough tissue for all, not stopping when just one need is met Cytopathology if called for rapid on site evaluation, request more tissue to ensure sufficient quantity for testing Pathology establish tissue preservation mechanism If sending a patient for biopsy specifically for molecular testing, upfront discussion with pathology to request no IHC and tissue preservation Semi automated processes for all of the above can be established IHC, immunohistochemistry Aisner DL, et al. Arch Path Lab Med

25 Considerations for Testing in Early Stage NSCLC Pro Test results are available immediately if the patient recurs Presence of a targetable alteration may signal suitability for an interventional trial Example: ALCHEMIST Con Unnecessary if no recurrence Testing may evolve between diagnosis and recurrence Patient knowledge Insurance may not cover testing Patient anxiety

26 Multifocal Disease Molecular testing can assist in resolving the relatedness of synchronous tumors Can alter staging considerations Panel based testing best for this purpose Example: Same KRAS mutation in two tumors is NOT proof that they are related (because KRAS mutations are so common) Example: A complex mutation pattern with identical KRAS and TP53 mutations is much more convincing

27 Squamous To Test or Not to Test? Unknown, 56% PIK3CA mutation, 4% DDR2 mutation, 4% AKT1 mutation, 6% PTEN mutation, 10% FGFR1 amplification, 20% Low but appreciable incidence of targetable alterations in squamous cell carcinoma EGFR: 1% 4% ALK: 0.5% 1% These may represent misclassified squamous or adenosquamous Other abnormalities in chart are of unknown significance for treatment Response to TKIs in squamous cell with EGFR or ALK alterations not as well defined However, sometimes squamous vs adeno distinction is hard to make and/or erroneous from a biopsy, especially if it is small Drilon A, et al. Lancet Oncol

28 Squamous To Test or Not to Test? Biopsy/FNA specimen with a diagnosis of squamous cell carcinoma Test in all never/light smokers Consider testing even if there is concern for an adenocarcinoma component Resected squamous cell carcinoma Test in all never/light smokers Test even if any adenocarcinoma component is present Dilemma: The presence/absence of adenocarcinoma component may not always be comprehensively evaluated

29 Recommendations for Testing Advanced Stage NSCLC At minimum, pursue testing for EGFR mutations ALK rearrangements ROS1 rearrangements BRAF p.v600e mutations NGS based testing can evaluate all of those while simultaneously evaluating for in development markers Can indicate clinical trial eligibility PD L1 IHC Lindeman NI, et al. J Thorac Oncol. 2018; NCCN Guidelines Non Small Cell Lung Cancer. Version

30 What about KRAS? There currently is no therapy specifically associated with improved outcomes in KRAS mutation positive tumors KRAS mutation testing should it happen? Identification of a KRAS mutation is very strong indicator that a targetable alteration (such as EGFR mutation or ALK rearrangement) is not present EGFR TKI should not be used in the setting of KRAS mutation positive tumor Lindeman NI, et al. J Thorac Oncol

31 Guidelines for Testing NCCN: (June, 2018) CAP/IASLC/AMP joint guidelines (released January, 2018) Major difference: NCCN endorses BRAF stand alone testing Common themes: Do not use clinical features for selecting patients for biomarker testing EGFR, ALK, ROS1 should be considered standard of care for all advanced NSCLC patients Panel based testing which includes exploratory markers improves the chances for matching to a clinical trial Lindeman NI, et al. J Thorac Oncol. 2018; NCCN Guidelines Non Small Cell Lung Cancer. Version

32 USING BIOMARKERS TO DETERMINE TREATMENT COURSE Focus on EGFR Mutation Positive NSCLC

33 Case 1 Newly diagnosed EGFR patient 62 year old female with a 15 pack/year smoking history, who quit 25 years ago, presents with visual complaints Ophthalmologist found her to have choroidal metastasis Chest CT shows large left lung mass, as well as smaller bilateral nodules Lung CT guided biopsy = adenocarcinoma IHC shows PD L1 = 60% Genotyping shows EGFR exon 19 deletion

34 EGFR TKIs With FDA Approved First Line Indication Study Agents N Median PFS Median OS IPASS trial 1,2 EURTAC 3 LUX Lung 3 4,5 FLAURA 6 Gefitinib vs carbopaclitaxel Erlotinib vs platinum doublet Afatinib vs cisplatinpem Osimertinib vs erlotinib or gefitinib mo vs 6.3 mo 21.6 mo vs 21.9 mo mo vs 5.2 mo 19.3 mo vs 19.5 mo mo vs 6.9 mo 28.2 mo vs 28.2 mo mo vs 10.2 mo Not yet reported 1 Fukuorka M, et al. J Clin Oncol. 2011; 2 Wu YL, et al. Lung Cancer. 2017; 3 Rosell R, et al. Lancet Oncol. 2012; 4 Sequist LV, et al. J Clin Oncol. 2013; 5 Yang JC, et al. Lancet Oncol. 2015, 6 Soria JC, et al. N Engl J Med 2018.

35 NCCN Guidelines Version FIRST LINE THERAPY Sensitizing EGFR mutation positive EGFR mutation discovered prior to first line chemotherapy EGFR mutation discovered during first line chemotherapy Erlotinib (category 1) or Afatinib (category 1) or Gefitinib (category 1) or Osimertinib (category 1) Complete planned chemotherapy, including maintenance therapy, or interrupt, followed by erlotinib or afatinib or gefitinib or osimertinib NCCN Guidelines Non Small Cell Lung Cancer. Version

36 Ramalingam SS, et al. ESMO Abstract LBA2_PR; Soria JC, et al. N Engl J Med

37 FLAURA Double Blind Study Design Patients with locally advanced or metastatic NSCLC Key inclusion criteria 18 years* WHO performance status 0/1 Exon 19 deletion/l858r (enrolment by local # or central EGFR testing) No prior systemic anti cancer/ EGFR TKI therapy Stable CNS metastases allowed Stratification by mutation status (Exon 19 deletion/l858r) and race (Asian/ non Asian) Osimertinib (80 mg po daily) (n=279) Randomised 1:1 EGFR TKI SoC ; Gefitinib (250 mg po daily) or Erlotinib (150 mg po daily) (n=277) RECIST 1.1 assessment every 6 weeks until objective progressive disease Crossover was allowed for patients in the SoC arm, who could receive open label osimertinib upon central confirmation of progression and T790M positivity Endpoints Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1) The study had a 90% power to detect a hazard ratio of 0.71 (representing a 29% improvement in median PFS from 10 months to 14.1 months) at a two sided alpha level of 5% Secondary endpoints: Objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety * 20 years in Japan; # With central laboratory assessment performed for sensitivity; Cobas EGFR Mutation Test (Roche Molecular Systems); Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation; Every 12 weeks after 18 months. Ramalingam SS, et al. ESMO Abstract LBA2_PR; Soria JC, et al. N Engl J Med

38 Primary Endpoint PFS by Investigator Assessment Probability of progression free survival events in 556 patients at DCO: 62% maturity Osimertinib: 136 events (49%) SoC: 206 events (74%) Median PFS, months (95% CI) Osimertinib 18.9 (15.2, 21.4) SoC 10.2 (9.6, 11.1) HR 0.46 (95% CI 0.37, 0.57) P<.0001 No. at risk Osimertinib SoC Time from randomisation (months) Soria JC, et al. N Engl J Med. 2018; Ramalingam SS, et al. ESMO Abstract LBA2_PR. 0 0

39 PFS* Across Subgroups Favours Osimertinib Subgroup Overall (n=556) Log Rank (primary) Cox PH Sex Male (n=206) Female (n=350) Age at screening <65 (n=298) 65 (n=258) Race Asian (n=347) Non Asian (n=209) Smoking history Yes (n=199) No (n=357) CNS metastases Yes (n=116) No (n=440) WHO performance status 0 (n=228) 1 (n=327) EGFR mutation at randomisation # Exon 19 deletion (n=349) L858R (n=207) EGFR mutation by ctdna ǂ Positive (n=359) Negative (n=124) Centrally confirmed EGFR mutation Positive (n=500) Negative (n=6) Favours SoC Hazard ratio (95% confidence interval) 0.46 (0.37, 0.57) 0.46 (0.37, 0.57) 0.58 (0.41, 0.82) 0.40 (0.30, 0.52) 0.44 (0.33, 0.58) 0.49 (0.35, 0.67) 0.55 (0.42, 0.72) 0.34 (0.23, 0.48) 0.48 (0.34, 0.68) 0.45 (0.34, 0.59) 0.47 (0.30, 0.74) 0.46 (0.36, 0.59) 0.39 (0.27, 0.56) 0.50 (0.38, 0.66) 0.43 (0.32, 0.56) 0.51 (0.36, 0.71) 0.44 (0.34, 0.57) 0.48 (0.28, 0.80) 0.43 (0.34, 0.54) NC (NC, NC) FLAURA data cut off: June 12, 2017; Hazard ratio <1 implies a lower risk of progression on osimertinib 80 mg. Size of circle is proportional to the number of events. *By Investigator assessment; # Local or central test; ǂ Result missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm; Result missing for 21 patients in the osimertinib arm and 29 patients in the SoC arm; Subgroup categories with less than 20 events were excluded from the analysis. 2.0 PFS hazard ratio and 95% confidence interval 10.0 Ramalingam SS, et al. ESMO Abstract LBA2_PR.

40 All Causality Adverse Events* ( 15% of patients) Median Duration of Exposure Osimertinib:16.2 months (range 0.1 to 27.4) SoC: 11.5 months (range ) Osimertinib (n=279) SoC (n=277) AEs by preferred term, n (%) Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Diarrhoea 161 (58) 120 (43) 35 (13) 6 (2) (57)* 116 (42) 35 (13) 6 (2) 0 Dry skin 88 (32) 76 (27) 11 (4) 1 (<1) 0 90 (32) 70 (25) 17 (6) 3 (1) 0 Paronychia 81 (29) 37 (13) 43 (15) 1 (<1) 0 80 (29) 46 (17) 32 (12) 2 (1) 0 Stomatitis 80 (29) 65 (23) 13 (5) 1 (<1) 1 (<1) 56 (20) 47 (17) 8 (3) 1 (<1) 0 Dermatitis acneiform 71 (25) 61 (22) 10 (4) (48) 71 (26) 50 (18) 13 (5) 0 Decreased appetite 56 (20) 27 (10) 22 (8) 7 (3) 0 51 (18) 24 (9) 22 (8) 5 (2) 0 Pruritis 48 (17) 40 (14) 7 (3) 1 (<1) 0 43 (16) 30 (11) 13 (5) 0 0 Cough 46 (16) 34 (12) 12 (4) (15) 25 (9) 16 (6) 1 (<1) 0 Constipation 42 (15) 33 (12) 9 (3) (13) 28 (10) 7 (3) 0 0 AST increased 26 (9) 18 (6) 6 (2) 2 (1) 0 68 (25) 38 (14) 18 (6) 12 (4) 0 ALT increased 18 (6) 11 (4) 6 (2) 1 (<1) 0 75 (27) 31 (11) 19 (7) 21 (8) 4 (1) FLAURA data cut off: June 12, Grade 3 QTc prolongation based on collected digital ECGs values were recorded for 3 patients in the osimertinib arm and 2 patients in the SoC arm. *In the SoC arm there was one patient with Grade missing and one patient with Grade 5 diarrhoea Ramalingam SS, et al. ESMO Abstract LBA2_PR.

41 FLAURA Efficacy in Patients With CNS Metastasis PFS in Patients WITH CNS Metastases PFS in Patients WITHOUT CNS Metastases Soria JC, et al. N Engl J Med

42 Sequencing of EGFR TKIs Which Strategy is Best? Erlotinib mpfs = 10mo Osimertinib mpfs = 10mo Chemo and others. ~60% + T790M status ~40% Chemo and others. Osimertinib mpfs = 19mo Chemo and others. Slide courtesy Lecia Sequist, MD.

43 How Many Make It to Second line Therapy After First line TKI? Study First line Therapy N Eligible for Second line* N (%) Receiving Any Second line Therapy IPASS Gefitinib (75%) EURAC Erlotinib (68%) WJOG 3405 Gefitinib (70%) LUX Lung 3 Afatinib (78%) LUX Lung 6 Afatinib (63%) LUX Lung 7 Gefitinib (81%) LUX Lung 7 Afatinib (74%) FLAURA SOC (G & E) 206 (?) 62 got osimertinib Assuming 50% T790M, this means 60% treated Assuming 60% T790M, this means 50% treated *Number who were no longer on first line treatment at the time of data cut off. Let s assume in the real world, 70% of patients make it to second line. Fukuoka M, et al. J Clin Oncol. 2011; Rosell R, et al. Lancet Oncol. 2012; Mitsudomi T, et al. ASCO Abstract 7521; Sequist L, et al. J Clin Oncol. 2013; Wu YL, et al. Lancet Oncol. 2014; Paz Ares L, et al. Ann Oncol. 2017; Mok TS, et al. ESMO Abstract LBA50.

44 Sequencing of EGFR TKIs Which Strategy is Best? Erlotinib mpfs = 10mo Osimertinib mpfs = 10mo Chemo and others. 100 ~60% + 42 T790M status ~40% Chemo and others. Osimertinib mpfs = 19mo % make it to second line Chemo and others. Slide courtesy Lecia Sequist, MD.

45 Summary of First line Recommendations for EGFR TKIs in 2018 FLAURA has potentially defined a new standard of care with improved PFS, AE profile, and likely better CNS penetration for osimertinib NCCN has adopted first line osimertinib as a treatment option and osimertinib was granted FDA approved for use in the first line setting in April 2018.

46 Case 2 Acquired Resistance 55 year old male, never smoker, presents with SOB and back pain. He is found to have a T spine vertebral lesion. Staging work up reveals bilateral lung nodules and a left pleural effusion. Thoracentesis = adenocarcinoma; genotyping = EGFR L858R mutation He begins erlotinib with good response Resolution of back pain Resolution of SOB Radiographic response on his first scans After 15 months, restaging shows innumerable new but tiny GGOs, all of which are too small to biopsy

47 Liquid Biopsy aka Cell free DNA Testing A non invasive approach to evaluation of tumor mutations (and other alterations) Methods can be highly targeted or more comprehensive Excellent specificity Sensitivity up to 30% false negative O'Leary B, Turner NC. Clin Oncol (R Coll Radiol)

48 Liquid Biopsy Important to be aware of the major caveats Clear indications for use not established Most studies show a consistent 20% 30% false negative rate Negative findings on liquid biopsy should be followed up with biopsy testing Best clinical case for use is in the setting of progression on EGFR TKI Targeted assays are best validated in this setting Real time PCR ddpcr Broader assays also can be used e.g., NGS Broader assays may compromise analytic sensitivity

49 Liquid Biopsy for T790M in AURA Study Very similar outcomes if positive by either assay Tissue T790M+ ORR 62% mpfs 9.7 mo Plasma T790M+ ORR 63% mpfs 9.7 mo Oxnard GO, et al. J Clin Oncol

50 Liquid Biopsy for T790M in AURA Study Very similar outcomes if positive by either assay Tissue T790M+ ORR 62% mpfs 9.7 mo Plasma T790M+ ORR 63% mpfs 9.7 mo But because ~1/3 of tumors don t shed ctdna, a negative plasma test does not mean negative result! Oxnard GO, et al. J Clin Oncol

51 Liquid Biopsy Bottom line cfdna success is dependent on tumor shedding and, potentially, disease burden Negative results from cfdna testing are uninformative If you are using liquid biopsy in the diagnostic setting, have a backup plan for what to do if uninformative Consider parallel biopsy order

52 Immunotherapy in EGFR Mutants

53 Immunotherapy It s So Appealing But Is It Right for EGFR Patients? FDA Approvals To Date of Immune Checkpoint Inhibitors for NSCLC 03/04/15 Second line nivolumab, squamous 10/09/15 Second line nivolumab, any histology 10/22/15 Second line pembrolizumab, PDL 1> 1% 10/18/16 Second line atezolizumab 10/24/16 First line pembrolizumab, PDL 1>50% 05/10/17 First line carbo/pem/pembrolizumab 02/16/18 Adjuvant durvalumab, stage III unresectable

54 Meta Analysis Shows Lack of Efficacy of Immune Checkpoint Inhibitors in EGFR Mutants (n=3025) Lee CK, et al. JAMA Onc

55 Possible Safety Concern with EGFR TKI and Immune Checkpoint Inhibitors IP, interstitial pneumonitis Oshima Y, et al. JAMA Oncol

56 Immune Checkpoint Inhibitor Monotherapy in EGFR Mutants Preponderance of evidence suggests low activity for PD1 and PD L1 drugs alone in EGFR pts; second line docetaxel is superior to ICI monotherapy. Note first line KEYNOTE 021 (for PD L1 >50%) did NOT include EGFR. There may be safety concerns for pts who receive both ICI and EGFR TKI in sequence ( pneumoni s) More data needed for IO combinations, either with chemo or a second IO agent Note KEYNOTE 021 cohort G study with carboplatin/pemetrexed + pembrolizumab did not include EGFR pts, but IMpower 150 study did include

57 IMpower150: Study Design Maintenance therapy (no crossover permitted) Stage IV or recurrent metastatic non squamous NSCLC chemotherapy naive a tumour tissue available for biomarker testing any PD L1 IHC status Stratification Factors Sex PD L1 IHC expression Liver metastases N=1202 R 1:1:1 Arm A Atezolizumab b + Carboplatin c + Paclitaxel d 4 or 6 cycles Arm B Atezolizumab b + Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Arm C (control) Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Atezolizumab b Atezolizumab b + Bevacizumab e Bevacizumab e Treated with atezolizumab until PD by RECIST v1.1 or loss of clinical benefit AND/OR Treated with bevacizumab until PD by RECIST v1.1 Survival follow up The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit. a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m 2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w. Socinski MA, et al. ASCO Abstract 9002; Socinski MA, et al. N Engl J Med

58 IMpower150 Study Populations and Objectives ITT All randomised patients ITT WT a (87% of patients) a WT refers to patients without EGFR or ALK genetic alterations EGFR/ALK + (13% of patients) T eff high WT a High T effector gene signature expression T eff low WT a Low T effector gene signature expression Co primary objectives Investigator assessed PFS in ITT WT Investigator assessed PFS in T eff high WT OS in ITT WT Key secondary objectives Investigator assessed PFS and OS in ITT Investigator assessed PFS in PD L1 IHC subgroups Independent review facility (IRF) assessed PFS ORR and DOR per RECIST v1.1 Safety in ITT The T effector (T eff ) gene signature is defined by expression of PD L1, CXCL9 and IFNγ and is a surrogate of both PD L1 IHC expression and pre existing immunity (Kowanetz M, et al. WCLC, 2017). Socinski MA, et al. ASCO Abstract 9002; Socinski MA, et al. N Engl J Med

59 Updated PFS Analysis in the ITT WT (Arm B vs Arm C) Statistically significant and clinically meaningful PFS benefit with atez + bev + chemotherapy vs bev + chemotherapy was previously observed (Reck M, et al. ESMO Abstract LBA1_PR) and continued to improve with additional follow up Socinski MA, et al. ASCO Abstract 9002.

60 Updated OS in the ITT WT (Arm B vs Arm C) Statistically significant and clinically meaningful OS benefit with atezo + bev + chemotherapy vs bev + chemotherapy was observed Socinski MA, et al. ASCO Abstract 9002.

61 OS in Key Subgroups (Arm B vs Arm C) Median OS, mo Socinski MA, et al. ASCO Abstract 9002.

62 Safety Summary Socinski MA, et al. ASCO Abstract 9002.

63 Take Home Points Biomarker testing is critical for optimal care of NSCLC patients. Please become familiar with 2018 CAP guidelines. Close, multidisciplinary conversations between medical oncology, pathology, and service obtaining diagnostic biopsies are key. Clinical pathways for EGFR mutants are changing in Osimertinib is a new choice for first line EGFR TKI therapy Push single agent immunotherapy off until after 2 lines of chemo

64 References and Suggested Reading Aisner D, Rumery M, Merrick D, et al. Do more with less: tips and techniques for maximizing small biopsy and cytology specimens for molecular and ancillary testing: the University of Colorado Experience. Arch Pathol Lab Med. 2016;140: Drilon A, Rekhtman N, Ladanyi M, et al. Squamous cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Lancet Oncol. 2012;13(10):e418 e426. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open label, first line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non small cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21): Le D, Durham J, Smith K, et al. Mismatch repair deficiency predicts response of solid tumors to PD 1 blockade. Science. 2017; 357(6349): Lee CK, Man J, Lord S, et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non small cell lung carcinoma: a systematic review and meta analysis. JAMA Oncol. 2018;4(2): Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3): Mitsudomi T, Morita S, Yatabe Y, et al. Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first line treatment for patients with non small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR). Abstract Presented at: ASCO; June 5, 2012; Chicago, Illinois. J Clin Oncol. 2012;30 (15_Suppl):

65 References and Suggested Reading Mok TS, Kim D, Wu Y, et al. Overall survival (OS) for first line crizotinib versus chemotherapy in ALK+ lung cancer: updated results from PROFILE Abstract LBA50. Presented at: ESMO; September 11, 2017; Madrid, Spain. Ann Oncol. 2017;28(Suppl 5):v National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: non small cell lung cancer. Version Accessed July O'Leary B, Turner NC. Science in focus: circulating tumour DNA as a liquid biopsy. Clin Oncol (R Coll Radiol). 2016;28(12): Oshima Y, Tanimoto T, Yuji K, et al. EGFR TKI associated interstitial pneumonitis in nivolumab treated patients with non small cell lung cancer. JAMA Oncol. January 11, 2018 [Epub ahead of print]. Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non small cell lung cancer. J Clin Oncol. 2016;34(28): Paz Ares L, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation positive advanced non small cell lung cancer: overall survival data from the phase IIb LUX Lung 7 trial. Ann Oncol. 2017;28(2): Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR TKI as first line treatment in patients (pts) with EGFRm advanced NSCLC: FLAURA. Abstract LBA2_PR. Presented at: ESMO; September 9, 2017; Madrid, Spain. Ann Oncol. 2017;28(suppl_5):v605 v649. Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized Phase III study of carbopla n + paclitaxel +/ bevacizumab, with or without atezolizumab in 1L non squamous metastatic NSCLC (Impower150). Abstract LBA1_PR. Presented at: ESMO Immuno Oncology Congress; December 7, Geneva, Switzerland.

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