Targeting Acquired Resistance to EGFR Kinase Inhibitors: Beyond T790M Mutation

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1 Targeting Acquired Resistance to EGFR Kinase Inhibitors: Beyond T790M Mutation James Chih-Hsin Yang, MD, PhD National Taiwan University Hospital National Taiwan University Cancer Center Taipei, Taiwan

2 EGFR TKI Resistance Gefitinib Erlotinib Afatinib Dacomitinib T790M+ T790M Osimertinib T790M+ T790M?? Osimertinib T790M? Platinum + Pemetrexed Or platinum doublet

3 EGFR TKI Resistance Gefitinib Erlotinib Afatinib Dacomitinib T790M+ T790M Osimertinib T790M+ T790M?? Osimertinib T790M?? Targeted Tx? Anti PD-1 + CT Platinum + Pemetrexed Or platinum doublet

4 Resistance Mechanisms to 1 st- and 2 nd- Generation EGFR TKI EGFR Mutant NSCLC HER2 amplification in gefitinib/erlotinib resistance HGF Production 2 EGFR T790M 1 MET Amplification PI3K mut Small Cell Transformation

5 INC280X2202 Gefitinib + INC280 (Capmatinib) Study Design This study was a phase IB/II, openlabel, multicenter study of INC280 administered orally in combination with gefitinib in adult patients with EGFR-mutant, c-met-positive NSCLC who have progressed after EGFR inhibitor treatment Primary Objectives Phase Ib Estimate MTD or RP2D Phase II Estimate overall clinical activity Endpoints Frequencies and characteristics of DLTs ORR Molecular prescreen c-met dysregulation in patients with NSCLC who had developed resistance to gefitinib or erlotinib NCT Phase Ib Dose escalation to determine MTD or RP2D INC280 + gefitinib N 18 RP2D (capsule) 400 mg BID Phase II Dose expansion at MTD or RP2D INC280 + gefitinib N = 40 DLT, dose-limiting toxicity; MTD, maximum tolerate dose; ORR, overall response rate; RP2D, recommended phase II dose Wu Y-L, et al. J Clin Oncol. 2018;36(31):

6 Gefitinib + INC280 (Capmatinib) Efficacy Results Phase II: GCN 6 17/36 (47%) PR IHC 3+ 33/78 (42%) PR Wu Y-L, et al. J Clin Oncol. 2018;36(31):

7 Tepotinib + Gefitinib vs Pemetrexed/Platinum Phase II Study Design Asian patients with: Locally-advanced/metastatic stage IV NSCLC, EGFR+, T790M, MET+ MET2+ or 3+ by IHC (D1C1 antibody) and/or MET amplification by ISH (GCN 5 and/or MET/CEP-7 ratio 2) Resistance to prior EGFR TKI (Jackman criteria) a No prior HGF/MET pathway-directed therapy R b Stratification factors: Type of MET+ (IHC2+ vs IHC3+ vs MET amplification) c Prior EGFR-TKI treatment Tepotinib 500 mg oral qd Gefitinib 250 mg oral qd Pemetrexed 500 mg/m 2 IV on day 1 Cisplatin 75 mg/m 2 or carboplatin AUC 5 or 6 IV on day 1 21-day cycles until PD or toxicity Up to 6 x 21-day cycles (or 4 cycles plus pemetrexed maintenance) until PD or toxicity Endpoints: Primary: investigator-assessed PFS Secondary: ORR, safety Pre-planned analyses: MET IHC3+ subgroup MET amplification subgroup Initial plan to enroll 156 patients Enrollment halted after 55 patients randomized due difficulties in identifying patients who met the eligibility criteria a Prior treatment with gefitinib, erlotinib, icotinib, or afatinib; Jackman D et al. J Clin Oncol. 2010: b Initially 1:1 and changed to 2:1 on implementation of a protocol amendment. c Patients with co-existence of MET amplification and MET IHC overexpression were included in the MET amplification group. AUC, area under the curve; EGFR, epidermal growth factor receptor; GCN, gene copy number; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; NSCLC, non-small cell lung cancer; PD, disease progression; PFS, progression-free survival; qd, once daily; TKI, tyrosine kinase inhibitor Wu Y-L, et al. Ann Oncol. 2018;29(Suppl 8): Abstract 1377O.

8 MET IHC Yes N = 72 (58.1%) IHC 2+ N = 23 (18.5%) IHC 3+ N = 49 (39.5%) No N = 52 (41.9%) IHC 0 N = 12 (9.7%) IHC 1 N = 40 (32.3%) Patient Disposition Biomarker Screening Patients screened N = 260 EGFR-mutation positive N = 186 T790M-mutation negative N = 124 MET IHC 2+/3+ and/or MET amplification N = 55 MET amplification by ISH Yes N = 31 (25.0%) GCN 5 N = 30 (24.2%) MET/CEP-7 ratio 2 N = 24 (19.4%) No N = 93 (75.0%) Screen failure n = 19 Tepotinib/gefitinib ITT n = 31 Safety (all treated patients) n = 31 Treatment ongoing a n = 4 Wu Y-L, et al. Ann Oncol. 2018;29(Suppl 8): Abstract 1377O. Chemotherapy ITT n = 24 Safety (all treated patients) n = 23 MET amplification, defined as mean GCN 5 and/or MET/CEP-7 copy number ratio 2. a All 4 patients have MET amplification.

9 Wu Y-L, et al. Ann Oncol. 2018;29(Suppl 8): Abstract 1377O. Tepotinib + Gefitinib vs Pem/Platinum

10 AURA3 Primary Endpoint: PFS by Investigator Assessment 1.0 Median PFS, months (95% CI) HR (95% CI) Probability of Progression-Free Survival Osimertinib Platinum-pemetrexed 10.1 (8.3, 12.3) 0.30 (0.23, 0.41) 4.4 (4.2, 5.6) P<.001 No. at risk Osimertinib Platinum-pemetrexed Months Analysis of PFS by BICR was consistent with the investigator-based analysis: HR 0.28 (95% CI 0.20, 0.38), P<.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. 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. 2017;376(7):

11 Analysis of Resistance Mechanisms to Osimertinib in Patients With EGFR T790M Advanced NSCLC From the AURA3 Study Study objective To investigate the mechanisms of acquired resistance to osimertinib in patients who progressed or discontinued treatment in the AURA3 study Methods Patients in the AURA3 study had T790M+ locally advanced or metastatic NSCLC and were treated with osimertinib or platinum-pemetrexed until progression Paired plasma samples were taken from patients at baseline and at progression/discontinuation for ctdna genomic profiling NGS was undertaken using the Guardant360 assay Analysis set of valid paired NGS data were available for 113 patients Osimertinib: 83/279 (30%) Platinum-pemetrexed: 30/140 (21%) Papadimitrakopoulou VA, et al. Ann Oncol. 2018;29(Suppl 8): Abstract LBA51.

12 Acquired Resistance Mechanisms Post-Osimertinib (N = 73) Summary Acquired EGFR mutations: 21% MET amp*: 19% Cell-cycle gene alterations: 12% HER2 amp*: 5% PIK3CA amp* / mutation: 5% Oncogenic fusion: 4% BRAF V600E: 3% No known mechanism of resistance identified: 60% EGFR mutations only: 10% + BRAF V600E + FGFR3-TACC3: 1% + HER2 amp* + PIK3CA amp* + CCND2 amp: 1% + HER2 amp* + MET amp*: 1% + MET amp* + BRAF V600E + CDK6 amp*: 1% + MET amp* + CDK6 amp + CCNE1 amp*: 1% + MET amp* + KRAS mutation: 1% + MET amp*: 3% PIK3CA amp* + HER2 amp* + CCNE1 amp*: 1% PIK3CA E545K: 1% MET amp*: 3% RET-ERC1: 1% CCNE1 amp*: 1% HER2 amp*: 1% PIK3CA amp*: 1% MET amp* + NTRK1-TPM3: 1% MET amp* + CDK6 amp*: 1% MET amp* + CCNE1 amp* + CDK6 amp*: 1% MET amp* + CDKN2A E27fs: 1% MET amp* + CCND1 amp* + CCNE1 amp* + CDK6 amp*: 1% Papadimitrakopoulou VA, et al. Ann Oncol. 2018;29(Suppl 8): Abstract LBA51. *Amplification events may be underrepresented in plasma analyses amp, amplification

Heterogeneous Acquired Resistance Mechanism After Osimertinib Therapy Small cell transformation Loss of T790M is associated with early resistance 13 Bypass Squamous cell carcinoma 16 0% small cell

13 Heterogeneous Acquired Resistance Mechanism After Osimertinib Therapy Small cell transformation Loss of T790M is associated with early resistance 13 Bypass Squamous cell carcinoma 16 0% small cell transformation 6,8,13,16,28 6% Her2 ampl/mut T790M- 7,12,19,30 5% FGFR ampl/mut/fusion T790M- 6,13 1% NF1, NF2 16 0% Met ampl T790M- 7,10,12,13,16,24,28,30 10% BRAF V600E + Met ampl. 26 0% L792H 27 3% G796R 27 2% Loss of T790M w/o other mutation 1,6,10,13 15% EGFR ampl T790M+ 6 0% ErbB3 30 6% C797S T790M+ 1,2,3,9,10,11,12,13, 14,15,16,19,20,23, 30* *C797S >80% in cis 2,3,15 EGFR 10% 1. Thress KS. Nat Med Niederst MJ. Clin Cancer Res Hidaka N. Lung Cancer Ho C-C. J Thorac Oncol Bersanelli M. J Thorac Oncol Kim TM. J Thorac Oncol Planchard D. Ann Oncol Liu Y. Oncotarget Ou S-HI. Lung Cancer Piotrowska Z. ASCO Ercan D. Cancer Res Ramalingam SS. J Clin Oncol Oxnard G. WCLC 2017: Abstract OA Wang Z. J Thoracic Oncol Piotrowska Z. WCLC 2017: Abstract OA Yang JC. WCLC 2017: Abstract P Iams WT. WCLC 2017: Abstract P Liu Y. Lung Cancer Ortiz-Cuaran S. Clin Cancer Res Yu HA. JAMA Oncol Zheng D. Oncotarget Chen KJ. Thorac Oncol Knebel FH. Lung Cancer Ou SI. Lung Cancer Martinez-Marti, A. Ann Oncol Minari T. J Thorac Oncol Zhang. J Thorac Oncol Le X. ASCO Vojnik M. ASCO Zhou C. ASCO % Kras, MEK, PIK3CA, JAK, Ret fusion T790M- 12,13,16,17,19,28,30 T790M+ w/o other mutation 1,10,13,16,28 9% L781Q T790M+ 5 0% BRAF T790M+ (+C797S) 4,16,29 1% Met T790M+ 16,25,28 4% PIK3CA T790M+ 1 0% C797S, L792F, T790M+ L718V, G796D 22,28 6% T790M- 18,21 1% BRAF T790M- 13,16 1%

14 C797S in Osimertinib-Resistant Lung Cancer Cystein UGU UGC UGU UGC UCU UCC UCA UCG AGU AGC Serine

15 Acquired Osimertinib Resistance in Tissue and Plasma Samples in 53 Pts (AURA in NTUH) Lin CC, et al. Lancet Res Med. 2018;6(2):

16 cfdna Detection Predictive or Prognostic for Osimertinib? A. PFS (n = 53) of shedders vs nonshedders B. OS (n = 53) of shedders vs nonshedders C. PPS (n = 47) of shedders vs nonshedders Lin CC, et al. Lancet Res Med. 2018;6(2):

Survival Among 40 Patients With Plasma Samples Available at the Time of Disease Progression Group A: Loss of T790M Group B: Postprogression nonshedders Group C: Maintainers/new-shedders A vs B: P =.

17 Survival Among 40 Patients With Plasma Samples Available at the Time of Disease Progression Group A: Loss of T790M Group B: Postprogression nonshedders Group C: Maintainers/new-shedders A vs B: P =.0066 A vs C: P =.013 B vs C: P =.67 A vs B : P =.034 A vs C: P =.50 B vs C: P =.037 A vs B: P =.019 A vs C: P =.023 B vs C: P =.13 Group A Group B Group C Group A Group B Group C Group A Group B Group C Lin CC, et al. Lancet Res Med. 2018;6(2):

18 FLAURA: PFS by Investigator Assessment 342 events in 556 patients at DCO: 62% maturity; osimertinib: 136 events (49%), SoC: 206 events (74%) Probability of Progression-Free Survival Osimertinib SoC Median PFS, months (95% CI) 18.9 (15.2, 21.4) 10.2 (9.6, 11.1) HR 0.46 (95% CI 0.37, 0.57) P<.0001 No. at risk Osimertinib SoC FLAURA data cut-off: 12 June 2017 Tick marks indicate censored data; Time From Randomisation, Months CI, confidence interval; DCO, data cutoff; HR, hazard ratio; SoC, standard-of-care Soria JC, et al. N Engl J Med. 2018;378(2):

19 Alterations Observed at the Time of 1L and 2L Osimertinib Resistance Ramalingam SS, et al. Ann Oncol. 2018;29(Suppl 8): Abstract LBA50.

20 FLAURA Paired Plasma NGS Ramalingam SS, et al. Ann Oncol. 2018;29(Suppl 8): Abstract LBA50.

Results: Candidate Acquired Resistance Mechanisms With Osimertinib (n=91)* No evidence of acquired EGFR T790M The most common resistance mechanisms were MET amplification and EGFR C797S mutation

21 Results: Candidate Acquired Resistance Mechanisms With Osimertinib (n=91)* No evidence of acquired EGFR T790M The most common resistance mechanisms were MET amplification and EGFR C797S mutation Other mechanisms included HER2 amplification, PIK3CA and RAS mutations EGFR EGFR Secondary EGFR mutations: # C797X: 7%; L718Q+C797S: 1%; L718Q + ex20ins: 1%; S768I: 1% PIK3CA mtor AKT p53 HER2 HER2 HER2 HER2 amplification: 2% HER2 mutation: 1% PIK3CA mutations: 7% HER2 SPTBN1 ALK SPTBN1-ALK: 1% MET MET MET MET MET amplification: 15% BRAF mutations (V600E): 3% RAF KRAS mutations (G12D/C, A146T): 3% RAS MEK BIM Apoptosis BCL2 Survival Cell cycle gene alterations CCND amps: 3% CCNE1 amps: 2% CDK4/6 amps: 5% ERK Proliferation Ramalingam SS, et al. Ann Oncol. 2018;29(Suppl 8): Abstract LBA50. *Resistance mechanism reported may overlap with another; # Two patients had de novo T790M mutations at baseline of whom one acquired C797S at progression

22 TATTON: Osimertinib + Savolitinib Preliminary Antitumor Activity in All MET-Positive Patients, a n = 64 Best % Change From Baseline In Tumor Lesion Size 100 Waterfall plot based on evaluable patients (n = 64): all patients dosed and with on-treatment assessment or discontinuation prior to first tumor assessment Data cutoff 31 Aug 2017 a 17 patients did not have central FISH confirmation of MET-positive status (n = 6 MET-negative; n = 11 unknown by central lab); b Confirmed by a later scan performed at least 4 weeks after initial response observed Objective response rate, n (%) Ahn M-J, et al. J Thorac Oncol. 2018;13(10 Suppl): Abstract Prior 3 rd -Gen T790M directed EGFR TKI n = 30 No prior 3 rd- Gen T790M- directed EGFR TKI T790M+ n = 11 Prior 3 rd -gen T790M-directed EGFR TKI No prior 3 rd -gen EGFR TKI, T790M+ No prior 3 rd -gen EGFR TKI, T790M- T790Mn = 23 Total n = 64 ORR b 10 (33) 6 (55) 14 (61) 30 (47) TATTON Part B NCT

23 A Phase I Study of Osimertinib in Combination or Alternating With Gefitinib in EGFR Inhibitor Naïve Advanced EGFR-Mutant Lung Cancer Osimertinib Osimertinib + Gefitinib Del19/L858R Del19/L858R + T790M Del19/L858R + C797S Del19/L858R + T790M + C797S Del19/L858R + XXX osimertinib gef osi gef osi National Institutes of Health. Accessed November 7, 2018.

24 Summary 1. Resistance to 1 st - and 2 nd- generation EGFR TKI is different from osimertinib resistance 2. Heterogeneous resistance mechanisms develop after EGFR TKI treatment 3. The standard of care for EGFR TKI resistant EGFRmut patients is combination chemotherapy 4. MET amplification/overexpression is an important EGFR TKI resistance mechanism EGFR TKI + MET inhibitor is a promising strategy to overcome resistance

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