Saturday, June 2, 2018 MODERATOR Lecia V. Sequist, MD, MPH

Sequencing Therapy in EGFR-Mutated NSCLC Consensus, Debates, and Dilemmas
Saturday, June 2, 2018 MODERATOR Lecia V. Sequist, MD, MPH Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts, United States EGFR = epidermal growth factor receptor NSCLC = non-small cell lung cancer

Program Agenda Welcome and Introduction
Lecia V. Sequist, MD, MPH Case 1: The Newly Diagnosed Patient With EGFR-Mutated Disease Suresh S. Ramalingam, MD Case 2: The Patient Who Has Progressed on an EGFR TKI Heather A. Wakelee, MD Looking to the Future With Ongoing Clinical Trials Rolf A. Stahel, MD Immunotherapy in EGFR-Mutation Positive Patients What Does an Updated Treatment Algorithm Look Like? Question and Answer Session Panel TKI = tyrosine kinase inhibitor

Case 1: The Newly- Diagnosed Patient With EGFR-Mutated Disease
Suresh S. Ramalingam, MD Professor of Hematology and Medical Oncology Roberto C. Goizueta Chair Cancer Research Assistant Dean Deputy Director Winship Cancer Institute Emory University School of Medicine Atlanta, Georgia, United States

Patient Case Initial Presentation
Female, 61 years Former smoker, 15-pack year Presented with cough and dyspnea Chest radiograph showed large right pleural effusion Pleural effusion cytology positive for adenocarcinoma Computed tomography scan showed bilateral pulmonary nodules ECOG PS = 1 Transcript - Dr Ramalingam presents a patient case for consideration ECOG = Eastern Cooperative Oncology Group PS = performance status

Which of the following would you recommend?
Polling Question ? Which of the following would you recommend? A. NGS testing plus PD-L1 expression in tumor tissue B. NGS testing in plasma sample (ctDNA) and PD-L1 expression in tumor tissue C. PD-L1 testing only D. Test only for EGFR, ALK, ROS1, BRAF, MET, RET, and PD-L1 Transcript Option D was the most common answer There are wide patterns of molecular testing in the US and abroad NGS testing can give you all molecular information with one test, which may be easier as more biomarkers are identified and more treatment options become available Presentation only No correct answer NGS = next-generation sequencing PD-L1 = programmed death cell-ligand 1 ctDNA = circulating tumor DNA Show results

Lung Cancer: Adenocarcinoma or SCC?
Positive for TTF-1 and Napsin A Recommended testing NGS or EGFR, ALK, ROS1, and BRAF PD-L1 expression SCC Positive for P63 and P40 Molecular testing in never-smokers Transcript Diver mutations are seen in non-squamous/adenocarcinoma lung cancer In squamous cell cancer, it is not known which are driver mutations, co-mutations, or passenger mutations Lung cancers are typically CK7 positive and CK20 negative Molecular testing may be helpful in never smokers with squamous cell histology as they may have a mixed histology tumor TTF-1 = thyroid transcription factor 1 SCC = squamous cell carcinoma

Biomarker Testing Techniques: What Is Common?
Allele-Specific Testing[a] Analyzes DNA for a predefined abnormality Multiplex mutation screening assays EGFR, BRAF, KRAS FISH Used to detect gene translocations, amplifications, and other rearrangements[b] ALK, ROS1[c] IHC Evolving role[d] Definitive method for PD-L1 detection[c] Prescreening method for ALK rearrangements[c] Not currently recommended for other genomic alterations[d] Transcript Allele-specific testing can be used to look for mutation of interest FISH is commonly used for ALK and ROS1 ALK and PD-L1 can be detected with IHC At the very least, a patient with non-squamous, stage 4 NSCLC should be tested for EGFR, ALK, ROS1, BRAF, and PD-L1 FISH = fluorescence in situ hybridization IHC = immunohistochemistry NCCN = National Comprehensive Cancer Network a. Khoo C, Rogers T-M, Fellowes A, Bell A, Fox S. Molecular methods for somatic mutation testing in lung adenocarcinoma: EGFR and beyond. Transl Lung Cancer Res. 2015;4: b. Bishop R. Applications of fluorescence in situ hybridization (FISH) in detecting genetic aberrations of medical significance. Bioscience Horizons: The International Journal of Student Research. 2010;3:85–95. c. National Comprehensive Cancer Network. Non-small cell lung cancer. (Version ). Accessed August 16, 2017. d. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. J Clin Oncol. 2014;32: a. Khoo C, et al. Transl Lung Cancer Res. 2015;4: b. Bishop R. Bioscience Horizons. 2010;3:85-95; c. NCCN Guidelines®; d. Leighl NB, et al. J Clin Oncol. 2014;32:

Emerging Biomarker Testing Techniques
Plasma Genotyping (Liquid Biopsy, Plasma Biopsy) Molecular diagnostics of blood[a] Less invasive[b] Potential to monitor molecular features over the treatment course[b] Currently being used for EGFRm[a] NGS A single test integrating up to hundreds of genes[c] Can detect panels of mutations and gene rearrangements (ie, abnormalities historically tested with FISH)[d] Can identify new abnormalities[c] Primer dependent: what is detected depends on design of the given platform[d] Retains sensitivity even in specimens with low tumor cellularity[c] Gradually replacing traditional single-gene sequencing[c] DILEMMA: Can liquid biopsy be used in the frontline setting? Transcript Tissue testing is still preferred in the front-line setting If tissue is not available, encourage patients to get another biopsy If additional tissue cannot be obtained, then use NGS to test for EGFR Plasma may not be appropriate for ALK and other abnormalities due to differences in sensitivity between assays U.S. Food and Drug Administration. Cobas EGFR Mutation Test v2 – P Accessed August 17, 2017. Huang W-L, Chen Y-L, Yang S-C, et al. Liquid biopsy genotyping in lung cancer: ready for clinical utility? Oncotarget. 2017;8: Magee M, Arnaud A, Bowling M. Costs And Outcomes Comparison Of Tissue And Blood Based Biopsies For The Purpose Of Biomarker Testing For Advanced Non-Small Cell Lung Cancer. Poster presented at: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 21st Annual International Meeting. May 21-25, 2016; Washington DC, USA. Poster PCN57. Lu W, Lu K. Advancements in next-generation sequencing for diagnosis and treatment of non-small-cell lung cancer. Chronic Dis Transl Med. 2017;3:1-7. National Comprehensive Cancer Network. Non-small cell lung cancer. (Version ). Accessed August 16, 2017. a. FDA website. Cobas EGFR Mutation Test; b. Huang W-L, et al. Oncotarget. 2017;8: ; c. Lu W, Lu K. Chronic Dis Transl Med. 2017;3:1-7. d. NCCN Guidelines®.

Lung Adenocarcinoma Molecular Properties and Personalized Therapy
31% unknown oncogenic driver 25% KRAS 17% EGFR sensitizing: Gefitnib, erlotinib, afatinib, osimertinib, necitumumab, rociletinib 7% ALK: Crizotinib, alectinib, ceritinib, lorlatinib, brigatinib 4% EGFR other 3% MET: Crizotinib, cabozantinib > 1 mutation 2% HER2: Trastuzumab emtansine, afatinib, dacomitinib ROS1: Crizotinib, cabozantinib, ceritinib, lorlatinib, DS-6051b BRAF: Dabrafenib RET: Cabozantinib, alectinib, apatinib, vandetanib, pontinib, lenvatinib 1% NTRK1: Entrectinib, LOXO-101, cabozantinib, DS-6051b PIK3CA: LY , PQR 309 < 1% MEK: trametinib, selumetinib, cobemetinib Transcript 50% to 60% of patients harbor a driver mutation There is not currently an effective treatment option for KRAS EGFR exon 20 mutations do not respond well to EGFR TKIs EMA = European Medicines Agency Permissions: Tsao Figure 2 Tsao AS, Scagliotti GV, Bunn PA Jr, et al. Scientific advances in lung cancer J Thorac Oncol. 2016;11: Tsao AS, et al. J Thorac Oncol. 2016;11:

Polling Question ? Molecular testing revealed the presence of EGFR exon 19 mutation and PD-L1 expression of 51%. What is your recommendation? A. Erlotinib B. Osimertinib C. Pembrolizumab D. Pembrolizumab + chemotherapy Transcript This question refers back to the patient presented at the beginning of this section Voting was split with approximately 2/3 selecting osimertinib and 1/3 selecting erlotinib Presentation only No correct answer Show results

First-Generation TKIs vs Chemotherapy Gefitinib and Erlotinib
IPASS: phase 3, open- label, never/former smokers[a] EURTAC: phase 3, open- label, first non-Asian cohort[b] Figure No Longer Available Figure No Longer Available Transcript There are 3 generations of EGFR TKIs; first generation TKIs are erlotinib and gefitinib IPASS investigated gefitinib whereas EURTAC investigated erlotinib These studies led to the adoption of EGFR TKIs as standard front-line therapy TKI = tyrosine kinase inhibitor Medscape permissions: left figure: Mok, figure 2B; right figure: Rosell Fig 2A a. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxes in pulmonary adenocarcinoma. N Engl J Med. 2009;361: b. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advnanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicenter, open-label, randomized phase 3 trial. Lancet Oncol. 2012;13: From N Engl J Med., Mok TS, et al., Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma, 361, , Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Reprinted from Lancet Oncol., 13, Rosell R, et al., Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial, , Copyright 2016, with permission from Elsevier. a. Mok TS, et al. N Engl J Med. 2009;361: b. Rosell R, et al. Lancet Oncol. 2012;13:

Second-Generation TKIs Afatinib vs Gefitinib
LUX-Lung 7: phase 2B open-label study Afatinib: irreversible EGFR inhibitor Gefitinib: reversible EGFR inhibitor Afatinib vs gefitinib demonstrated: Similar mPFS (11 vs 10.9 months) Longer 24-month PFS (17.6% vs 7.6%) Longer time to treatment failure (median 13.7 vs 11.5 months; HR = 0.73 [95% CI: 0.58, 0.92], P = .0073) Increased rate of skin and GI toxicities PFS Figure No Longer Available Transcript Second generation TKIs, afatinib and dacomitinib, bind EGFR irreversibly A modest improvement in PFS and a modest increase in adverse events were the main findings in this trial HR = hazard ratio CI = confidence interval Medscape permissions: Park Fig 2A Park K, Tan E, O'Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomized controlled trial. Lancet Oncol. 2016;17: Reprinted from Lancet Oncol., 17, Park K, et al., Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial, , Copyright 2018, with permission from Elsevier. Park K, et al. Lancet Oncol. 2016;17:

Second-Generation TKIs Dacomitinib vs Gefitinib
ARCHER 1050: randomized, open-label, phase 3 trial Dacomitinib 45 mg daily Gefitinib 250 mg daily Endpoints Primary: PFS (blinded independent review) Secondary: PFS (investigator-assessed), ORR, DoR, TTF, OS, safety, PROs Outcomes in the ITT Population Dacomitinib (n = 227) Gefitinib (n = 225) No. of events, n (%)[a] 136 (59.9) 179 (79.6) mPFS, mo (95% CI)[a] 14.7 (11.1, 16.6) 9.2 (9.1, 11.0) PFS HR (95% CI)[a] 0.59 (0.47, 0.74) P < .0001 PFS rate, %[a] 30.6 9.6 OS, HR (95% CI)[b] 0.76 (0.582, 0.993) P = .0438 Transcript This trial excluded patients with brain metastases Updated survival results from this trial were presented at ASCO ITT = intent to treat mPFS = median progression-free survival ORR = overall response rate DoR = duration of response TTF = time to treatment failure OS = overall survival PRO = patient-reported outcome a. Wu YL, et al. Lancet Oncol. 2017;18: ; b. Mok T, et al. ASCO® Abstract 9004.

FLAURA Study Design Endpoints
Patients with locally advanced or metastatic NSCLC Key Inclusion Criteria ≥ 18 years WHO PS 0/1 Exon 19 deletion/L858R (enrollment by local or central EGFR testing) No prior systemic anticancer/EGFR TKI therapy Stable CNS metastases allowed Stratification by mutation status (exon 19 deletion/L858R) and race (Asian/ non-Asian) Osimertinib 80 mg PO once daily (n = 279) EGFR TKI SoC Gefitinib: 250 mg PO once daily or Erlotinib: 150 mg PO once daily (n = 277) RECIST 1.1 assessment every 6 weeks until objective PD R 1:1 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 an improvement in median PFS from 10 months to 14.1 months) at a 2-sided α level of 5% Secondary endpoints: ORR, DoR, DCR, depth of response, OS, safety Transcript FLAURA was a head-to-head trial of osimertinib vs gefitinib or erlotinib The study allowed for crossover of patients from the control group to the osimertinib group upon progression and T790M mutation PO = orally CNS = central nervous system ORR = objective response rate DoR = duration of response DCR = disease control rate OS = overall survival Soria JC, et al. N Engl J Med. 2018;378:

Third-Generation TKI Osimertinib
Figure No Longer Available Figure No Longer Available Transcript There was a 54% reduction in the risk of progression for patients who received osimertinib Survival data were 20% mature at the time of analysis but are encouraging despite the fact that patients were allowed to crossover NC = not calculable From N Engl J Med., Soria JC, et al., Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer, 378, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Soria JC, et al. N Engl J Med. 2018;378:

CNS Efficacy With Osimertinib
Figure No Longer Available Figure No Longer Available Transcript The HR was identical for both patients with and without CNE metastases, suggesting that osimertinib has activity in the brain Only 6% of patients who received osimertinib had progression in the brain Figure 1 B and C From N Engl J Med., Soria JC, et al., Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer, 378, Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Soria JC, et al. N Engl J Med. 2018;378:

Patient Case Occurrence of AEs
The patient was started on treatment with osimertinib 80 mg daily She tolerated the treatment well The main AE was grade 1 skin rash Transcript - This is a continuation of the patient presented at the beginning of this segment AE = adverse event

Summary of AEs With First- and Second- Generation TKIs
Gefitinib[a] Rash or acne 66.2% of 607 patients vs 22.4% of 589 patients receiving chemo Diarrhea 46.6% vs 21.7% Dry skin 23.9% vs 2.9% Stomatitis 17% vs 8.7% Paronychia 13.5% vs 0% Erlotinib[b] Rash Grade 1-2: 67% of 84 patients vs 5% of 82 patients receiving chemo Grade 3: 13% vs 0% Grade 1-2: 52% vs 18% Grade 3: 5% vs 0% Afatinib[c] Grade 1-2: 79% of 160 patients vs 78% of 159 patients receiving gefitinib Grade 3: 9% vs 3% Grade 1-2: 78% vs 60% Grade 3: 12% vs 1% Grade 1-2: 33% vs 37% Grade 1-2: 60% vs 24% Grade 3: 4% vs 0% Grade 1-2: 54% vs 16% Grade 3: 2% vs 1% Increased ALT/AST Grade 1-2: 10% vs 16% Grade 3: 0% vs 8% Dacomitinib[d] Grade 1-2: 13% of 227 patients vs 11% of 224 patients receiving gefitinib Grade 1-2: 78% vs 55% Grade 3: 8% vs 1% Grade 1-2: 26% vs 17% Grade 3: 1% vs 0% Grade 1-2: 40% vs 17% Grade 3: 4% vs < 1% Paroncyhia Grade 1-2: 54% vs 19% Grade 3: 7% vs 1% ALT increased Grade 1-2: 19% vs 31% Grade 3: 1% vs 8% AST increased Grade 1-2: 19% vs 32% Grade 3: 0% vs 4% Transcript Skin and GI toxicities are the most common among first-generation TKIs Second generation TKIs commonly have rash, diarrhea, stomatitis, paronychia, and liver enzyme elevation Grade 3-4 events often require dose reduction ALT = alanine aminotransferase AST = aspartate aminotransferase a. Mok TS, et al. N Engl J Med. 2009;361: ; b. Rosell R, et al. Lancet Oncol. 2012;13: ; c. Park K, et al. Lancet Oncol. 2016;17: ; d. Wu L, et al. Lancet Oncol. 2017;18:

AEs With Third-Generation EGFR TKIs
Osimertinib (n = 279) Standard EGFR TKI (n = 277) AE, % Grade 1 Grade 2 Grade 3 Grade 4 Rash or acne 48 9 1 40 31 7 Diarrhea 43 13 2 42 Dry skin 4 < 1 27 8 Stomatitis 23 5 17 3 Paronychia 19 16 20 12 ALT elevation 11 AST elevation 6 14 Transcript Tolerability from the FLAURA trial was favorable with less frequent skin toxicities and liver enzyme elevation The overall treatment discontinuation due to toxicity was also lower with osimertinib compared with standard of care Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: ESMO 2017 Congress; September 9, 2017; Madrid, Spain. Abstract LBA2_PR. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SoC, standard-of-care Soria JC, et al. N Engl J Med. 2018;378:

Consensus: Strategies for Managing AEs
Patient education regarding common AEs Prompt initiation of antidiarrheal therapy Skin toxicity management with topical and systemic therapies Dose reduction in patients with severe toxicity Transcript Events usually occur in the first few weeks to 3-4 months of therapy Doxycycline and clindamycin can be used to manage skin toxicity

Erlotinib Plus Bevacizumab From ASCO® 2018
JO25567 Updates[a] 35 patients received combination vs 40 who received erlotinib alone mOS was 47 months vs months HR = 0.81 (0.53, 1.23), P = .3267 5-year survival was 41% vs 35% OS did not differ based on patient characteristics NEJ026[b] 112 patients received combination vs 114 who received erlotinib alone mPFS was 16.9 months vs months HR = (0.417, 0.877) Increase in hemorrhage, proteinuria, and hypertension with combination Transcript These abstracts were scheduled to be presented during the Monday lung session at ASCO The underlying mechanism of synergy for EGFR TKI plus VGF TKI is not known, but multiple studies now show similar results There are ongoing studies combining osimertinib and bevacizumab in the front-line setting ASCO® = American Society of Clinical Oncology a. Yamamoto N, et al. ASCO® Abstract 9007; b. Furuya N, et al. ASCO® Abstract 9006.

Summary EGFR TKI is recommended first-line therapy for patients with exon 19 or 21 EGFRm Osimertinib has demonstrated superiority over erlotinib/gefitinib with substantial improvement in PFS Favorable tolerability profile Novel combination approaches based on osimertinib are already under development Immunotherapy is not recommended frontline therapy even in patients with high PD-L1 expression Transcript Remaining questions include: What can we do to improve efficacy beyond this point? How do patients develop resistance to osimertinib in the front-line setting? What is the role of immunotherapy in this setting?

Case 2: The Patient Who Has Progressed on an EGFR TKI
Heather A. Wakelee, MD Professor of Medicine, Oncology Stanford University Faculty Director Cancer Clinical Trials Office Stanford Cancer Institute Stanford, California, United States

Patient Case MT is a 71-year-old healthy white woman with hyperlipidemia She developed chest/rib pain while doing home repairs Radiography revealed rib fractures and a density in the right lung Computed tomography scan confirmed right apical mass, multiple bony abnormalities consistent with metastases, and mediastinal adenopathy EBUS biopsy of station 4R LN showed lung adenocarcinoma with EGFR del19 mutation PET scan confirmed right apical lung mass, extensive adenopathy, multiple bone metastases, hepatic metastases MRI revealed 3 brain metastases In July 2017, she started erlotinib at 150 mg daily after completing stereotactic radiation to the 3 brain metastases Transcript - Dr Wakelee presents a patient case for consideration EBUS = endobronchial ultrasound bronchoscopy LN = lymph node PET = positron emission tomography MRI = magnetic resonance imaging

Patient Case (cont) From July 2017 through February 2018, the patient felt well with a PR to erlotinib and no new symptoms In February 2018, progression was noted in the liver metastases Plasma testing for T790M is negative with no mutations detected including no EGFR mutation detected (del19 or T790M) PR = partial response What Do You Do Now? Perform liver biopsy Start carboplatin/pemetrexed Start osimertinib

Treatment-Naive EGFRm Patients EGFR TKIs vs Chemotherapy
Study Treatment N mPFS, mo Median OS, mo Maemondo[a] Gefitinib vs carboplatin/paclitaxel 230 10.8 vs 5.4 (P < .001) 30.5 vs 23.6 (P = .31) Mitsudomi[b] cisplatin/docetaxel 177 9.2 vs 6.3 (P < .0001) 30.9 vs NR (HR = 1.638) OPTIMAL[c] Erlotinib vs carboplatin/gemcitabine 165 13.1 vs 4.6 Immature at time of publication EURTAC[d] platinum-based chemotherapy 174 9.7 vs 5.2 19.3 vs 19.5 (P = .87) LUX-Lung 3[e,f] Afatinib vs cisplatin/pemetrexed 345 11.1 vs 6.9 (P = .001) 28.2 vs 28.2 HR = 0.88 (P = .39) LUX-Lung 6[f,g,h] cisplatin/gemcitabine 364 11.0 vs 5.6 23.1 vs 23.5 HR = 0.93 (P = .61) Transcript - Most front-line trials report PFS of under a year due to the development of resistance a. Maemondo M, et al. N Engl J Med. 2010;362: ; b. Mitsudomi T, et al. Lancet Oncol. 2010;11: ; c. Zhou C, et al. Lancet Oncol. 2011;12: ; d. Rosell R, et al. Lancet Oncol. 2012;13: ; e. Sequist LV, et al. J Clin Oncol. 2013; 31: ; f. Yang JC-H, et al. ASCO® Abstract 8004; g. Wu YL, et al. Lancet Oncol. 2014;15: ; h. Yang JC-H, et al. Lancet Oncol. 2015;16:

Resistance Despite impressive results in first-line trials, resistance almost always develops Strategies using the addition of drugs to delay resistance are being looked at Promise with chemotherapy or bevacizumab, but limited with other agents Strategies to overcome resistance once it has developed are also being explored Exciting data with afatinib/cetuximab, third-generation EGFR TKIs We are starting to understand resistance to third-generation EGFR TKIs The erlotinib-bevacizumab strategy is one of the few with some success Additional data will be presented during ASCO® 2018 Transcript There are multiple strategies, some in development, to address resistance The Monday lung session at ASCO included two presentations on erlotinib combined with bevacizumab

Phase 3: Erlotinib With or Without Ramucirumab Trial
Arm 1 Erlotinib + placebo EGFR-mutated NSCLC (n = 462) Arm 2 Erlotinib + ramucirumab 10 mg/kg every 2 weeks Treatment continued until disease progression Transcript - Ramucirumab is another VGF inhibitor - No data has been reported from this trial Primary endpoint: PFS ClinicalTrials.gov. NCT

Consensus: Need for Repeat Testing Mechanisms of Resistance After First-/Second-Generation TKIs
Transcript - These data are why you cannot assume that resistance is due to T790M Yu HA, et al. Clin Cancer Res. 2013;19:

Targeted Therapy for Resistance Mechanisms
MET inhibitor trials[a] Small cell transformation -- platinum/etoposide[b-d] BRAF, RET, HER2 -- TKIs exist but unclear if efficacy in this setting[e-g] Ongoing inhibitor trials Eg, IGF1R, FGFR, PI3K/AKT, mTORC1, RAF/MEK, CRKL, CK1α, Src, BIM (HDAC) Transcript - Targeted therapy for resistance mechanisms is only available in the setting of clinical trials Cheng N, Cai W, Ren S, Li X, Wang Q, Pan H, Zhao M, Li J, Zhang Y, Zhao C, Chen X, Fei K, Zhou C, Hirsch FR. Long non-coding RNA UCA1 induces non-T790M acquired ressitance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer. Oncotarget. 2015;6: Lantermann AB, Chen D, McCutcheon K, Hoffman G, Frias E, Ruddy D, Rakiec D, Korn J, McAllister G, Stegmeier F, Meyer MJ, Sharma SV. Inhibition of casein kinase 1 alpha prevents acquired drug resistance to erlotinib in EGFR-mutant non-small cell lung cancer. Cancer Res. 2015;75: Suda K, Mizuuchi H, Murakami I, et al. CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation. Lung Cancer. 2014;85: a. Ahn M, et al. WCLC Abstract 09.03; b. Furugen M, et al. Intern Med. 2015;54: c. Hashida S, et al. Cancer Sci. 2015;106: ; d. Suda K, et al. Sci Rep. 2015;5:14447; e. Baik CS, et al. Oncologist. 2017;22: ; f. Tsuta K, et al. Br J Cancer. 2014;110: ; g. Garrido-Castro AC, Felip E. Transl Lung Cancer Res. 2013;2:

Strategies to Overcome Resistance After First- or Second-Generation EGFR TKI
Chemotherapy EGFR antibodies Third-generation EGFR TKIs Transcript - This segment will review options beyond starting osimertinib

2 Trials to Compare Ongoing EGFR TKI Therapy for Acquired Resistance
Cisplatin/pemetrexed Activating EGFR TKI[a] No prior chemotherapy R Cisplatin/pemetrexed + ongoing gefitinib Primary endpoint: progression-free survival PI: Leora Horn (Vanderbilt)2 Cisplatin/carboplatin + pemetrexed + ongoing erlotinib Advanced NSCLC[b] Activating EGFR TKI No prior chemotherapy PS 0/1 R Transcript - These two trials were designed to determine if you should continue an EGFR TKI after progression or switch to chemotherapy ClinicalTrials.gov. A study of IRESSA treatment beyond progression in addition to chemotherapy versus chemotherapy alone (IMPRESS). NCT Accessed August 28, 2017. ClinicalTrials.gov. Pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride in treatment patient with stage IV non-small cell lung cancer resistant to first-line therapy with erlotinib hydrochloride or gefitinib. NCT Accessed August 28, 2017. Cisplatin/carboplatin + pemetrexed Primary endpoint: progression-free survival Erlotinib retreatment a. ClinicalTrials.gov. NCT b. ClinicalTrials.gov. NCT

IMPRESS 2016: Final OS (66% Maturity)
PFS (primary endpoint)[a] Final OS (66% maturity)[b] Figure No Longer Available Figure No Longer Available Transcript - These data indicate that a patient who progresses on an EGFR TKI should be switched to chemotherapy; there are a very small number of patients who are exceptions to this a. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16: b.Soria J, Kim S, Wu Y, et al. Gefitinib/chemotherapy vs chemotherapy in EGFR mutation-positive NSCLC after progression on 1st line gefitinib (IMPRESS study): Final overall survival (OS) analysis. Ann Oncol. 2016;27. Abstract 1201O. T790M positive: HR[b] (95% CI) = 1.49 (1.02, 2.21) T790M negative: HR[b] (95% CI) = 1.15 (0.68, 1.94) Reprinted from Lancet Oncol., 16, Soria JC, et al., Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial, , Copyright 2015, with permission from Elsevier. Soria J, et al. Ann Oncol. 2016;27. Abstract 1201O. By permission of Oxford University Press. a. Soria JC, et al. Lancet Oncol. 2015;16: ; b. Soria J, et al. ESMO Abstract 1201O.

Sequencing TKIs Afatinib after erlotinib[a]
LUX-Lung 4 was a nonrandomized phase 2 trial of afatinib (50 mg) after erlotinib or gefitinib RR = 8.2% mPFS = 4.4 months Afatinib/cetuximab after erlotinib or gefitinib[b] Phase 1B, open-label, multicenter study of dual EGFR inhibition Tumor response as measured by ORR 32% in T790M-positive 25% in T790M-negative mPFS of ≤ 5 months Transcript Switching to afatinib after erlotinib was not successful Afatinib plus cetuximab had a relatively short PFS with a cost of toxicity RR = response rate Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31: a. Katakami N, et al. J Clin Oncol. 2013;31: ; b. Janjigian YY, et al. Cancer Discov. 2014;4:

Afatinib + Cetuximab Toxicity
AE, % Select Drug-Related AEs All Grade Toxicity Grade 3/4 Any drug-related AEs 99 46 Rash 90 20 Diarrhea 71 6 Transcript - You have to be mindful of increased toxicity, particularly in the skin, when you add an EGFR TKI to an EGFR antibody - Management of rash requires working with a dermatologist Janjigian YY, Smit EF, Groen JH, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4: Janjigian YY, et al. Cancer Discov. 2014;4:

AURA3 Endpoints Primary Secondary Exploratory
Osimertinib 80 mg daily (n = 279) Endpoints Primary Investigator-assessed PFS Secondary RR OS QoL Exploratory Biomarkers Patients Chemotherapy naive Activating EGFRm Centrally confirmed T790M PD on first- and second-generation EGFR TKI Platinum/pemetrexed (n = 140) EGFRm = EGFR mutation Transcript - In contrast to the study design for FLAURA, osimertinib was compared with chemotherapy in the AURA3 trial Mok TS, et al. N Engl J Med. 2017;376: 36 36 36

AURA3: Post First-Generation EGFR TKI Osimertinib vs Chemotherapy
Characteristic Osimertinib (n = 279) Platinum-Pemetrexed (n = 140) Median age (range), y 62 (25-85) 63 (20-90) Race, n (%) White Asian 89 (32) 182 (65) 45 (32) 92 (66) No history of smoking, n (%) 189 (68) 94 (67) Disease classification, n (%) Adenocarcinoma histology NOS Metastatic disease Extrathoracic visceral metastases 232 (83) 266 (95) 145 (52) 122 (87) 138 (99) 80 (57) Type of EGFRm, n (%) Exon 19 del Exon 21 L858R 191 (68) 83 (30) 87 (62) Transcript Patients in AURA3 were well balanced between the osimertinib and chemotherapy arms Patients were predominantly Asian as the trial was performed in Asia NOS = not otherwise specified Mok TS, et al. N Engl J Med. 2017;376:

Osimertinib in T790M-Positive TKI- Resistant Disease
Outcome Osimertinib (n = 279) Platinum-Pemetrexed (n = 140) Statistics mPFS, mo (95% CI) 10.1 (8.3, 12.3) 4.4 (4.2, 5.6) HR = 0.30 (0.23, 0.41) P < .001 ORR, % 71 31 OR = 5.39 (3.47, 8.48) Grade ≥ 3 AEs, % 23 47 Transcript - These are key data from the AURA3 trial OR = odds ratio Permission: Fig 1A Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Padimitrakopoulou VA, AURA3 investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376: All subsets benefited with osimertinib compared with chemotherapy Mok TS, et al. N Engl J Med. 2017;376:

Second-Line Osimertinib Toxicity
AE, % Osimertinib (n = 279) Platinum-Pemetrexed (n = 136) Any Grade Grade ≥ 3 Rash 34 1 6 Diarrhea 41 11 Dry skin 23 4 Stomatitis 15 Paronychia 22 AST elevation 5 ALT elevation Transcript - Similar to what was seen with FLAURA, toxicity is favorable with low grade rash and diarrhea in addition to other toxicities Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Padimitrakopoulou VA, AURA3 investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376: Mok TS, et al. N Engl J Med. 2017;376:

Second-Line Osimertinib: PFS in Patients With Brain Metastases
Figure No Longer Available Transcript - The results here are similar to what was seen in the FLAURA trial Medscape permissions: Fig 1b Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Padimitrakopoulou VA, AURA3 investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376: From N Engl J Med., Mok TS, et al., Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer, 376, Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. CNS ORR was 70% of 30 patients with osimertinib vs 31% of 16 patients with chemotherapy OR = 5.13 (1.44, 20.64); P = .015 a. Mok TS, et al. N Engl J Med. 2017;376: ; b. Mok T, et al. ASCO® Abstract 9005.

Even with multiple tests, we can miss some T790M mutations
Plasma, Tissue, and Urine Identify Unique and Overlapping Subsets of T790M-Positive Patients 177 samples had matched pretreatment T790M results in plasma, tissue, and urine 7 (4%) were T790M negative or inadequate by all 3 sample types 170 (96%) were T790M positive by at least 1 sample type 141 (79.7%) positive by urine 141 (79.7%) positive by plasma 146 (82.5%) positive by tissue 162 (91.5%) positive by plasma or urine 165 (93.2%) positive by tissue or plasma 167 (94.4%) positive by tissue or urine Transcript Urine testing is not readily used or available In general there is overlap between plasma and tissue, but there are patients who are only positive with one or the other If plasma is negative, it is worth considering a biopsy Medscape: reference may be updated in time for enduring Wakelee HA, Gadgeel SM, Goldman JW, et al. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol. 2016;34: Even with multiple tests, we can miss some T790M mutations Goldman JW, et al. JCO Precision Oncol [Epub ahead of print]

Dilemma: Tissue or Liquid Biopsy
ctDNA Assay Logistics Easy to draw Variable venipuncture risks Easy serial testing Biology Cannot directly correlate ctDNA results with histology or cellular phenotype More likely to represent whole tumor, but differential tumor cell turnover may bias representation Pre-analytical Easier to standardize across sites Requires special processing and handling unless using cell-stabilization tubes Limited data on confounding patient-related factors Clinical utility Limited evidence for treatment selection in advanced cancer No evidence for other potential indications Tissue Assay Invasive, more challenging to obtain Variable biopsy risks Serial testing more difficult Can correlate with histology and cellular phenotype Represents one small tumor region More difficult to standardize across sites Uses existing, validated tissue processing and handling approaches Substantial evidence for treatment selection in multiple malignancies for early and advanced cancers Transcript - This tables summarizes pros and cons of blood vs tissue testing Table 3 Merker JD, et al. J Clin Oncol [Epub ahead of print].

Best Treatment Options for T790M- Negative Disease
Options include[a-e] Platinum/pemetrexed/(bevacizumab) Carboplatin/paclitaxel/bevacizumab/(atezolizumab) Afatinib/cetuximab -- response rates ≈25% Osimertinib -- response rate ≈20% Target any targetable resistance mechanisms -- but there are limited data Transcript Platinum-pemetrexed is commonly used in the United States and can be used in combinationwith bevacizumab IMpower150 data is providing insight to combining atezolizumab with carboplatin/paclitaxel/bevacizumab Osimertinib can be used in the T790M-negative setting; however, PFS tends to be short Other resistance mechanisms would be treated within a clinical trial a. National Comprehensive Cancer Network. Non-small cell lung cancer. (Version ). Accessed August 16, 2017. b. Otsuka K, Hata A, Takeshita J, et al. EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer. Cancer Chemother Pharmacol. 2015;76: c. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31: d. Janjigian YY, Smit EF, Groen JH, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4: e. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18): More research is needed in this area. Do not forget local therapy for oligometastatic disease. a. NCCN Guidelines®. b. Otsuka K, et al. Cancer Chemother Pharmacol. 2015;76: c. Katakami N, et al. J Clin Oncol. 2013;31: ; d. Janjigian YY, et al. Cancer Discov. 2014;4: e. Jänne PA, et al. N Engl J Med. 2015;372:

T790M Changes Over Time With Third- Generation EGFR TKIs
Transcript - These data show that patients who had T790M may lose it as resistance develops Figure 1 Chabon JJ, et al. Nat Commun. 2016;7:11815. Reprinted by permission from Springer Nature. Nat Commun. 2016;7: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients, Chabon JJ, et al., Copyright 2016.

Interpatient/Intrapatient Heterogeneity of Resistance to Third-Generation EGFR TKIs
Transcript - Clones that arose had non-T790M mutations such as MET or HER2 amplification, KRAS mutation, or SCLC transformation Figure 2 Chabon JJ, et al. Nat Commun. 2016;7:11815. Reprinted by permission from Springer Nature. Nat Commun. 2016;7: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients, Chabon JJ, et al., Copyright 2016.

C797S as a Resistance Mechanism to Osimertinib
Transcript C797S can develop after third generation TKI treatment If C797S occurs with T790M, treatment can be challenging If C797S occurs without T790M, there is some activity with first and second generation TKIs Slide 6 MET or EGFR amplification and BRAF mutations can also occur as C797S coevents Piotrowska Z, et al. WCLC Abstract OA

Consensus: Need for Repeat Testing Mechanisms of Resistance After Osimertinib
Tissue Biopsy Results, n = 23[a] 34% T790M loss (unknown acquired resistance) 29% MET amplification 21% T790M/C797S 8% other 4% SCLC transformation 4% T790M loss (EGFR amplification) Plasma Biopsy Results, n = 67[b] 46% T790M "loss" 27% C797S 1 case of HER2 amplification 1 case of PIK3CA mutation 1 case of BRAF mutation Transcript These data are after osimertinib treatment The resistance patterns from FLAURA are not known yet SCC = squamous cell carcinoma AR = acquired resistance Piotrowska Z, Thress KS, Mooradian M, et al. MET amplification (amp) as a resistance mechanism to osimertinib. J Clin Oncol. 2017;35: Oxnard GR, Thress K, Paweletz C, et al. Mechanisms of acquired resistance to ACZ9291 in EGFR T790M positive lung cancer. Presented at: 16th World Conference on Lung Cancer; September 8, 2015; Denver, Colorado. Abstract OA a. Piotrowska Z, et al. ASCO® Abstract b. Oxnard GR, et al. WCLC Abstract ORAL17.07.

Resistance to First-Line Osimertinib
Resistance Mechanism n EGFR C797S 2 JAK2 V617F 1 PIK3CA E545K HER2 ex20 Ins MEK1 G128V KRAS G12D MET CNV KRAS CNV Other Mutations Identified Postdose P53 7 RB1 4 Patients treated with osimertinib n = 60 Patients with RECIST PD n = 42 Patients with postdose plasma sample n = 38 Patients with detectable ctDNA n = 19 Patients without detectable ctDNA Transcript - These data are from ctDNA TTP = time to progression Mean TTP No detectable ctDNA: months Detectable ctDNA: months Ramalingam SS, et al. J Clin Oncol. 2017;39:

Trial Designs Based on Resistance Mechanisms
MET amplification = osimertinib + MET inhibitor Proof of concept seen already[a-c] C797S[d-f] Though often seen to date with T790M, will likely emerge as solo mutation after first-line AURA first-line cohort: 2 cases thus far with C797S alone C797S (+ activating mutation) may be susceptible to first- generation EGFR TKI Fourth-generation TKIs are in early development Other combinations such as brigatinib + cetuximab are also being studied Other combinations Transcript MET inhibitor trials have not all been successful, but we have seen proof of concept in some settings C797S has been challenging Piotrowska Z, Thress KS, Mooradian M, et al. MET amplification (amp) as a resistance mechanism to osimertinib. J Clin Oncol. 2017;35: York ER, Varella-Garcia M, Bang TJ, et al. Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplication sequentially emerging after T790M positivity in EGFR-mutant non-small cell lung cancer. J Thorac Oncol. 2017;12:e85-e88. Ahn MJ, Han JY, Sequist LV, et al. TATTON Ph1b expansion cohort: osimertinib plus savolitinib for pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. WCLC Presented at: 18th World Conference on Lung Cancer (WCLC); October 14-18, 2017; Yokohama, Japan. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol [Epub ahead of print] Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensivity to subsequent treatment strategies. Clin Can Res. 2015;21: Uchibori K, Inase N, Araki M, et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutatednon-small-cell lung cancer. Nat Commun. 2017;8:14768. a. Piotrowska Z, et al. J Clin Oncol. 2017;35:9020; b. York ER, et al. J Thorac Oncol. 2017;12:e85-e88; c. Ahn MJ, et al. WCLC Abstract 09.03; d. Ramalingam SS, et al. J Clin Oncol. 2017;39: ; e. Niederst MJ, et al. Clin Can Res. 2015;21: ; f. Uchibori K, et al. Nat Commun. 2017;8:14768.

Presentations of Interest From ASCO® 2018
Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. Furuya et al. Abstract 9006 Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive non- squamous non-small-cell lung cancer (NSCLC): survival follow-up results of JO Yamamoto et al. Abstract 9007 Landscape of osimertinib resistant mutations between the two common subtypes of EGFR 19del or L858R in NSCLC. Zhang, et al. Abstract 12108 Acquired BRAF fusions as a mechanism of resistance to EGFR therapy. Vojnic et al. Abstract 12122 Transcript - There were 2 trials of bevacizumab plus erlotinib as well as a presentation on osimertinib resistance mutations and acquired BRAF fusions during the Monday lung session at ASCO

Looking to the Future With Ongoing Clinical Trials
Rolf A. Stahel, MD Chair Cancer Center Zurich Head Thoracic Oncology Center University Hospital Zurich Zurich, Switzerland

Section Overview Experimental approaches in first line
Experimental approaches in acquired resistance T790M-positive T790M-negative Independent of T790M Transcript - The hope is that clinical trials will lead to stepwise improvement of outcomes

Improving Results in EGFR-Mutated NSCLC: Upfront Targeted Combinations With First-Generation EGFR TKIs -- VEGF Target Phase Primary Endpoint Secondary Endpoint Sample Size Identifier Study comparing bevacizumab + erlotinib vs erlotinib alone as first-line treatment of patients with EGFR-mutated advanced non squamous NSCLC (BEVERLY) (NCI Naples) VEGF 3 PFS OS 200 NCT [a] A study of tarceva vs avastin + tarceva for advanced NSCLC with EGFR m(+) (AvaTa) (Roche Korea) R2 RR 128 NCT [b] Erlotinib hydrochloride with or without bevacizumab in treating patients with stage IV NSCLC with epidermal growth factor receptor mutations (NCI) cDNA 112 NCT [c] Gefitinib combined with chemotherapy or antiangiogensis in patients with Bim deletion or low EGFR mutation abundance (Shanghai Pulm) 180 NCT [d] VEGF = vascular endothelial growth factor Transcript These trials are looking at the combination of anti-angiogenesis, bevacizumab, with a TKI One trial of particular interest is from Shanghai in a subset of patients who have a BIM1 deletion known to be associated with shorter PFS on EGFR TKIs a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT ; d. ClinicalTrials.gov. NCT

Most Frequent Co-Mutations in EGFR- Mutated NSCLC
Most frequent comutation in treatment-naive tumors: TP53 (60)% PIK3CA (12%) RB1 (10%) Potential targetable amplifications: HER2 (4%) MET (2%) Transcript - These targets might also be present with activating EGFR mutations Yu H, et al. Clin Can Res [Epub ahead of print]

INC280 and Gefitinib in Patients With Acquired Resistance and MET Amplification or 2/3+ IHC
ORR 18% and DCR 80% PR in 12 of 65 patients SD in 40 of 65 patients Patients with gene copy number ≥ 5 ORR 19% PR in 10 of 53 patients with 2/3+ IHC Patients with gene copy number ≥ 6 ORR 30% PR in 7 of 23 patients with 2/3+ IHC Transcript - This trial was performed in patients who have acquired EGFR TKI resistance and demonstrated MET amplification Wu Y-L, et al. ASCO® Abstract 9020.

Improving Results in EGFR-Mutated NSCLC: Upfront Targeted Combinations With First-Generation EGFR TKIs -- Other Target Phase Primary Endpoint Secondary Endpoint Sample Size Identifier A safety and efficacy study of INC280 alone, and in combination with erlotinib, compared to chemotherapy, in advanced/metastatic NSCLC patients with EGFR mutation and cMET amplification (Novartis) MET 1/2 DLT PFS 135 NCT Transcript - This is a larger trial in untreated patients with de novo MET amplification. ClinicalTrials.gov. NCT

Effect of Dasatinib on EMT-Mediated Mechanism of Resistance Against EGFR TKIs in EGFR-Mutated NSCLC Cell Lines erlotinib erlotinib + dasatinib HCC4006 Apoptosis HCC4006ER EMT © Medscape, LLC Transcript Cultured EGFR mutated NSCLC cells were continually exposed to erlotinib It was found that a larger proportion of cells undergo mesenchymal transition as a means of erlotinib resistance Cells that were cocultured with erlotinib and dasatinib did not undergo epithelial to mesenchymal transition EMT = epithelial to mesenchymal transition Mitsudomi T. ELCC 2018.

Osimertinib + Selumetinib Efficacy
Phase 1b EGFRm-positive Progression on prior EGFR TKI Responses in 9 of 23 patients (ORR of 39.1%) Transcript Selumetinib is a MEK inhibitor This is a second-line trial, but the concept is used in front-line treatment Figure 5 Oxnard GR, et al. ASCO® Abstract 2509.

Improving Results in EGFR-Mutated NSCLC: Upfront Targeted Combinations With Osimertinib
Phase Primary Endpoint Secondary Endpoints Sample Size Identifier Dasatinib and osimertinib (AZD9291) in NSCLC with EGFR mutations (Georgetown) Src 1/2 Tolerance Non-progression 38 NCT [a] Osimertinib and gefitinib in EGFR inhibitor naive advanced EGFR mutant lung cancer (Dana Farber) EGFR 1 Completing therapy 64 NCT [b] A phase 2 study of osimertinib in combination with selumetinib in EGFR inhibitor naive advanced EGFR mutant lung cancer (Dana Farber) MEK 2 ORR PFS, OS 25 NCT [c] Osimertinib and bevacizumab as treatment for EGFR-mutant lung cancers (MSCC) VEGF MTD PFS 58 NCT [d] Transcript - These are all early trials with primary endpoints of tolerance and response rate MTD = maximum tolerated dose a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT ; d. ClinicalTrials.gov. NCT

EGFR TKI + Metformin From ASCO® 2018
Phase 2 EGFRm-positive 116 patients Outcome EGFR TKI + Metformin (n = 49) EGFR TKI (n = 67) P Value mPFS, mo 14.0 10.0 .017 ORR, % 67.4 47.5 .044 DCR, % 97 88.5 .085 mOS, mo 27.2 19.0 .015 Transcript - This abstract was scheduled to be presented during the Monday lung session Rodriguez OGA, et al. ASCO® Abstract 9013.

Mechanism of Resistance in Paired Tumor Samples
Known drivers EGFR T790M EGFR T790M & EGFR amplification MET amplification EGFR T790M & HER2 EGFR T790M & PIK3CA & SCLC transformation HER2 amplification EGFR amplification & PIK3CA EGFR amplification & CDKN2A/B del KRAS Potential drivers YES1 amplification & IDH1 AGK-BRAF fusion & TP53 MTOR FGFR3-TACC fusion & PIK3CA KEAP1 del TP53 & ARID1A TP53 Variants of unknown significance NOTCH2 NF2 Transcript Approximately two-thirds of patients have had repeat biopsies Approximately 20% of patients have alterations that have not yet been proven to be an oncogenic driver In 20% of patients, no new targetable mutation is found VUS = variant of uncertain significance Yu H, et al. Clin Can Res [Epub ahead of print]

Improving Results in EGFR-Mutated NSCLC: Acquired EGFR TKI Resistance -- T790M Positive
Target Phase Primary Endpoint Secondary Endpoints Sample Size Identifier G1T38, a CDK 4/6 inhibitor, in combination with osimertinib in EGFR-mutant NSCLC (G1 Therapeutics, Inc) CDK4/6 1/2 DLT RR 144 NCT [a] Osimertinib and navitoclax in treating patients with EGFR-positive previously treated advanced or metastatic NSCLC (NCI) BCL2 1 Safety 50 NCT [b] An open-label phase 1/2 study of INCB in combination with osimertinib in subjects with NSCLC (Incyte) JAK1 60 NCT [c] Osimertinib and bevacizumab vs osimertinib alone as second-line treatment in stage IIIb-IVb NSCLC with confirmed EGFRm and T790M (BOOSTER) (ETOP) VEGF R2 PFS 154 NCT [d] Transcript These are the ongoing clinical trials looking to improve results in EGFR-mutated NSCLC with acquired TKI resistance due to T790M Most of these are early trials with a primary endpoint of safety a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT ; d. ClinicalTrials.gov. NCT

ETOP BOOSTER: Osimertinib With or Without Bevacizumab for NSCLC With Activating EGFR and T790M Mutation Trial chairs: Solange Peters and Rolf Stahel Cochairs: Ross Soo and Ji-Youn Han Study design: Multicenter, randomized, open label, phase 2 trial, ETOP sponsored Patients randomized to osimertinib or osimertinib plus bevacizumab Primary endpoint: PFS Sample size: 154 randomized patients ETOP = European Thoracic Oncology Platform Transcript - This trial will soon be completed European Thoracic Oncology Platform website BOOSTER.

Improving Results in EGFR-Mutated NSCLC: Acquired TKI Resistance -- T790M Negative
Target Phase Primary Endpoint Secondary Endpoints Sample Size Identifier DS-1205c with osimertinib for metastatic or unresectable epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (Daiichi Sankyo) AXL 1 DLTs, AEs ORR, DoR, DCR 118 NCT [a] Sapanisertib and osimertinib in treating patients with stage IV EGFR mutation positive NSCLC after progression on a previous EGFR tyrosine kinase inhibitor (NCI) TORC1/ TORC2 MTD Tolerance 36 NCT [b] Osimertinib and necitumumab in treating patients with EGFR-mutant stage IV or recurrent NSCLC who have progressed on a previous EGFR tyrosine kinase inhibitor (NCI) EGFR Safety RR 82 NCT [c] MEDI9447 EGFRm NSCLC novel combination study (MedImmune) CD73 1/2 98 NCT [d] Transcript These are ongoing trials in patients with acquired resistance but no demonstrable T790M One trial of particular interest targets CD73, which is thought to increase cytotoxic T cell activity and activate macrophages in the tumor microenvironment These trials are also early with primary endpoints of safety DCR = disease control rate a. ClinicalTrials.gov. NCT ; b. ClincialTrials.gov. NCT ; c. ClinicalTrials.gov. NCT ; d. ClinicalTrials.gov. NCT

Preclincal Data on Targeted Combinations
Erlotinib and JAK2 inhibitor in H1975L858R/T790M xenograft[a] Erlotinib and HSP90 inhibitor in HCC827del19 NSCLC xenograft[b] Figure No Longer Available Figure No Longer Available Transcript - Based on these data, there appears to be some synergy with erlotinib and JAK2 or HSP90 inhibitors Figure 1C (first graph only) and Figure 1A Reprinted by permission from Springer Nature, Br J Cancer. 2016;115: Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib, Courtin A, Copyright 2016. a. Gao SP, et al. Sci Signal. 2016;9:ra33; b. Courtin A, et al. Br J Cancer. 2016;115: Gao SP, et al. Sci Signal. 2016;9:ra33. Reprinted with permission from AAAS."

Osimertinib + Savolitinib Efficacy
Phase 1b expansion cohort EGFR and MET amplification-positive patients with WHO PS 0/1 Progressed on prior EGFR TKI DoR, mo Prior 3rd gen: NR (2.2, 9.6) No prior 3rd gen (T790M+): 9.7 (2.8, 9.7) No prior 3rd gen (T790M-): NR (1.6, 5.9) Transcript MET is the most likely next target for combination treatment These data are from the TATTON trial looking at the combination of osimertinib with the MET inhibitor savolitinib Patients who have not been exposed to third-generation T790M-directed treatment have higher response rates than those with no prior T790M-targeted treatment WHO = World Health Organization CR = complete response PR = partial response SD = stable disease PD = progressive disease NE = not evaluable Ahn M, et al. IASLC WCLC Abstract

Improving Results in EGFR-Mutated NSCLC: Acquired EGFR TKI Resistance -- Independent of T790M
Target Phase Primary Endpoint Secondary Endpoints Sample Size Identifier Assessing an oral Janus kinase inhibitor, AZD4205, in combination with osimertinib in patients who have advanced non-small cell lung cancer Janus kinase 1/2 Safety RR 120 NCT [a] A study of ramucirumab (LY ) or necitumumab (LY ) + osimertinib in participants with lung cancer (Lilly) VEGFR EGFR 1 DLT 74 NCT [b] Erlotinib hydrochloride and onalespib lactate in treating patients with recurrent or metastatic EGFR-mutant non-small cell lung cancer HSP90 46 NCT [c] Transcript - These trials are examining acquired TKI resistance, independent of whether they are T790M positive or not a. ClinicalTrials.gov. NCT ; b. ClinicalTrials.gov. NCT ; c. ClinicalTrials.gov. NCT

1941 activator impaired mutant
Overcoming EGFR T790M and EGFR C797S With Mutant-Specific Allosteric Inhibitors 1941 activator impaired mutant EA1045-inhibitor Cetuximab N C ©Medscape, LLC Exon19del/T790M L858R/T790M/C797S Transcript An allosteric inhibitor is not designed to block the ATP binding site as the current inhibitors due, but rather it changes the confirmation of the protein The allosteric inhibitor that has been developed is only able to interact with one part of the homodimer Cetuximab segregates the homodimers and allows the allosteric inhibitor to interact with both sides This has not yet entered clinical trials Figure 1 and Figure 3 Jia Y, et al. Nature. 2016;534:

Immunotherapy in EGFR- Mutation Positive Patients
Lecia V. Sequist, MD, MPH Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts, United States

Immune Therapy: It's So Appealing…
2018 2016 2015 2017 March 4, 2015 Nivolumab, second-line, squamous histology only October 9, 2015 Nivolumab, second-line, all patients October 24, 2016 Pembrolizumab, first-line for PD-L1 ≥ 50% May 10, 2017 Carbo/pem/ pembro, first-line February 16, 2018 Durvalumab, adjuvant therapy for stage III October 18, 2016 Atezolizumab, second-line October 22, 2015 Pembrolizumab second-line Transcript This timeline is specific to lung cancer approvals over the last 3 years There are a lot of caveats around the use of immunotherapy for EGFR-mutated patients WARNING It's not for everyone.

EGFR-Positive and ALK-Positive Lung Cancer and Innate Immune Resistance
IFN-γ PD-L1 PD-L1 Intrinsic Oncogenic Signaling MHC ALK Adaptive Immune Resistance PD-L1+/TIL+ Innate Immune Resistance PD-L1+/TIL- Transcript EGFR-mutated cancer has a relative immune cold state as is depicted on the right hand side of the illustration by a lack of infiltrating T cells It is rate to have PD-L1 greater than 50% in EGFR-mutated cancer, and it is even more rare to have PD-L1 greater than 50% along with tumor infiltrating lymphocytes TIL = tumor-infiltrating lymphocyte EGFR Mutant (n = 62) ALK Rearranged (n = 19) PD-L1+ (≥ 50%) 7 (11%) 5 (26%) PD-L1+ (≥ 50%) and high CD8+ TILs/mm2 2/46 (4.3%) 0/11 (0%) Image courtesy of Justin Gainor, MD. Gainor JF, et al. Clin Cancer Res. 2016;22:

TMB in EGFR- and ALK-Positive NSCLC
Mutational Load: Smokers vs Non-Smokers[b] TMB and Activity of PD-(L)1[a] Figure No Longer Available Figure No Longer Available Reprinted from Mol Cancer Res., Copyright 2014, 12, 2-13, Gibbons DL, et al., Smoking, p53 Mutation, and Lung Cancere, with permission from AACR TMB in EGFR+ NSCLC[c] Transcript The data on the left hand side show that TMB-high patients have better outcomes with checkpoint inhibitors compared with TMB-low patients The top right shows that lifelong non-smokers had fewer mutations compared to heavier smokers The bottom right shows that EGFR-mutated patients were below the TMB-high threshold TMB = tumor mutation burden Rizvi N, et al. Science. 2015;348: Reprinted with permission from AAAS. Reprinted from Nahar R, et al. Nat Commun. 2018;9:216 with permission from Creative Commons a. Rizvi N, et al. Science. 2015;348: ; b. Gibbons DL, et al. Mol Cancer Res. 2014;12:2-13; c. Nahar R, et al. Nat Commun. 2018;9:216.

Meta-Analysis of Second-Line Studies
Figure No Longer Available Transcript - Patients with EGFR mutations did poorly in second-line immune checkpoint inhibitor trials Reprinted from J Thorac Oncol., 12(2), Lee CK, Man J, Lord S, et al., Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis, , Copyright 2017, with permission from Elsevier. Lee CK, et al. J Thorac Oncol. 2017;12:

ATLANTIC Trial Patients with EGFR and ALK
At least 1 prior TKI, at least 1 platinum-based chemotherapy doublet PD-L1 ≥ 25% (amended one-third of the way through study) 97 EGFR-positive patients and 15 ALK-positive patients enrolled EGFR-positive cohort with PD-L1 ≥ 25% (n = 64): ORR = 14%, PFS = 2.0 months ALK-positive cohort with PD-L1 ≥ 25% (n = 10): ORR = 0, PFS = 1.8 months 8 of 10 of the responding EGFR-positive patients had PD-L1 ≥ 90% Transcript These were third-line and beyond patients The trial was amended from all comers to limit the patient population to those with PD-L1 of at least 25% These data suggest that if you are considering checkpoint inhibitors in a driver mutation positive patient, you may want to focus on the very highest of PD-L1 expressers Garrassino MC, et al. Lancet Oncol. 2018;19:

First-Line Immunotherapy in EGFR- Mutated NSCLC
Key eligibility criteria: Advanced NSCLC EGFR-Mutation PD-L1 ≥ 1%* TKI-naive Pembrolizumab 200 mg q3 weeks Treat until progression or total of 35 study infusions Post-progression EGFR TKI Safety/Efficacy Analysis Sample size: 25 subjects Planned Enrollment: 25pts Closed (10/2017): 11 pts enrolled (8 with PDL > 50%) RR: 0% Transcript This abstract was scheduled to be presented as a poster at ASCO The key takeaway is that there were 0 responses NSCLC = non-small cell lung cancer ORR = overall survival PFS = progression-free survival TKI = tyrosine kinase inhibitor Finally, we will learn on Sunday at the poster discussion about the role of single agent IO in treatment naïve, EGFR positive patients. Give you a spoiler alert with permission from Aaron Lisberge and Eddie Garon Primary objective: ORR of pembrolizumab prior to TKI Secondary objectives: Safety, PFS, OS of pembrolizumab; safety and efficacy of subsequent EGFR TKI therapy *Performed with 22C3 assay in a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory. Lisberg AE, et al. ASCO® Abstract 9014.

Response to Checkpoint Blockade Among Never/Light Smokers with NSCLC and High PD-L1 Expression
45 patients Objective responses 7 of 15 WT 4 of 11 KRAS 1 of 8 EGFR 1 of 5 MET 1 of 1 PIK3CA 1 of 1 ROS1 0 of 2 BRAF 0 of 1 RET EGFR-mutant NSCLC objective responses 12.5% Transcript These data are a collaboration among several Stand Up to Cancer Dream Team sites There was 1 objective response out of the 8 EGFR-positive patients who had high PD-L1 Gainor JF, et al. ASCO® Abstract 9011.

Duration of Response Heavy smokers Light/Never smokers Patients at risk Never/light Heavy 2 26 13 6 4 Median, mo HR (95% CI) P Value Heavy Smokers 17.77 4.32 (1.30, 14.35) .009 Light/Never Smokers 10.81 Transcript Those light smokers who did respond had shorter duration of response than heavy smokers Single agent immunotherapy is not very active in EGFR-positive patients, even those with the highest PD-L1 expression Despite similar ORRs, duration of response was significantly longer in the heavy smoker cohort Gainor JF, et al. ASCO® Abstract 9011.

Key Immunotherapy Trials That Excluded EGFRm-Positive Patients
KEYNOTE-024 (first-line, pembro vs chemo)[a] CheckMate-026 (first-line, nivo vs chemo)[b] KEYNOTE-021 Cohort G (first-line, chemo/pembo vs chemo)[c] KEYNOTE-189 (first-line, chemo/pembro vs chemo)[d] KEYNOTE-042 (first-line, pembro vs chemo)[e] CheckMate-227 (first-line, ipi/nivo vs chemo)[f] Transcript - Most of the studies on which we base our current standard of care for WT patients specifically excluded EGFR-positive patients pembro = pembrolizumab chemo = chemotherapy nivo = nivolumab ipi = ipilimumab a. Reck M, et al. N Engl J Med. 2016;375: ; b. Carbone DP, et al. N Engl J Med. 2017;376: ; c. Langer CJ, et al. Lancet Oncol. 2016;17: ; d. Gandhi L, et al. N Engl J Med [Epub ahead of print]; e. Lopes, G, et al. ASCO® Abstract LBA4; f. Hellmann MD, et al. N Engl J Med [Epub ahead of print]

IMpower150 Study Design Maintenance therapy (no crossover permitted) Stage IV or recurrent metastatic nonsquamous 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 Arm A Atezolizumab[b] + carboplatin[c] + paclitaxel[d] 4 or 6 cycles Atezolizumab[b] 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 Arm B Atezolizumab[b] + carboplatin[c] + paclitaxel[d] + bevacizumab[e] 4 or 6 cycles Atezolizumab[b] + bevacizumab[e] R 1:1:1 Arm C (control) Carboplatin[c] + paclitaxel[d] + bevacizumab[e] 4 or 6 cycles Bevacizumab[e] Transcript - This trial did include EGFR-positive patients who were chemotherapy naive, but previously treated with TKIs The principal question is to access whether the addition of atezolizumab to Arm C provides clinical benefit. a. Patients with a sensitizing EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with ≥1 approved targeted therapies; b. atezolizumab: 1200 mg IV every 3 weeks; c. carboplatin: AUC 6 IV every 3 weeks; d. paclitaxel: 200 mg/m2 IV every 3 weeks; e. bevacizumab: 15 mg/kg IV every 3 weeks. Kowanetz M, et al. AACR Abstract CT076.

PFS Benefit Observed in Key Populations
HR mPFS, mo Atezo + bev + chemo Bev + Chemo ITT 800 (100) 0.61 8.3 6.8 EGFR/ALK+ ALK EGFR 108 (14) 34 (31) 80 (74) 0.59 0.65 0.60 9.7 10.2 6.1 5.9 6.9 ITT- WT 692 (87) 0.62 Transcript - Results with the EGFR/ALK subgroup are inline with the WT patients Kowanetz M, et al. AACR Abstract CT076.

What We Don't Know Yet About IMpower150
Subtype of mutations Number of prior TKIs that the patients received Resistance profile (T790M, etc) PD-L1 data for mutant cohort Transcript - Survival data from this trial was scheduled to be presented at the Monday lung session

Proportion of Pneumonitis, Point Estimate (95% CI)
Safety Concerns Therapy Cases, N Pneumonitis, n Proportion of Pneumonitis, Point Estimate (95% CI) Nivolumab 5178 330 6.4 (5.7, 7.1) EGFR TKI Afatinib Erlotinib Gefitinib Osimertinib 5777 1358 3195 678 702 265 86 67 47 75 4.6 (4.1, 5.2) 6.3 (5.1, 7.8) 2.1 (1.6, 2.7) 6.9 (5.1, 9.1) 10.7 (8.5, 13.2) Nivolumab plus EGFR TKI 70 18 25.7 (16.0, 37.6) Transcript This trial examined post-approval data of serious adverse events and looked for patients with any incidence of pneumonitis Patients who received nivolumab and an EGFR TKI, in any order, had increased risk of pneumonitis compared with either therapy alone Oshima Y, et al. JAMA Oncol [Epub ahead of print]

My Personal Practice for Immunotherapy in EGFRm-Positive Patients
If giving immunotherapy, try to enroll in a clinical trial Preference to not use single-agent checkpoint inhibitors until all EGFR TKIs and at least 2 lines of chemotherapy have been tried Given ATLANTIC results, could consider after 1 line of chemotherapy if PD-L1 > 90% Preference to not give an EGFR-positive patient chemotherapy + immunotherapy off-trial, but if IMpower regimen is approved, it is something to consider (after applicable TKIs) It is not clear at this time that carbo/pem/pembro would be effective in mutant patients -- it is a data-free zone Giving ipi/nivo outside a trial is not recommended

What Does an Updated Treatment Algorithm Look Like?
Lecia V. Sequist, MD, MPH Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts, United States

Current Algorithm for EGFR-Positive Patients: First-Line Options
Osimertinib is likely the current best option Erlotinib, gefitinib, afatinib are also current options Afatinib has an expanded indication in G719X, L861Q, S768I Updates about erlotinib + bevacizumab, dacomitinib, and chemo + gefitinib presented at the Metastatic Lung Oral Session on Monday, June 4, 2018, at 3 PM Immune therapy should never be given before TKIs Always consider clinical trials if feasible

Second-Line Options and Key Decision Points
Analysis for acquired resistance mechanisms is important For legacy patients after first-/second-generation TKIs, look for T790M → osimertinib In general, tissue analysis is favored, especially after osimertinib This allows you to look for SCLC and avoid the pitfalls of clonal hematopoiesis "false positives" MET amplification patients -- try to get them on a MET inhibitor + EGFR inhibitor If no targeted options, then time to move to chemotherapy Always consider clinical trials if feasible

Chemotherapy Alone or With CPI for EGFR Mutants?
IMpower150 results are exciting, but we need a bit more information (and access to the quadruplet regimen) before it enters practice. OS results presented at the Metastatic Lung Oral Session on Monday, June 4, 2018, at 3 PM Recall carbo/pem/pembro did not allow EGFR-positive patients, so we lack data on the efficacy of this regimen At the current time, chemotherapy is still favored alone because of safety concerns, but the landscape is changing quickly Always consider clinical trials if feasible

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Saturday, June 2, 2018 MODERATOR Lecia V. Sequist, MD, MPH

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Saturday, June 2, 2018 MODERATOR Lecia V. Sequist, MD, MPH

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