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Targeted/Precision Therapies Beyond EGFR and ALK Alterations

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Targeted/Precision Therapies Beyond EGFR and ALK Alterations Targeted/precision therapies beyond EGFR and ALK alterations: novel therapies and mechanisms of resistance (ROS1, BRAF-V600E, NTRK, MET, RET, ERBB2, KRAS-G12C and others) Daniel B. Costa, MD, PhD, MMSc Associate Professor of Medicine Harvard Medical School Medical Director Cancer Clinical Trials Office Thoracic Oncology Group Leader Division of Medical Oncology Beth Israel Deaconess Medical Center Disclosures Relevant financial relationships with a commercial interest: _ Clovis Oncology, research funding (previous 2016) _ Boehringer Ingelheim Pharm. Inc., consulting/honoraria (previous 2016) _ Pfizer Inc., consulting/honoraria (previous 2017) _ Takeda/Millennium Pharmaceuticals, consulting/honoraria (previous 2016-2019) _ AstraZeneca, consulting/honoraria/research funding (previous 2016-2019) Non-financial support (institutional research support): _ Merck Sharp & Dohme Corporation _ Pfizer _ Takeda/Millennium Pharmaceuticals _ Astrazeneca _ Merrimack Pharmaceuticals _ Novartis “Off-label” use disclosure relevant to my presentation: _ To be indicated during presentation Outline • Historical view of non-small-cell lung cancer (NSCLC) from 2004 to 2019 • Background in evolution of kinase inhibitors for EGFR mutations and ALK rearrangements • Precision oncology for lung cancer in 2019 • Focus on ROS1 rearrangements (crizotinib, entrectinib) • Focus on BRAF-V600E mutation (dabrafenib/trametinib) • Focus on NTRK rearrangements (larotrectinib, entrectinib) • Focus on RET rearrangements • Focus on MET exon 14 skipping • Focus on ERBB2 exon 20 mutations • Focus on KRAS-G12C mutation Presented by: Daniel B. Costa, MD, PhD, MMSc Clinical relevance and scope of the problem: Lung Cancer Evidence-based therapies for advanced non-small-cell lung cancer circa 2004 Medical Oncology management of evidence-based therapies for advanced non-small-cell lung cancer from BIDMC – Dec. 2019 Contemporary View of Lung Cancer 2007-2019: NSCLCs are heterogeneous at the genomic level Adapted from: American Cancer Society (2014) Adapted from: Imielinski M. et al. Cell 150, 1107-1120 (2012) EGFR mutations (~15%) squamous cell carcinoma unselected histology-based KRAS genomics-driven non-small-cell lung cancer (NSCLC) other/unknown mutations (~25%) cytotoxic adenocarcinoma cytotoxic precision therapies chemotherapies chemotherapies ALK rearrangements (1990s) (2000s) ROS1 (~5%) (2010s) rearrangements Adapted from: Shaw AT et al. N Engl J Med;368:2385-94 (2013) (~2%) Driver oncogene genotypes with kinase inhibitor approval/development (advanced lung adenocarcinoma) in 2019 Genetic aberrations that EGFR mutations can modulate gefitinib/erlotinib targeted or immune afatinib/dacomitinib therapies: osimertinib STK11/LKB1 ALK rearrangements TP53 crizotinib/ceritinib alectinib/brigatinib PIK3CA other/ RB1 approved lorlatinib non-targetable ROS1 rearrang. crizotinib/entrectinib HDR genes (BRCA1/2 BRAF-V600E mut. PALB2) dabrafenib + trametinib NTRK rearrang. MSI/MMR larotrectinib/entrectinib genes emerging (MLH1 MET amplification MSH2 MSH6 MET exon 14 other MSI-H) skipping KRAS evolving RET rearrangements Tumor mut. burden mutations (TMB) ERRB2 mutations other possible targetable PD-L1 driver oncogenes KRAS-G12C (FGFR, NRAS, NF1, MAP2K1, BRAF[non-V600E], RIT1) The Achilles' heel of oncogene “addicted” tumors differentiation vascular collapse survival Driver proliferation oncogene apoptosis senescence kinase inhibitor : target Anaplastic lymphoma kinase (ALK) is an oncogene in NSCLC: Identification of ALK rearrangements/translocations in 2007 ALK rearrangements activate signaling pathways Or Inversion Translocation ALK ALK fusion protein* PI3K RAS PLC-Y STAT3/5 AKT MEK PIP mTOR 2 BAD ErK S6K IP3 Cell survival Tumor cell proliferation Soda M., et al. Nature. 2007 Aug 2;448(7153):561-6. Adapted from: Bang Y et al. Proc ASCO 2010;Abstract 3. ALK inhibitors (multitargeted TKIs) in clinical development in late 2007 - early 2010: crizotinib A549 H3122 (KRAS G12S) (EML4–ALK E13;A20) crizotinib 0 0.1 1.0 0 0.1 1.0 (µM) pALK ALK 120kDa pAKT AKT 60kDa actin 45kDa RR (CR+PR) = 57% (95% CI: 46–68%) DCR (CR+PR+SD) = 87% (71/82) crizotinib 250 mg BID Yasuda et al. J Thorac Oncol. 2012 Jul;7(7):1086-90. Kwak, E. et al. N Engl J Med 2010 Oct28; 363(18):1693-703. ALK TKI crizotinib as first line therapy for ALK rearranged NSCLC: PROFILE1014 – results Solomon BJ et al N Engl J Med 2014;371:2167 Acquired resistance to crizotinib (pharmacokinetic or biologic) - crizotinib pharmacokinetic issues (major component): low serum conc., poor CNS penetration, p-glycoprotein - crizotinib biological resistance: ALK kinase domain mutations or bypass oncogenes ALK mutations: L1196M Activated 1151Tins oncogenes: C1156Y F1174L EGFR G1202R S1206Y KIT G1269A (crizotinib resistant) IGF-1R G1202R P2Y/PKC F1174C/L (ceritinib resistant) Inadequate central nervous system/brain penetration: G1202R I1171T/N/S (alectinib resistant) Adapted from: Costa DB. Lancet Oncol 2017;18(7):837-839. Costa DB. Cell Cycle. 2017;16(1):19-20. Initial results of the second generation ALK kinase inhibitor alectinib (600 mg twice daily) - 138 patients with NSCLC received 600 mg/twice day of alectinib; - Overall response rate (RR) was 50% (95%CI, 41-59); - The median progression-free survival (PFS) was 8.9 months (95% CI, 5.6-11.3). - Adverse events were mild (grade 1 or 2) with constipation, fatigue and edema the most common Ou SH et al. JCO 2016; 34:661 What is the best 1st line ALK TKI for ALK rearranged NSCLC ALEX clinical trial of alectinib vs crizotinib: improved systemic and intracranial control with fewer toxicities Peters S. et al. NEJM 2017; 377:829-838 The Achilles' heel of oncogene “addicted” tumors differentiation vascular collapse survival Driver proliferation oncogene apoptosis senescence kinase inhibitor : target EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR S768I N-lobe exon 19 T790M deletions/ exon 18 insertions indel C-helix A763_Y764 G719X insFQEA P-loop exon 20 erlotinib insertions L858R L861Q activation loop C-lobe Adapted from Yasuda, Kobayashi, Costa DB. Lancet Oncology; 13(1):e23-31. (2012) Palliative therapies for advanced EGFR mutated NSCLC: (Nov. 2019) “SM” = sensitizing mutation. “X” in G719X = substitution for several different amino acids and is not a stop codon. Adapted from Sheikine Y, Rangachari D Approved doses of TKIs are: gefitinib 250mg daily, erlotinib 150mg daily (1st generation TKIs); afatinib 40mg daily (2nd et al. Clin Lung Cancer; 17(6):483. generation TKI); osimertinib 80mg daily (3rd generation TKI). #Most common exon 19 deletion is delE746_A750 (LREA (2016) motif). *Cause of acquired resistance to gefitinib, erlotinib and afatinib in >50%. ^Cause of osimertinib resistance in 30%. EGFR TKIs as first line therapy for EGFR mutated NSCLC: 1st/2nd generation EGFR TKIs vs chemotherapy ) erlotinib EURTAC ( Summary: (EGFR-L858R and exon 19 deletions) - ORRs significantly higher for EGFR TKIs - PFSs were 42-84% longer with EGFR TKIs - No detriment in OS with EGFR TKIs (cross over) Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014) Rossel R., et al. Lancet Oncol;13(3):239 .(2012) Preclinical development of covalent pyrimidine EGFR mutant- specific TKIs and clinical development of the current “evidence- based” first line EGFR TKI osimertinib for common EGFR mutants Head-to-head trials of different EGFR TKIs: 2nd generation (afatinib/dacomitinib) vs 1st generation (gefitinib/erlotinib) 3rd generation (osimertinib) vs 1st generation (gefitinib/erlotinib) Why is osimertinib the current “evidence-based” first line EGFR TKI for common EGFR mutants (FL-AURA trial)? Mechanisms of resistance to covalent pyrimidine EGFR inhibitors such as osimertinib (preclinical models and initial clinical studies of cfDNA/re-biopsy) The future for covalent pyrimidine EGFR inhibitors such as osimertinib: combinations therapies to delay/prevent resistance (↑PFS/OS) What we have learned from the development of EGFR and ALK inhibitors for lung cancers that applies to other oncogene-driven tumors 1. The need to identify an oncogene, its variants, prove in preclinical models that the oncogene drives tumor dependence and can be inhibited with pathway- specific inhibitors, and then develop a clinical test to allow for diagnosis in routine pathology specimens in a timely fashion; 2. The need to prove in clinical trials high response rate, that then can translate into improved outcomes against previously established evidence-based cytotoxic chemotherapy +/- immunotherapy; 3. The need to then develop/test more potent inhibitors (for both systemic disease and central nervous system penetration) and less toxic oral monotherapies that become newest evidence-based backbones for future attempts to improve palliative therapies in advanced disease or be used in the adjuvant setting to attempt to improve cure rates; 4. The understanding that combination therapies to delay/prevent resistance will be part of the clinical trial portfolio for treatment-naïve oncogene-driven tumors within the next decade. Driver oncogene genotypes with kinase inhibitor approval/development (advanced lung adenocarcinoma) in 2019 Genetic aberrations that EGFR mutations can modulate gefitinib/erlotinib targeted or immune afatinib/dacomitinib therapies: osimertinib STK11/LKB1 ALK rearrangements TP53 crizotinib/ceritinib alectinib/brigatinib PIK3CA other/ RB1 approved lorlatinib non-targetable ROS1 rearrang. crizotinib/entrectinib HDR genes (BRCA1/2 BRAF-V600E mut. PALB2) dabrafenib + trametinib
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