Expanding Therapeutic Options for Cancer Patients with Comprehensive Profiling Alexander Drilon MD

Transcription

1 Expanding Therapeutic Options for Cancer Patients with Comprehensive Profiling Alexander Drilon MD Clinical Director, Early Drug Development Service Memorial Sloan Kettering Cancer Center

2 COI Disclosure Information I have the following financial relationships to disclose. Honoraria/Advisory board Ignyta, Loxo Oncology, Helsinn, AstraZeneca, Roche/Genentech, BeiGene, TP Therapeutics, Pfizer

3 Disclaimer The information contained herein may refer to use of the product for indications other than those approved and/or listed in the Hong Kong package inserts or relating to molecules currently undergoing experimental trials. The issues addressed are not meant to suggest that the product be employed for indications other than those authorised. The information is presented for the purpose of scientific knowledge exchange only.

4 The number of known and putative drivers in NSCLC has risen substantially tumor samples from patients with lung adenocarcinoma sequenced on MSK-IMPACT TM Jordan et al, Cancer Discovery 2016

5 NSCLCs are enriched in clinically actionable drivers BRAF V600E EGFR Exon 19 del L858R ALK fusion MET exon 14 splice Mt ERBB2/HER2 Mt ROS1 fusions RET fusions NTRK1/2/3 fusions NRG1 fusions Mt - mutation

6 NGS identifies additional clinicallyrelevant alterations in NSCLCs A broad, hybrid capture-based NGS assay (FoundationOne) was performed Drilon et al, Clin Cancer Res 2015

7 Not all next-generation sequencing (NGS) panels are the same Hybrid capturebased testing MSK-IMPACT FoundationOne Clinically actionable mutation found PCR- Ampliconbased testing Clinically actionable mutation missed 81% of mutations detected by MSK- IMPACT (hybrid capture) missed by commercially-available PCR-based NGS hotspot panels 8 commercially-based amplicon panels in France missed: 100% of ROS1 alterations 47% of MET exon 14 alterations (some up to 86%) Zehir et al, Nature Med 2017, Poirot et al, J Thoracic Oncol 2017

8 Targeted RNA sequencing can complement DNA-based NGS by increasing driver detection no driver identified DNA RNA Benayed et al, ASCO 2018

9 Clinically actionable drivers of NSCLC BRAF V600E

10 BRAF V600E-mutant lung cancers are sensitive to combination therapy No oncogenic driver detected 36% Mut >1 gene 3% MET 1% NRAS 1% MEK1 <1% ALK 8% PIK3CA 1% EGFR (sensitizing) 17% BRAF 2% (V600E 1.6%) EGFR (other) 4% HER2 3% KRAS 25% Lung Cancer Mutation Consortium (n = 733 lung adenocarcinomas) Multicenter single-arm phase 2 study Dabrafenib 150mg twice daily + Trametinib 2 mg daily Primary endpoint: overall response overall response 63 2% [95% CI ] 36 PRs of 57 BRAF V600E-mutant patients V600E-mutant: more likely to be light/never smokers mutually exclusive with other oncogenic drivers in most cases Planchard et al, Lancet Oncol 2016; Paik et al JCO 2011; 29:2046. Kris et al. JAMA. 2014;311(19):

11 Non-V600E BRAF mutations and BRAF fusions are identified in NSCLC n=63 BRAF-mutant lung adenocarcinomas BRAF fusions: 0.2% NSCLCs Advanced disease Mutations or Fusions Kinase activity Dimer dependency Vemurafenib sensitivity Wild type Neutral Yes Insensitive Class I V600E/K/D/R/M High No Sensitive Class II Class III K601E/N/T L597Q/V G469A/V/RF64V/E BRAF Fusions D287H, V459L, G466V/E/A, S467L, G469E, N581S/I, D594N/G/A/H, F595L, G596D/R Intermediate to High Yes Insensitive Low Yes Insensitive Litvak and Riely, et al JTO 2014; Yao et al Nature 2017; Reddy et al ASCO 2017

12 Clinically actionable drivers of NSCLC MET exon 14 splice Mt

13 MET exon 14 alterations lead to increased MET expression and oncogenesis MET MET mutations that lead to decreased MET degradation deletions, insertions, or base substitutions many disrupt splice sites flanking MET exon 14 exon 14 skipping impaired CBL binding and decreased MET degradation increased MET receptor on the tumor cell surface mrna Drilon et al, Clin Cancer Res 2016 MET exon 14

14 Tyr1003 MET exon 14-altered lung cancers have unique features Incidence c.2888-del (n= 2) c.3028g>c/t/a (n= 5) 3-4% of nonsquamous NSCLCs 20-30% of sarcomatoid lung carcinomas plasma profiling c del (n= 1) (n= 1) # c.3029c>t c del (n= 1) SNV Clinicopathologic Features Exon (n=1)* Exon 14 D1010 Indel Exon 15 older patients c.2888 Splice acceptor site c.3028 Splice donor site proportion of never smokers patients should be screened regardless of these clinical features c-met 15-20% with concurrent MET amplification Diagnosis DNA-based next-generation sequencing RNA sequencing IHC alone is insufficient Drilon et al, Clin Cancer Res 2016; Paik PK et al. Cancer Discov 2015;5. Awad MM et al. J Clin Oncol 2016;34 Frampton et al, Cancer Discovery 2015

15 % change from baseline Drug MET exon 14-altered lung cancers are sensitive to MET inhibition METspecific Other targets Type Crizotinib No ALK, ROS1 Ia Multicenter phase 1 expansion cohort Crizotinib 250 mg twice daily Primary endpoint: overall response Crizotinib ORR 39% Best Percent Change From Baseline in Size of Target Lesions (n=22)* Progressive disease Stable disease Partial response Complete response Capmatinib Yes - Ib Tepotinib Yes - Ib Savolitinib Yes - Ib AMG337 Yes - Ib Objective response rate (ORR) 11/28 (39%, 95% CI: 22, 59) Best overall response n (%) Complete response 2 (7) Median duration of response: Partial response 9 (32) 9.1 months (95% CI: 5.9, 10.5) Stable disease 10 (36) Progressive disease 2 (7) Indeterminate 5 (18) Tepotinib ORR 43% *Includes patients with measurable disease at baseline and 1 response assessment scan; excludes 1 patient with early death, 4 patients with indeterminate response and 1 patient (CR responder) with no measurable target lesions at baseline Cabozantinib No RET, ROS1, VEGFR2, KIT Merestinib No TIE-1, AXL, ROS1, DDR1/2, FLT3, MERTK, RON Glesatinib No MET, VEGFR, RON, TIE-2 II II II Capmatinib Drilon et al, WCLC; Felip et al ASCO 2018; Schuler et al, IASLC MSTO 2016

16 On target resistance to MET inhibition identified after prior MET TKI therapy Drug Administered MET alteration Putative resistance mechanism Notes Crizotinib 8 mo of disease control MET D1010H MET D1228N (acquired second site mutation on tumor rebiopsy) high total MET and phospho-met IHC+ on post-pd biopsy Crizotinib 13 mo of disease control MET D1010H MET Y1230C (pre-existing in tumor, detected again in ctdna on progression) Savolitinib + Osimertinib 9 mo of disease control MET amplification (+EGFR ex19 del) MET D1228V (acquired second site mutation on tumor rebiopsy) thereafter responded to Cabozantinib + Erlotinib Type I MET inhibitor interacting with Y1230 residue, stabilized by D1228 residue in DFG-in configuration --> potentially abrogated by Type II drugs binding to DFG-out conformation Heist R et al, J Thoracic Oncol, 2016; Ou et al, J Thoracic Oncol, 2017; Bachall et al, Cancer Discov, 2017; Qi et al, Cancer Res, 2011; Tiedt et al, Cancer Res 2011

17 Clinically actionable drivers of NSCLC ERBB2/HER2 Mt

18 HER2-mutant lung cancers can benefit from HER2 inhibition HER2 mutations are found in 2% of lung cancers ORR 44% Median PFS 5 months Other agents being explored: HER2 TKIs =(e.g. pyrotinib); other HER2 ADCs Li et al, WCLC 2017

19 Clinically actionable drivers of NSCLC ROS1 fusions

20 ROS1 fusion-positive lung cancers are sensitive to ROS1 TKI therapy Crizotinib ORR 72% median PFS 19.2 mos Ceritinib ORR 62% median PFS 19.3 mos Entrectinib ORR 69% median PFS 29.6 mos Shaw et al, New Engl J Med 2014; Lim et al, JCO; Ahn et al WCLC 2017

21 Later generation ROS1 TKIs are currently in clinical development crizotinib Lorlatinib ORR 36% entrectinib ceritinib TPX-0005 (ongoing phase 1 study) responses noted in: ROS1 G2302R post crizotinib Cabozantinib (ongoing phase 2 study) response noted in: ROS1 D2033N post crizotinib Gainor et al, JCO-PO 2017; Besse et al, ESMO 2017; Drilon et al, ASCO 2018; Drilon et al, Clin Cancer Res 2016

22 Clinically actionable drivers of NSCLC RET fusions

23 Maximum reduction from baseline measurement(%) RET fusion-positive lung cancers can respond to RET TKI therapy cabozantinib: # % 20% Best confirmed response Partial response Stable disease ORR 28% (95% CI 12-49%) Trial met its primary endpoint. 0% -20% -40% -60% -80% -100% Baseline Week 4 Median PFS 5.5 mo (95% CI 3 8 to 8 4) Median OS 9.9 mo (95% CI 8 1-NR) Drilon et al, Lancet Oncol 2016

24 Outcomes with older RET inhibitors were modest: newer drugs show more promise RET LOXO-292 RET BLU-667 Drilon et al, Nat Rev Clin Oncol 2017; Velcheti et al, WCLC 2017; Subbiah et al, ASCO 2018

25 Selective RET inhibitors are active in RET-rearranged NSCLCs RET BLU-667 ORR 50% BLU-667 RET LOXO-292 LOXO-292 ORR 77% Velcheti and Drilon et al, WCLC 2017

26 Clinically actionable drivers of NSCLC NTRK1/2/3 fusions

27 NTRK fusions are found in diverse cancers including lung cancers Cancers enriched for TRK fusions Secretory breast carcinoma Mammary analogue secretory carcinoma Infantile fibrosarcoma Frequency 75% to >90% Cancers harboring TRK fusions at lower frequencies Congenital mesoblastic nephroma Pontine glioma Spitzoid melanoma Thyroid Cancer GIST ( pan-negative ) Frequency 5% to 25% Lung cancer Other sarcomas Astrocytoma/Glioblastoma Colorectal cancer Cholangiocarcinoma Pancreatic cancer Head and neck squamous cancer Breast cancer Melanoma Frequency <1% to <5% Estimated 1,500 5,000 patients harbor TRK fusionpositive cancers in the United States annually

28 Tumor agnostic drug development can address the long tail Histology-specific drug development Alteration-specific drug development (agnostic of tumor type) Traditional designs BASKET TRIAL NTRK fusion NTRK fusion NTRK fusion NTRK fusion NTRK fusion Umbrella trials One qualifying group of alterations Tumor agnostic patient accrual Offin and Drilon et al, ASCO Ed Book 2018

29 Tumor Reduction, % NTRK fusion-positive cancers are sensitive to TRK TKI therapy Response achieved in 100% of tumors Rapid and prolonged (~1 year, ongoing) responses were observed Response achieved in a variety of histologies and fusion types CRC: LMNA-NTRK1 Astrocytoma: BCAN-NTRK1 NSCLC: SQSTM1-NTRK1 MASC: EVT6-NTRK3 ETV6-NTRK3 Gene-Rearranged Fibrosarcoma (20-Month-Old) Baseline Day 35 entrectinib 0% -10% -20% -30% -40% -50% -60% -70% -80% -90% -100% CRC Astrocytoma NSCLC MASC RECIST V1.1 3D volumetric assessment (Courtesy of P Brastianos, MD, MGH) SD by RECIST V1.1 Massive peritumoral edema, midline shift, transtentorial herniation, progressive lethargy Decreased tumor and edema, patient with increased alertness, resumed eating and crawling Drilon et al, Cancer Discov 2017

30 NTRK fusion-positive cancers are sensitive to TRK TKI therapy in a tissueagnostic manner larotrectinib ORR 75%, median PFS not reached Drilon et al, New Engl J Med 2017 *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy. Pathologic CR.

31 Larotrectinib is active in an NTRK fusion-positive secretory breast carcinoma Baseline Day 6 Day 20 14F, prior therapy: 4 lines of chemotherapy and repeated resections Treated with larotrectinib under expanded access Shukla et al, J Clin Oncol Precision Oncol 2017

32 On-target resistance can respond to a next-generation TRK inhibitor 1st gen drug Entrectinib 2nd gen drug TPX-0005 baseline week 4 week 12 Baseline Day 10 Day 15 Day 28 Larotrectinib LOXO-195 Drilon et al, Cancer Discov 2018; Drilon et al, ASCO 2018

33 Clinically actionable drivers of NSCLC NRG1 fusions

34 NRG1 fusions are found across a wide variety of solid tumors CANCER TYPE breast pancreas SQCLC head/neck ovarian lung adeno kidney prostate uterine Drilon et al, Cancer Discov 2018

35 NRG1 fusion-positive cancers can respond to targeted therapy invasive mucinous adenocarcinoma resection for stage IIA (pt2bn0m0) disease followed by radiation recurrent metastatic disease TUMOR NORMAL CD74-NRG1 fusion identified Anti-ERBB3 mab: GSK carboplatin pemetrexed (1.4 mo SD) paclitaxel (5.5 mo SD) paclitaxel bevacizumab (9 months SD) nivolumab (1.3 mo PD) 19 months confirmed partial response Drilon et al, Cancer Discov 2018

36 Summary Select mutations/fusions are clinically actionable drivers of lung cancer growth. Mutations: BRAF V600E, MET exon 14, HER2 MUTATIONS Fusions: ROS1, RET, NTRK1-3, NRG1 TKI therapy for select drivers: high ORR (60-80%), durable disease control Comprehensive molecular profiling is important. Tumor-based testing complemented by plasma-based testing RNA-based testing may detect additional drivers Challenges Understanding acquired resistance and determining how to rationally sequence therapies. Establishing data in the non-metastatic setting.