EGFR-MUTATED METASTATIC NSCLC:
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2 EGFR-MUTATED METASTATIC NSCLC: Opening Remarks Suresh S. Ramalingam, MD Professor of Hematology and Medical Oncology Assistant Dean for Cancer Research Emory University School of Medicine Roberto C. Goizueta Chair for Cancer Research Deputy Director, Winship Cancer Institute of Emory University Atlanta, GA Disclosures: Dr. Ramalingam has disclosed he is a consultant for Amgen, Ariad, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Lilly, Merck.
3 Non-small Cell Lung Cancer Improvements in outcomes have been achieved for all stages of NSCLC Early detection will shift the proportion of patients to earlier stages of the disease Targeted therapies and immune checkpoint inhibitors provide robust benefits Molecular selection allows for personalized therapy
4 Recently FDA-Approved Drugs for NSCLC EGFR Osimertinib Necitumumab ALK Alectinib Brigatinib Ceritinib ROS1 Crizotinib Other Targeted Therapy Ramucirumab Immune Checkpoint Inhibitors Nivolumab Pembrolizumab Atezolizumab FDA Prescribing Information.
5 Mutation Landscape for Lung Adenocarcinoma Hirsch FR, et al. Lancet
6 Treatment Algorithm for Advanced NSCLC Stage IV NSCLC Molecular testing for EGFR, ALK, ROS1 IHC for PD-L1 Expression EGFR, ALK or ROS1 PD-L1 50% No targetable mutation PD-L1 <50% No targetable mutation Targeted therapy *Bevacizumab/necitumumab added when appropriate Pembrolizumab +/- Chemotherapy Platinum-based chemotherapy + Pembrolizumab NCCN NSCLC Guidelines Version
7 EGFR Mutation EGFR is Predictive and Prognostic Predictive If you give EGFR inhibitor to a patient with EGFR mutation they respond well. Without mutation, these agents don t work well. Prognostic Patients with EGFR mutation do better than patients without EGFR mutation.
8 EGFR Mutated NSCLC ~10-15% of all NSCLC in the United States Exon 19 and 21 mutations account for nearly 90% of all EGFR mutations EGFR TKI is superior to chemotherapy for patients with EGFR activating mutation Exon 20 insertion is not sensitive to EGFR TKI therapy Resistance to therapy emerges in approximately 9-13 months with 1 st /2 nd generation TKIs NCCN NSCLC Guidelines Version
9 DEBATE 1 Should Specific EGFR Mutation Type (Exon 19 vs. 21) Drive Treatment Selection? Moderator: Mark G. Kris, MD, FACP, FACCP Chief, Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center Professor of Medicine, Cornell University Medical College New York, NY
10 POINT: No, Evidence is Lacking Tony S.K. Mok, BMSc, MD, FRCPC Professor and Chair Department of Clinical Oncology The Chinese University of Hong Kong Hong Kong, China
11 COI Disclosures Grant/Research Support Speaker s Fees Major Stock Shareholder Advisory Board Board of Directors AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, Eisai, Taiho AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho Sanomics Ltd. AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, Bristol- Myers Squibb, genedecode, OncoGenex, Celgene, Ignyta, Cirina International Association for the Study of Lung Cancer (IASLC), Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS)
12 No No? No!!!
13 19 = 21?
14 Basic Biology of EGFR Mutation Exon 19 deletion: commonly 15 base-pair delete = loss of 5 amino acid Exon 21 point mutation: L858R, change of single nucleotide = change of 1 amino acid Paez JG, et al. Science
15 Early Hints on Differences Between Exon 19 and 21 Mutations Sirera, et al. ESMO Abstract 230 PD. CR % PR % SD % All patients with EGFR mutations (n=193) Exon 19 (n=116) Exon 21 (n=76) Exon 19 Exon 21 Median=11 mos Overall RR: 71% Exon 19 RR: 74% Exon 21 RR: 65% Exon 19 Exon 21 Median OS=25 mos Median OS=17 mos
16 French Cooperative Thoracic Intergroup (IFCT) Database (N=1,837) Histology (N=1,837) All patients (N=1,837) Exon 18 (N=102) Exon 19 (N=931) Exon 20 (N=102) Exon 21 (N=702) Squamous 23 (1.3%) 0 14 (1.5) 2 (2.0) 7 (1.0) NS Adenocarcinoma 1563 (85.1%) 87 (85.3) 791 (85.0) 88 (86.3) 597 (85.0) Large Cell 26 (1.4%) 3 (2.9) 14 (1.5) 1 (1.0) 8 (1.1) Other 225 (12.2%) 12 (11.8) 112 (12.0) 11 (10.8) 90 (12.8) Smoking History (N=1,158) Smoker 142 (12.3%) 9 (20%) 68 (11.5%) 10 (19.2%) 55 (11.8%) Former smoker 323 (27.9%) 19 (42.2%) 152 (25.6%) 17 (32.7%) 135 (28.8%) Never-smoker 693 (59.8%) 17 (37.8%) 373 (62.9%) 25 (48.1%) 278 (59.4%) Personal history of cancer (N=1,177) Yes 226 (19.2%) 9 (18.4) 105 (17.5) 11 (19.6) 101 (21.4) NS No 951 (80.8%) 40 (81.6) 494 (82.5) 45 (80.4) 372 (78.6) Leduc C, et al. Ann Onc P
17 French Cooperative Thoracic Intergroup (IFCT) Database PFS and OS with First-line EGFR TKI in Exon 19 and 21 Leduc C, et al. Ann Onc
18 Meta-analysis of First Line TKI vs. Chemotherapy: Exon 19 vs 21 Trial HR 95% CI HR 95% CI Exon 19 deletions Exon 21 L858R substitution ENSURE to to 0.91 EURTAC to to 0.97 LUX-Lung to to 1.16 LUX-Lung to to 0.54 NEJ to to 0.54 OPTIMAL to to 0.48 WJTOG to to 1.07 All to to 0.58 Never-smoker Current or former smoker Lee CK, et al. J Clin Oncol
19 19 May Not be Exactly the Same as 21 Does it really drive our treatment decision?
20 Response Complete response Partial response Stable disease Progressive disease Not evaluable Objective response P WJOG5108L: Gefitinib vs. Erlotinib Full-Analysis Set Erlotinib (n=227) Gefitinib (n=244) EGFR Mutation-Positive Erlotinib (n=160) Gefitinib (n=175) Response to Treatment Erlotinib (n=83) Number of Patients (%) Ex19del Gefitinib (n=78) Erlotinib (n=67) L858R Gefitinib (n=80) Uncommon mutation Erlotinib (n=7) Gefitinib (n=12) Wild Type Erlotinib (n=41) 3 (1.3) 1 (0.4) 2 (1.3) 1 (0.6) 2 (2.4) (1.3) Gefitinib (n=43) 97 (42.7) 111 (45.5) 86 (53.8) 102 (58.3) 52 (62.7) 51 (65.4) 31 (46.3) 45 (56.3) 3 (42.9) 3 (25.0) 5 (12.2) 1 (2.3) 71 (31.3) 61 (25.0) 47 (29.4) 40 (22.9) 22 (26.5) 14 (17.9) 22 (32.8) 19 (23.8) 2 (28.6) 5 (41.7) 17 (41.5) 14 (31.6) 46 (20.3) 61 (25.0) 17 (10.6) 25 (14.3) 4 (4.8) 10 (12.8) 10 (14.9) 12 (15.0) 1 (14.3) 3 (25.0) 17 (41.5) 25 (58.1) 10 (4.4) 10 (4.1) 8 (5.0) 7 (4.0) 3 (3.6) 3 (3.8) 4 (6.0) 3 (3.8) 1 (14.3) 1 (8.3) 2 (4.9) 3 (7.0) 100 (44.1) 112 (45.9) 88 (55.0) 103 (58.9) 54 (65.1) 51 (65.4) 31 (46.3) 46 (57.5) 3 (42.9) 3 (25.0) 5 (12.2) 1 (2.3) Disease Control Rate P 171 (75.3) 173 (70.9) 135 (84.4) 143 (81.7) 76 (91.6) 65 (83.3) 53 (79.1) 65 (81.3) 5 (71.4) 8 (66.7) 22 (53.7) 15 (34.9) Urata Y, et al. J Clin Oncol
21 WJOG5108L: Gefitinib vs. Erlotinib Urata Y, et al. J Clin Oncol
22 Estimated OS probability Estimated OS probability Pooled Analysis of LUX Lung 3 and 6: OS Benefit Only in Exon 19 Del19 Afatinib n=236 Chemo n= Median, Median, months Confounding Factors months HR (95%CI), 0.59 ( ), 0.8 HR (95%CI), P-value P=.0001 P-value 1. Cross over rate to second line TKI Cross over rate to second line chemo 3. Portion of patients who 0.4 had treatment beyond progression Incidence of CNS metastasis L858R Afatinib n=183 Chemo n= ( ), P= No of patients Afatinib Chemo Time (months) No of patients Afatinib Chemo Time (months) Exon 19 Exon 21 Yang JC, et al. Lancet Oncol
23 LUX Lung 7: Study Design Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumor tissue* No prior treatment for advanced/ metastatic disease ECOG PS 0/1 1:1 Afatinib 40 mg once daily Stratified by Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 250 mg once daily Primary endpoints: PFS (independent) TTF OS Secondary endpoints: ORR Time to response Duration of response Duration of disease control Tumor shrinkage HRQoL Safety Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter *Central or local test Dose modification to 50, 30, 20 mg permitted in line with prescribing information ECOG PS=Eastern Oncology Cooperative Group performance status; HRQoL=health-related quality of life; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria In Solid Tumors; TTF=time to treatment failure Park K, et al. Lancet Oncol
24 Estimated PFS probability PFS by Independent Review Afatinib (n=160) Gefitinib (n=159) Median PFS (months) HR (95% CI) 0.73 ( ) P value No. of patients Afatinib Gefitinib P= % P= % 15% 8% Time (months) Park K, et al. Lancet Oncol
25 Estimated OS probability LUX Lung 7: OS in the Overall Population and Patient Subgroups Afatinib (n=160) Gefitinib (n=159) Median, mo HR (95% CI) P-value 0.86 ( ) Time (months) No. at risk: Afatinib Gefitinib Median follow-up: 42.6 months (as of 08 April 2016) Factors N HR (95% CI) Total ( ) EGFR mutation Brain metastases Baseline ECOG PS Gender Age Race Smoking hx L858R Del19 Absent Present 0 1 Male Female <65 years 65 years Non-Asian Asian Never smoked Light ex-smoker Other current/ex-smokers Favors afatinib 4 Favors gefitinib 1/16 1/ ( ) 0.83 ( ) 0.81 ( ) 1.16 ( ) 1.32 ( ) 0.75 ( ) 0.80 ( ) 0.88 ( ) 0.66 ( ) 1.22 ( ) 0.78 ( ) 0.95 ( ) 0.92 ( ) 1.13 ( ) 0.63 ( ) Paz-Ares L, et al. Ann Oncol
26 Estimated OS probability Estimated OS probability OS By EGFR Mutation Exon 19 vs. 21 Del19 L858R Afatinib n=93 Gefitinib n=93 Median, mo HR (95% CI) P-value 0.83 ( ) Afatinib n=67 Gefitinib n=66 Median, mo HR (95% CI) P-value 0.91 ( ) Time (months) No. at risk: Afatinib Gefitinib No. at risk: Time (months) Afatinib Gefitinib Paz-Ares L, et al. Ann Oncol
27 ARCHER 1050: Randomized Phase III Study Dacomitinib vs. Gefitinib Advanced NSCLC Adenocarcinoma EGFR exon 19/21 mut+ First-line treatment PS 0-1 N= 440 patients R A N D O 1 ASCO 2017 June M 6, I Z E Stratification -Race -Exon 19 v 21 Dacomitinib 45mg daily Gefitinib 250mg daily Primary endpoint in PFS 14.8 vs 9.5 months NCT
28 AURA 3 Study Design Randomize patients 2:1 Central testing of biopsy samples at time of EGFR TKI resistance T790M + (N=420) T790M- Osimertinib (80 mg PO daily) Platinum-based doublet chemotherapy* every 3 weeks Not eligible for enrollment Primary endpoint: PFS *Pemetrexed 500 mg/m 2 + carboplatin AUC5 or Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 AUC5=area under the plasma concentration time curve 5 mg/ml 1 per minute; EGFRm+=EGFR mutation-positive; EGFR-TKI=EGFR tyrosine kinase inhibitor; NSCLC=non-small cell lung cancer; T790M+=T790M mutation-positive; T790M-=T790M mutation-negative Mok TS, et al. N Engl J Med
29 AURA 3 Primary Endpoint: PFS by Investigator Assessment Exon 19 AZD mg (46.6) , 0.46 L858R Missing/ unknown Chemotherapy AZD mg Chemotherapy AZD mg Chemotherapy (78.4) (56.6) , (82.2) 5 4 (80.0) NC NC 7 4 (57.1) Analysis of PFS by BICR was consistent with the investigator-based analysis: HR 0.28 (95% CI 0.20, 0.38), P<0.001; Median PFS 11.0 vs. 4.2 months. Population: intent-to-treat Progression-free survival defined as time from randomisation until date of objective disease progression or death; calculated using the Kaplan-Meier approach. Progression included deaths in the absence of RECIST progression. Tick marks indicate censored data; CI, confidence interval Mok TS, et al. N Engl J Med
30 Exon 19 May Be Different From Exon 21 However, the Choice of Therapy Would Have No Impact on Independent Outcome!
31 Should EGFR Mutation Type Drive Treatment Decision? NO!!!!
32 COUNTERPOINT: Yes, Specific Mutations Should Guide TKI Selection Lecia V. Sequist, MD, MPH Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Cancer Center Boston, MA
33 Disclosures Consultant for ARIAD, AstraZeneca, Bristol-Myers Squibb, and Genentech.
34
35 Not all EGFR mutations are the same
36 I grant the data are not perfect, but
37 Predictive vs. Prognostic Biomarker Mukohara T. Breast Cancer (Dove Med Press).2015.
38 IPASS: EGFR+ Prognostic and Predictive Treatment by subgroup interaction test, p< Mok TS, et al. N Engl J Med
39 EGFR Deletion 19 Mutation is Prognostic is it also predictive? Jackman DM, et al. Clin Cancer Res. 2006; Riely GJ, et al. Clin Cancer Research
40 LUX-Lung 3 and 6: Design Stage IIIB/IV Adenocarcinoma of the lung Presence of EGFR mutation in the tumor tissue* No prior treatment with chemotherapy for advanced/metastatic disease or EGFR inhibitors ECOG PS 0 or 1 Afatinib 40mg once daily Randomization 2:1 LUX-Lung 3: Cisplatin + pemetrexed up to 6 cycles LUX-Lung 6: Cisplatin + gemcitabine up to 6 cycles Primary endpoint: PFS (independent review) Secondary endpoints: ORR, DCR, OS, PRO, safety Stratification by EGFR mutation type: Del 19/L858R/other and by race (LUX-Lung 3 only): Asian/non-Asian *EGFR29:19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A, G719C (or G719X), S768I Sequist LV, et al. J Clin Oncol. 2013; Wu YL, et al. Lancet Oncol
41 LUX-Lung 3 and 6: OS in Common Mutations Yang JC, et al. Lancet Oncology
42 Yang JC, et al. Lancet Oncol
43 Erlotinib/Gefitinib Meta-analysis Lee CK, et al. JNCI 2017.
44 LUX Lung 7: Study Design Stage IIIB/IV adenocarcinoma of the lung EGFR mutation (Del19 and/or L858R) in the tumor tissue* No prior treatment for advanced/ metastatic disease ECOG PS 0/1 1:1 Afatinib 40 mg once daily Stratified by Mutation type (Del19/L858R) Brain metastases (present/absent) Gefitinib 250 mg once daily Primary endpoints: PFS (independent) TTF OS Secondary endpoints: ORR Time to response Duration of response Duration of disease control Tumor shrinkage HRQoL Safety Treatment beyond progression allowed if deemed beneficial by investigator RECIST assessment performed at Weeks 4, 8 and every 8 weeks thereafter until Week 64, and every 12 weeks thereafter *Central or local test Dose modification to 50, 30, 20 mg permitted in line with prescribing information Park K, et al. Lancet Oncol
45 LUX Lung 7: Showed No Diff OS Median OS: Afatinib Gefitinib Exon 19 del 30.7 m 26.4 m L858R 25.0 m 21.2 m Resp Rate: Exon 19 del 73% 66% L858R 66% 42% Park K, et al. Lancet Oncol. 2016; Paz-Ares L, et al. Ann Oncol
46 Importantly. In LL7 toxicity patterns differed with more diarrhea, rash for afatinib and more ALT/AST for gefitinib An equal number of patients dropped out of each arm for toxicity (n=10 in each arm) QoL improvements were similar in each arm Park K, et al. Lancet Oncol
47 Structure of EGFR protein wildtype L858R Del 19 Eck MJ, Yun CH. Biochem Biophys Acta. 2010; Kannan S, et al. Sci Rep
48 Each Drug Interacts with the EGFR Receptor in a Unique Manner Gefitinib Erlotinib Afatinib All have quinazoline core Afatinib has an acrylamide group that leads to its covalent binding Both gefitinib and afatinib are halogenated, which may affect its interaction with water molecules within the ATP binding site Chiba M, et al. BMC Cancer
49 ATP Pocket is Affected by TKI and Mutation Afatinib Wildtype L858R Del 19 Gefitinib Erlotinib Kannan S, et al. Sci Rep
50
51 Conclusion Is there perfect evidence that afatinib is the best choice for exon 19 deletion mutant patients? NO Is there a pattern of data that suggest there may be a benefit for afatinib in del19 patients? YES In my practice, I lean toward afatinib for del 19 patients
52 DEBATE 2 Understanding Mechanism of Resistance to Therapy: Tissue vs. Liquid Biopsy? Moderator: Pasi A. Jänne, MD, PhD Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute Boston, MA
53 POINT: Tissue Biopsy is the Gold Standard Mark G. Kris, MD, FACP, FACCP Chief, Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center Professor of Medicine, Cornell University Medical College New York, NY
54 Disclosures Consultant for AstraZeneca Additional Disclosures I was born a medical oncologist but was raised by thoracic surgeons I am a chemotherapy guy who has gone molecular I am a wanna be neurologist
55 Tissue Biopsy the Gold Standard to Detect EGFR Mutations Introduction All patients get a biopsy Targeting EGFR not enough Multiplex NGS testing provides the most comprehensive view Blood-based testing Inherently less sensitive low DNA content Can be slower Right test for some not all
56
57 DNA fragments of bp with half life of ~2 hours Real-time, non-invasive, multilesions Cheaper only because it does not require a biopsy Often very low amount of ctdna in the sea of wild type DNA - Needle in a farm Specific to tumor Diaz Jr LA, Bardella A. J Clin Oncol
58 Other Cytology Specimens Can Also Be Used For NGS FNA Pleural Effusions and other Exfoliative Specimens NGS Cell Free DNA
59 Fine Needle Aspiration Represents a Good Complementary Source of Material for NGS FNA Adequacy Assessment At Least 2 More Passes Cell Block Cell block >1,000 cells/section IMPACT & IHC Cell block 270-1,000 cells/section?impact Cell block <270 cells/section No Impact on cell block Smears (>20,000 cells) Digital Image Smears (<20,000 cells) Use cell pellet IMPACT
60 FACT: Cytology Specimens Have a Lower Failure Rate Than Core Biopsies Resection Cytology Cell Pellet Biopsy Percent failure rate Percent Failure Rate Adapted from Shiau CJ, et al. J Thorac Oncol
61 Evolution of Multiplexed Testing Platforms Now-Gen MSK LC-MAP 8 genes Point mutations only Next-Gen MSK IMPACT 468 genes Point mutations plus deletions, insertions, amplifications Comparable cost
62 MSK-IMPACT Integrated Mutation Profiling of Actionable Cancer Targets DNA from FFPE Tumor and Normal cells Capture DNA for 410 cancer genes* Next-gen Sequencing ( x) Align to genome and analyze *As of February 2017, 468 genes Won HH, et al. J Vis Exp. 2013; Cheng D, et al. J Mol Diagnostics Somatic Mutations (Tumor-Normal Pairs): Base Substitutions Small Indels Copy Number Alterations Select Rearrangements
63 MSK IMPACT Jordan EJ, et al. Cancer Discovery
64 MSK-IMPACT: Determinants of Success Courtesy of Ryma Benayed. Unpublished Data.
65 Gallant JN, et al. Cancer Discov
66 EGFR-KDD Kinase Domains (GLY 696-PRO 1370) Gallant JN, et al. Cancer Discov
67 DNA Sequence Not The Whole Story DNA Sequencing Copy Number Changes Fusion Proteins Epigenome Gene expression profiling Proteome Courtesy of Thomas Lynch, MD.
68 Couzin-Frankel J. Science
69 Reck M, et al. N Engl J Med
70 Tissue Biopsy the Gold Standard to Detect EGFR Mutations Conclusions For the foreseeable future, we have tissue the instant cancer is diagnosed Tissue-based tests the standard of care. No need to validate NGS tissue-based testing platforms more complete, expandable, and less costly Tiny specimens needed, cytology ok Until tissue is unnecessary to diagnose cancer, use it
71 COUNTERPOINT: Liquid Biopsy Should be the New Standard of Care Tony S.K. Mok, BMSc, MD, FRCPC Professor and Chair Department of Clinical Oncology The Chinese University of Hong Kong Hong Kong, China
72 COI Disclosures Grant/Research Support Speaker s Fees Major Stock Shareholder Advisory Board Board of Directors AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, Eisai, Taiho AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho Sanomics Ltd. AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, Bristol- Myers Squibb, genedecode, OncoGenex, Celgene, Ignyta, Cirina International Association for the Study of Lung Cancer (IASLC), Chinese Lung Cancer Research Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Therapy Society (HKCTS)
73 Noun Standard 1. A level of quality or attainment Quality, grade, degree, worth, merit 2. Something used as a measure, norm or model in comparative evaluation
74 Standard of Care of.what? 1. EGFR mutation positive lung cancer 2. ALK re-arrangement positive lung cancer 3. Lung cancer with uncommon mutation 4. Lung cancer without actionable mutations
75 Diagnosis EGFR exon 19/21 Resistance EGFR exon 20 T790M What is positive is truly positive: Specificity What is negative is truly negative: Sensitivity
76 Diagnosis EGFR exon 19/21 Resistance EGFR exon 20 T790M What is positive is truly positive: Specificity What is negative is truly negative: Sensitivity
77 EGFR Mutation Analysis of FASTACT 2 Using Real-time PCR-based Blood Test TISSUE SAMPLES 397 (88%) patients consented 451 (100%) patients consented 268 (59.4%) samples available PLASMA SAMPLES 447 (99.1%) samples available 241 (53.4%) samples analyzable 447 (99.1%) samples analyzable 224 patients with matched tumor and plasma samples Mok T, et al. Clin Cancer Res
78 Concordance Between Tumor and Plasma Samples Total of 238 patients had both tumor and baseline plasma samples with available EGFR mutation analysis results Sensitivity: 75% (72/96) Specificity: 96% (137/142) Positive predictive value: 94% (72/77) Negative predictive value: 85% (137/161) Overall concordance: 88% (209/238) EGFR Activating Mutations t-egfr Mut+ (Tumor) t-egfr Mut- (Tumor) p-egfr Mut+ (Plasma) p-egfr Mut- (Plasma) Total Total Mok T, et al. Clin Cancer Res
79 Plasma and Tumor EGFR Status is Equally Predictive Mok T, et al. Clin Cancer Res
80
81 Meta-analysis on cf DNA for EGFR Mutation 3110 subjects (27 studies) Tissue EGFR mutation status as gold standard Pooled Analysis Sensitivity is technology Sensitivity 62% Specificity 96% Diagnostic odd ratio 0.91 Area under summary ROC 0.91 dependent, High specificity eg implies clinical BEAM applicability vs Sanger for selection of first line EGFR TKI Qiu M, et al. Cancer Epidemiol Biomarkers Prev 2015.
82 Advantage of Liquid Biopsy for EGFR Mutation Non-invasive Fast Relatively economical (saved the cost of invasive procedure) Highly specific and relatively sensitive
83 Diagnosis EGFR exon 19/21 Resistance EGFR exon 20 T790M
84 What is T790M? Threonine (ACG) Methionine (ATG) Arcila ME, et al. Clin Cancer Res
85 Mechanisms of Resistance to TKI Yu H, et al. Clin Cancer Res
86 Clinical Data on Digital PCR
87 IMPRESS (Enrollment period: March 2012 December 2013) Patients Age 18 years ( 20 years in Japan) WHO PS 0-1 Histologically confirmed Stage IIIB / IV EGFR mutation-positive advanced NSCLC Chemotherapy-naïve Achieved CR / PR 4 months or SD >6 months with first-line gefitinib Disease progression (RECIST) a <4 weeks prior to study randomization Cisplatin 75 mg/m 2 + Pemetrexed 500 mg/m 2 ( 6 cycles) + Gefitinib 250 mg Cisplatin 75 mg/m 2 IV + Pemetrexed 500 mg/m 2 IV ( 6 cycles) + Placebo 250 mg Endpoints Primary PFS Secondary OS ORR DCR Safety and tolerability Health-related quality of life c Exploratory Biomarkers (incl. T790M EGFR mutation) at enrollment Soria JC, et al. Lancet Oncol
88 T790M by BEAMing Digital PCR T790M subtype: ctdna detection by BEAMing For patients with plasma samples available for biomarker analysis, there was a slight imbalance between treatment arms with the number of patients with T790M positive- / negative-mutation status Gefitinib, % (n/n) Placebo, % (n/n) Total, % (n/n) a T790M (+) 61.8 (81/131) T790M (-) 35.1 (46/131) 46.9 (61/130) 45.4 (59/130) 54.4 (142/261) 40.2 (105/261) a Includes unknowns T790M ctdna status assessed at baseline BEAMing digital PCR assay conducted at a central laboratory (positivity defined as 0.02% mutant DNA fraction) BEAMing analysis limited only to Exon 19 del, L858R, & T790M did not test for uncommon EGFR sensitizing mutations No matched tissue Diehl 1 et F, al. et 2006al. Nat Methods
89 Plasma cfdna for T790M from AURA 1 Study 402 patients enrolled onto AURA phase I escalation and expansion cohorts 308 patients eligible for this biomarker analysis 94 patients excluded: 60 previously untreated 9 with a known EGFR mutation other than L858R or exon 19 deletion 25 with no known EGFR mutation by tissue or plasma genotyping 71 patients with no central tumour genotyping results 237 patients eligible for analysis of tumour genotype and outcome 37 patients with no central plasma genotyping results 271 patients eligible for analysis of plasma genotype and outcome 216 patients eligible for diagnostic comparison, with both central tumour and plasma genotyping available Oxnard GR, et al. J Clin Oncol
90 Allelic fraction (%) Sensitivity/Specificity of Plasma Genotyping N/D Sensitivity of each assay 82.3% 86.3% 70.2% 19 del n=136 L858R n=73 T790M n= N/D Specificity of each assay 97.5% 96.5% 69.0% 19 del n=80 Sensitivity was 82 86% for sensitising mutations and 70% for T790M False positive rate was 3 4% for sensitising mutations but higher (31%) for T790M, perhaps due to heterogeneous presence of a resistance mutation missed in the reference tumor biopsy Sensitivity for T790M was highly associated with detection of a sensitising mutation in cfdna L858R n=143 T790M n= N/D Sensitivity of T790M assay 80.3% 4.8% plasma sens positive n=137 plasma sens negative n= Data cut-off: 1 May 2015; 19 del, exon 19 deletion; sens positive, detectable TKI-sensitive EGFR mutation; sens negative, no detectable TKI-sensitive EGFR mutation Oxnard GR, et al. J Clin Oncol. 2016
91 Plasma cfdna Positivity in T790M is Predictive of Tumor Response * Tumour T790M positive (n=173) ORR (95% CI): 62% (54, 70) What happen to the plasma+ive/ tumor-ive T790M patients Plasma T790M positive Plasma T790M negative Plasma T790M unknown * Plasma T790M positive (n=164) Tumor +ive T790M: RR 62% Plasma +ive T790M: RR 63% ORR (95% CI): 63% (55, 70) Tumour T790M positive Tumour T790M negative Tumour unknown Data cut-off: 1 May 2015 Oxnard GR, et al. J Clin Oncol
92 Cases T790M negative in tumor and T790M positive in plasma were further studied using orthogonal plasma genotyping assays: ddpcr or real-time PCR Of 18 false positives, 14 could be confirmed using an orthogonal assay Note, no false positives for T790M were seen in 100 NSCLC cases with no known EGFR mutation Oxnard GR, et al. J Clin Oncol Understanding Plasma T790M False Positives Pt Central tumor genotyping for T790M Central plasma BEAMing for T790M T790M allelic fraction (BEAMing) T790M detected with alternative assay Best Alternative Objective plasma Response assay used 1 Not detected Detected 7.051% Yes ddpcr PR 2 Not detected Detected 3.449% Yes ddpcr PD 3 Not detected Detected 2.243% Yes ddpcr PD 4 Not detected Detected 2.036% Yes cobas PR 5PR 8SD 5PD 5 Not detected Detected 1.653% Yes ddpcr PR 6 Not detected Detected 1.113% Yes cobas SD 7 Not detected Detected 0.636% Yes ddpcr SD 8 Not detected Detected 0.588% Yes ddpcr PD 9 Not detected Detected 0.447% Yes cobas SD 10 Not detected Detected 0.344% Yes cobas PD 11 Not detected Detected 0.340% Yes cobas PR 12 Not detected Detected 0.191% No ddpcr SD 13 Not detected Detected 0.124% Yes cobas PD 14 Not detected Detected 0.092% Yes ddpcr SD 15 Not detected Detected 0.091% No ddpcr SD 16 Not detected Detected 0.080% No cobas SD 17 Not detected Detected 0.073% No cobas PR 18 Not detected Detected 0.061% Yes ddpcr SD
93 New Paradigm These data support consideration of a paradigm where plasma genotyping is used as a screening test for T790M, prior to performing an EGFR resistance biopsy Acquired resistance to EGFR-TKI T790M positive Skip biopsy, start third gen. EGFR-TKI FDA approved plasma assay for T790M and sensitising mutations T790M positive Third gen. EGFR-TKI T790M negative Biopsy, FDA approved FFPE assay for T790M T790M negative Chemotherapy Oxnard GR, et al. J Clin Oncol FFPE, formalin-fixed paraffin-embedded
94 Liquid Biopsy Should Be the New Standard of Care Yes for diagnosis EGFR exon 19/21 -Moderate sensitivity -High specificity Yes for resistant EGFR exon 20 T790M -Moderate sensitivity -Moderate specificity (explained by tumor heterogeneity)
95 DEBATE 3 Treating T790M-Mediated Acquired Resistance to 1 st Line EGFR TKIs: Monotherapy vs. Combination Approaches Moderator: Tony S.K. Mok, BMSc, MD, FRCPC Professor and Chair Department of Clinical Oncology The Chinese University of Hong Kong Hong Kong, China
96 POINT: Single Agent Therapy with 3 rd Generation TKIs Suresh S. Ramalingam, MD Professor of Hematology and Medical Oncology Assistant Dean for Cancer Research Emory University School of Medicine Roberto C. Goizueta Chair for Cancer Research Deputy Director, Winship Cancer Institute of Emory University Atlanta, GA
97 Disclosures Ad hoc advisory board meetings AstraZeneca, Ariad, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Genentech, Merck.
98 T790M is the Most Common Mechanism of Resistance to EGFR TKI Yu HA, et al. Clin Cancer Res. 2013; Sequist LV, et al. Sci Transl Med 2011.
99 Osimertinib: AURA Study Phase I, open-label, multicenter study of AZD9291 administered once daily in Asian and Western patients with advanced NSCLC who have documented radiological progression while on prior therapy with an EGFR TKI (AURA; NCT ) Escalation Not preselected by T790M status Cohort 1 20 mg Cohort 2 40 mg Rolling six design Cohort 3 80 mg Cohort mg Cohort mg Expansion Enrollment by local testing followed by central laboratory confirmation* of T790M status or by central laboratory testing alone T790M+ T790M+ T790M+ 1st-line EGFRm+ Biopsy T790M+ T790M- T790M- T790M- 1st-line EGFRm+ Biopsy T790M+ *real-time PCR diagnostic test Tablet Jänne PA, et al. N Engl J Med
100 Best Percentage Change from Baseline in Target-Lesion Size D*D* D D D Osimertinib is a Mutation-specific T790 Inhibitor D DDDD DD D D ORR: 61%; Clinical benefit rate ~ 95%; Median PFS: 9.6 months DD DDD 20 mg 40 mg 80 mg 160 mg 240 mg D D D D D DD D D D D D D D D Jänne PA, et al. N Engl J Med
101 Osimertinib in T790M NSCLC: AURA Phase 2 Study N=201 Patients Yang JC, et al. J Clin Oncol
102 AURA Phase 2: Median PFS Yang JC, et al. J Clin Oncol
103 Osimertinib is Superior to Chemotherapy (AURA 3) Key eligibility criteria > 18 years (> 20 years in Japan) Locally advanced or metastatic NSCLC Evidence of disease progression following first line EGFR-TKI therapy Documented EGFRm and central confirmation of tumor EGFR T790M mutation from a tissue biopsy taken after disease progression on first-line EGFR-TKI treatment WHO performance status of 0 or1 No more than one prior line of treatment for advanced NSCLC No prior neo-adjuvant or adjuvant chemotherapy treatment within months prior to starting first EGFR-TKI treatment Stable* asymptomatic CNS metastases allowed R 2:1 Osimertinib (n=279) 80mg orally daily Platinum-pemetrexed (n=140) Pemetrexed 500 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 Q3W for up to 6 cycles + optional maintenance pemetrexed *RECIST 1.1 assessment performed every 6 weeks until objective disease progression Endpoints Primary: PFS by investigator assessment (RECIST 1.1) Secondary and exploratory: Overall survival Objective response rate Duration of response Disease control rate Tumor shrinkage BICR-assessed PFS Patient reported outcomes Safety and tolerability Optional crossover Protocol amendment allowed patients on chemotherapy to begin post-bicr confirmed progression open-label osimertinib treatment Mok TS, et al. N Engl J Med
104 Progression-free Survival Mok TS, et al. N Engl J Med
105 Tissue vs. Plasma T790M Positivity Wu YL, et al. WCLC Abstract MA08.03.
106 Comparison of Adverse Events Osimertinib (N=279) Platinum-pemetrexed (N=136) Any Grade Grade 3 Any Grade Grade 3 Number (%) Diarrhea 113 (41) 3 (1) 15 (11) 2 (1) Rash 94 (34) 2 (1) 8 (6) 0 Dry Skin 65 (23) 0 6 (4) 0 Paronychia 61 (22) 0 2 (1) 0 Decreased appetite 50 (18) 3 (1) 49 (36) 4 (3) Nausea 45 (16) 2 (1) 67 (49) 5 (4) Fatigue 44 (16) 3 (1) 38 (28) 1 (1) Constipation 39 (14) 0 47 (35) 0 Vomiting 31 (11) 1 (<1) 27 (20) 3 (2) Thrombocytopenia 28 (10) 1 (<1) 27 (20) 10 (7) Anemia 21 (8) 2(1) 41 (30) 16 (12) Neutropenia 22 (8) 4 (1) 31 (23) 16 (12) Interstitial Lung Disease 10 (4) 1 (<1) 1 (1) 1(1) QT prolongation 10 (4) 1 (<1) 1 (1) 0 Mok TS, et al. N Engl J Med
107 New Treatment Paradigm for EGFR Mt+ NSCLC 1 st /2 nd Gen TKI Median PFS 9-13 months Resistance Biopsy Evaluate for SCLC conversion, T790M status 3 rd Gen TKI Median PFS 9-13 months NCCN NSCLC Guidelines Version
108 COUNTERPOINT: Time to Study Combination Approaches Pasi A. Jänne, MD, PhD Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute Boston, MA
109 Disclosures Consultant for: AstraZeneca, Boehringer Ingelheim, Pfizer, Genentech/Roche, Chugai Pharmaceuticals, Merrimack Pharmaceuticals, Ariad, Ignyta, LOXO Oncology, Eli-Lilly Research Support: Astellas, AstraZeneca, Daiichi-Sankyo, PUMA, Eli-Lilly Stockholder in: Gatekeeper Pharmaceuticals Other: LabCorp post-marketing royalties from DFCI owned intellectual property on EGFR mutations
110 The Need for Combination Therapies Diseases where combination therapies have had major therapeutic impact HIV infection, Tuberculosis
111 The Need for Combination Therapies Diseases where combination therapies have had major therapeutic impact HIV infection, Tuberculosis Cancers that can be cured with combination chemotherapy Testicular cancer, Hodgkin s disease, Non-Hodgkin s lymphoma
112 The Need for Combination Therapies Diseases where combination therapies have had major therapeutic impact HIV infection, Tuberculosis Cancers that can be cured with combination chemotherapy Testicular cancer, Hodgkin s disease, Non-Hodgkin s lymphoma Cancers where combination targeted therapies improve survival Breast cancer (Trastuzumab/pertuzumab) & melanoma (BRAF and MEK inhibitors)
113 Successful Combination Therapies Lead to improved outcomes compared to single agent therapy Single agent osimertinib PFS ~ 10 months The added toxicity is tolerable to justify the use of a combination therapy The combination is based on science Strategies to enhance the efficacy of osimertinib
114 Phase II A+T Study: Erlotinib + Bevacizumab in EGFR Mutation Positive NSCLC Study Design Chemotherapy naive Stage IIIB/IV or postoperative recurrent NSCLC Nonsquamous Activating EGFR mutations* Exon 19 deletion Exon 21 L858R Age 20 years PS 0-1 No brain metastasis (N=154) R A N D O M I Z E 1:1 Erlotinib 150 mg/day po + Bevacizumab 15 mg/kg q3w (N=77) Stratification: Sex Smoking status Clinical stage EGFR mutation type Erlotinib 150 mg/day po (N=77) PD PD Primary endpoint: PFS (RECIST v1.1, independent review) Secondary endpoints: OS, tumor response, QOL, safety Correlative research: biomarker assessment *T790M excluded. 2 patients withdrew before treatment. Seto T, et al. Lancet Oncol
115 PFS Probability Erlotinib vs. Erlotinib/Bevacizumab: PFS N Median, Months Erlotinib + Bev Erlotinib Time, Months Number at risk E+B E HR=0.54 (95% CI, ) P=0.0015* *Log-rank test, two-sided. Seto T, et al. Lancet Oncol
116 Efficacy of Nivolumab in Advanced NSCLC Borghaei H, et al. N Engl J Med
117 EGFR Mutant Patients Rarely Benefit from Single Agent Immunotherapy Gainor JF, et al. Clin Cancer Res
118 Incidence of Interstitial Lung Disease is Increased by Combining Osimertinib with Durvalumab Ahn M, et al. Presented at ELCC Abstract 1360.
119 Probability of PFS IMPRESS Continuation Gefitinib vs. Placebo with Chemotherapy Patients at risk: Gefitinib Placebo Gefitinib (n=133) Placebo (n=132) Time of randomisation (months) Gefitinib (n=133) Placebo (n=132) Median PFS, months Number of events, n (%) 98 (73.7) 107 (81.1) HR a (95% CI) = 0.86 (0.65, 1.13); P=0.273 Soria JC, et al. Lancet Oncol
120 Evolution of Resistance Mechanisms in EGFR Mutant Lung Cancer Following Successive EGFR TKI Therapy Erlotinib T790M+ Osimertinib T790M+ plus C797S T790M+ T790M+ plus unknown resistance EGFR activating mutation = EGFR T790M = EGFR C797S = resistance mechanism due to activation of bypass or downstream signaling pathway T790M plus unknown resistance Loss of T790M Oxnard et al. IASLC 2015; Thress et al. Nature Medicine 2015; Planchard et al. Ann Oncol 2015.
121 Ongoing & Planned Combination Studies with Mutant Selective EGFR Inhibitors EGFR Inhibitor Osimertinib EGF816 Combination MEDI4736 INC280 (MET) Savolitinib (MET) Selumetinib Necitumumab Navitoclax MLN0128 Gefitinib JAKi Bevacizumab AXL Inhibitor Nivolumab
122 Efficacy of Osimertinib/Savolitinib in EGFR Mutant Lung Cancer Oxnard GR, et al. Presented at ASCO Poster 225.
123 Phase I Trial of Osimertinib & Selumetinib in EGFR Mutant Lung Cancer Oxnard GR, et al. Presented at ASCO Poster 225.
124 Time to Study Combination Approaches Single agent osimertinib has limited efficacy Combination therapies have led to major clinical improvements in outcome of cancer patients Osimertinib is amenable to combination approaches due to its favorable side effect profile
125 FUTURE DIRECTIONS: TKI Sequencing and Management of CNS Metastases Suresh S. Ramalingam, MD Professor of Hematology and Medical Oncology Assistant Dean for Cancer Research Emory University School of Medicine Roberto C. Goizueta Chair for Cancer Research Deputy Director, Winship Cancer Institute of Emory University Atlanta, GA
126 Osimertinib: CNS Activity AURA Phase 2 N=74 Pts mpfs (with CNS mets) 7.1 months mpfs (without CNS mets) 13.7 months ORR (CNS) 64% Yang JC, et al. J Clin Oncol
127 Expansion Escalation AURA Phase I Dose: First-line Cohorts First-line Cohort Objective Safety and tolerability of osimertinib (80 mg or 160 mg daily orally) as first-line therapy for patients with EGFRm advanced NSCLC Cohort 1 20 mg Cohort 2 40 mg Negative Rolling Six Design Cohort 3 80 mg Negative Tablet Cytology Cohort mg Negative Data cut-off: 4 January 2016 Data from cohorts in grayed out boxes are not included in the analyses reported here Cohort mg Positive Positive Positive Positive Positive First-line EGFRm 80 mg Biopsy First-line EGFRm 160 mg Biopsy T790M cohorts Key Inclusion Criteria: Aged 18 ( 20 in Japan) Locally advanced or metastatic NSCLC No prior therapy for advanced disease Measurable disease at baseline Patients must have EGFR mutation positive NSCLC (local test) Key Exclusion Criteria: Prior history of interstitial lung dx Symptomatic brain metastases Ramalingam S, et al. ELCC Abstract LBA1_PR.
128 Probability of PFS Survival Osimertinib as 1 st Line Therapy for EGFR Mt+ NSCLC Number of pts at risk: 1 st line 80 mg 1 st line 160 mg Month mg N= mg 160 mg N=30 Total N=60 Median PFS, months (95% CI) NC (12.3, NC) 19.3 (11.1, 19.3) 19.3 (13.7, NC) Remaining alive and progression-free, % (95% CI) 12 months 75 (55, 88) 69 (49, 83) 72 (59, 82) 18 months 57 (36, 73) 53 (32, 70) 55 (41, 67) Ramalingam S, et al. ELCC Abstract LBA1_PR. 80 mg
129 FLAURA Study Metastatic NSCLC No Prior Tx EGFR exon 19/21 Mt N=~450 pts Osimertinib Erlotinib/Gefitinib Primary Endpoint: PFS Status: Accrual Complete NCT
130 Optimal Sequencing of TKIs Current Paradigm* New Paradigm? Median PFS 1 st /2 nd Gen TKI Osimertinib Osimertinib Other Tx Considerations: Only 50-60% of patients will develop T790M after first-line therapy* Mechanisms of resistance to first-line osimertinib Osimertinib is better suited for combination regimens *NCCN NSCLC Guidelines Version
131 Adjuvant Therapy for Early Stage NSCLC Optimal adjuvant therapy for EGFRmt patients Chemotherapy vs. EGFR TKI vs. both? Wu, et al. ASCO ALCHEMIST Study (NCT ) Adjuvant chemotherapy followed by TKI ADAURA Study (NCT ) Adjuvant chemotherapy followed by osimertinib vs. placebo NCT , NCT
132 Thank You
133
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