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CLOSING LECTURE Avanços no Câncer de Pulmão 2016: um ano em análise (Advances in Lung Cancer 2016: a year in review) Daniel B. Costa, MD, PhD, MMSc Associate Professor of Medicine Harvard Medical School Thoracic Oncology Group Leader Division of Hematology/Oncology Beth Israel Deaconess Medical Center 2013-2016: A Golden Era For Approval of Anti-Cancer Therapies for Advanced Non-Small-Cell-Lung Cancer (EGFR, ALK, ROS1 TKIs, VEGF inhibitors, EGFR antibody, anti-PD-1, PD-L1 antibodies) crizotinib reg. approval ALK+ ramucirumab ceritinib 2ndline NSCLC ALK+ 2013 erlotinib approved EGFR+ necitumumab osimertinib approved squ. EGFR-T790M+ 2014 afatinib EGFR+ crizotinib ROS1+ 2015 gefitinib EGFR+ nivolumab pembrolizumab PD-1 approved PD-L1+ alectinib ALK+ 2016 atezolizumab PD-L1 ? 2017 Small cell lung cancer (no approvals for close to a decade) [the final frontier for novel anti-cancer compound approvals] 2013 2014 2015 ? 2017-2018 DLL3 target rovalpituzumab tesirine (Rova-T) ? 2017-2018 immune checkpoint inhibitors pembrolizumab or nivolumab 2016 My personal thoughts about upcoming drug approvals for ES-SCLC: SCLC stem cell markers (DLL3) rovalpituzumab tesirine (Rova-T) – likely by 2017/2018 Immune checkpoint inhibitors (anti-PD-1 agents) nivolumab (off-label use since 2015) pembrolizumab (off-label use since 2015) - likely FDA approval of anti-PD-1 by 2017/2018 1st, 2nd and 3rd generation EGFR tyrosine kinase inhibitors (TKIs) osimertinib EGFR-T790M+ 2013 erlotinib approved EGFR+ 2014 afatinib EGFR+ 2015 gefitinib EGFR+ 2016 EGFR mutations, ALK and ROS1 rearrangements in lung adenocarcinomas (minimal testing required) Lung Cancer Mutation Consortium (LCMC) n=733 CAP, IASLC and AMP recommend rapid testing for EGFR mutations and ALK rearrangements (plus add ROS1 rearrangement in 2016) in all patients with advanced stage adenocarcinoma, regardless of sex, race, smoking history or other clinical risk factors LCMC frequency: EGFR mutations 14-20% ALK rearrangements 6-10% ROS1 rearrangements 1-2% (Lindeman NI, et al. J Thorac Oncol 8:823 [2013]) (adapted from Kris MG, et al. JAMA 311:1998 [2014]) Palliative therapies for advanced EGFR mutated NSCLC: (November 2016) “SM” = sensitizing mutation. “X” in G719X = substitution for several different amino acids and is not a stop codon. Approved doses of TKIs are: gefitinib 250mg daily, erlotinib 150mg daily (1st generation TKIs); afatinib 40mg daily (2nd generation TKI); osimertinib 80mg daily (3rd generation TKI). #Most common exon 19 deletion is delE746_A750 (LREA motif). *Cause of acquired resistance to gefitinib, erlotinib and afatinib in >50%. ^Cause of osimertinib resistance in 30%. Evidence-based use of EGFR TKIs (gefitinib, erlotinib and afatinib) for EGFR-L858R or exon 19 deletions mutated advanced NSCLCs as first line systemic therapy April 23rd, 2009 (European Medicines Agency) and 2015 (US): Gefitinib (Iressa) approved by for the treatment of NSCLC with EGFR mutations (mostly exon 19 deletions and L858R) September 1st, 2011 (European Medicines Agency): Erlotinib (Tarceva) approved by European Union for the treatment of NSCLC with EGFR mutations (mostly exon 19 deletions and L858R) May 14th, 2013 (Food and Drug Administration/US): Erlotinib (Tarceva) approved by FDA for the treatment of NSCLC with EGFR mutations (exon 19 deletions and L858R) July 12th, 2013 (Food and Drug Administration/US): Afatinib (Gilotrif) approved by FDA for the treatment of NSCLC with EGFR mutations (exon 19 deletions and L858R) What is the best 1st line EGFR TKI for EGFR mutant NSCLC: LUX-Lung 7 clinical trial of afatinib vs gefitinib EGFR TKIs and EGFR mutated NSCLC: mechanisms of resistance to 1st/2nd gen. EGFR TKIs neuroendocrine transformation NSCLC SCLC LCNEC H&E Chromogranin Synaptophysin Kobayashi S. N Engl J Med;352:786. (2005) Yun CH. Proc Natl Acad Sci; 105:2070. (2008) Engelman JA. Science: 316:1039. (2007) Pao W. Proc Natl Acad Sci; 104: 20932. (2007) Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (covalent EGFR TKI, osimetinib) Phase I study of osimertinib/AZD9291 (clinicaltrials.gov - NCT01802632) The AURA Study – FDA approval Nov. 13th, 2015 Courtesy of Pasi Jänne – Santa Monica Conference (2014) Ranson M. European Cancer Congress: abstr33LBA. (2013) Ranson M. 15th WCLC: abstract.11-034. (2013) Cross. AACR-NCI-EORTC: abstract A109. (2013) Janne PA. N Engl J Med;372:1689. (2015) FDA approval of 3rd gen. EGFR TKI osimertinib for EGFR-T790M advanced NSCLC (AURA2 clinical trial) AURA2 The Lancet Oncology 2016 osimertinib – EGFR-T790M positive (rebiopsy) ORR 70% duration response 11.4 months median PFS 9.9 months 1-yr OS 81% only 3% participants required dose reductions and 5% discontinued drug from adverse event Whack-a-mole paradigm for EGFR TKI monotherapies 1st/2nd generation EGFR TKIs (gefitinib, erlotinib or afatinib) T790M(clinical assay) 3rd generation EGFR TKI (osimertinib) T790M+ (clinical assay) 12-16 months T790M+ / C797S+ (clinical assay) 9-12 months EGFR mutated cells sensitive to 1st/2nd generation EGFR TKIs T790M+ T790M- (other resistant mechanisms) T790M+ / C797S+ T790M(clinical assay) T790M+ or - / C797S(clinical assay) T790M± / C797S(other resistant mechanisms) Adapted from Costa DB, Kobayashi S. Trans Lung Cancer Research (2015) 1st and 2nd gen. ALK TKIs 1st generation ROS1 TKI upcoming inhibitors for other genomic cohorts (BRAF-V600E, MET) crizotinib reg. approval ALK+ 2013 ceritinib ALK+ 2014 crizotinib ROS1+ 2015 alectinib ALK+ 2016 ? 2016-2017 BRAF-V600E dabrafenib + trametinib ? 2018 MET-exon 14 skip. crizotinib (other MET TKI) ALK inhibitors (multitargeted TKIs) in clinical development in late 2007 - early 2010: crizotinib A549 H3122 (KRAS G12S) (EML4–ALK E13;A20) crizotinib (µM) 0 0.1 1.0 0 0.1 1.0 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 Crizotinib as an ALK TKI versus 1st line chemotherapy for CNS disease after radiotherapy platinum-based 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 1151Tins C1156Y F1174L G1202R S1206Y G1269A (crizotinib resistant) Activated oncogenes: G1202R F1174C/L (ceritinib resistant) P2Y/PKC G1202R I1171T/N/S (alectinib resistant) EGFR KIT IGF-1R Initial results of the second generation ALK/ROS1 kinase inhibitor ceritinib (750 mg once daily) - 114 patients with NSCLC received at least 400mg/day of ceritinib; - Overall response rate (RR) was 58% (95%CI, 48-67); - Among 80 patients who had received crizotinib previously, the RR was 56% (95% CI, 45-67); - Among patients with NSCLC who received at least 400mg/day of ceritinib, the median progression-free survival (PFS) was 7.0 months (95% CI, 5.6-9.5). Shaw AT et al. N Engl J Med 2014; 370:1189 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 J-ALEX clinical trial of alectinib vs crizotinib Summary of mechanisms of ALK inhibitor resistance and therapeutic strategies for ALK rearranged NSCLC (2016) ROS1 rearrangements define a novel actionable oncogene in NSCLC: clinical activity of crizotinib (PROFILE 1001 trial) ~ 1-2% of all NSCLC ~ 6% of never smokers sensitive to crizotinib Stumpfova M , and Jänne P A Clin Cancer Res 2012;18:4222 crizotinib 250 mg BID (PROFILE1001) RR 72% (95%CI 58-84%) [n=50] median PFS 19.2 months (95%CI: 14.4-NR) overall survival (OS) 85% at 12 months Shaw AT et al. N Engl J Med 2014; 371:1963 MET amplification as an actionable oncogene in NSCLC responsive to crizotinib - High grade MET amplification present in 1-2% NSCLCs (smokers and never smokers) (adenocarcinoma histology) - Ongoing clinical trials of MET TKIs (example: crizotinib) Adapted from: Camidge et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8001) Adapted from: Christine Lovly et al. MyCancerGenome.org 2014 MET exon 14 skipping mutations as actionable oncogenes in NSCLC responsive to crizotinib - MET exon 14 skipping mutations present in 4% NSCLCs (smokers and never smokers) (adenocarcinoma histology) - Ongoing clinical trials of MET TKIs (example: crizotinib) TCGA. Nature 511:543 (2014) Kong-Beltran Can Research (2006) Jenkins RW Clin Lung Cancer (2015) Shea M, Costa DB JTO (2016) BRAF mutations as actionable oncogenes in NSCLC (1) -somatic mutations in BRAF have been found in 1–3% of all NSCLC (smokers and never smokers); (adenocarcinoma histology) - BRAF V600E (~50% of cases) Adapted from: Planchard et al. J Clin Oncol 31, 2013 (suppl; abstr 8009) Adapted from Christine Lovly et al. MyCancerGenome.org 2013 Driver oncogene genotypes with kinase inhibitor approval/development (lung adenocarcinoma) in 2016/2017 EGFR mutations gefitinib erlotinib afatinib osimertinib none/other approved ALK rearrangements crizotinib ceritinib alectinib NF1 mutations emerging RIT1 mutations evolving HRAS mutations NRAS mutations future ROS1 rearrangements crizotinib BRAF-V600E mut. dabrafenib+trametinib MET amplification (high) MET exon 14 skipping mutation ERBB2 mutations MAP2K1 mutations RET rearrangements FGFR2/3/4 mutations/ rearrangements KRAS mutations NTRK1 rearrangements Adapted from: Shea M. Ther Adv Respir Dis. 2016 Immune checkpoint inhibitors for NSCLC (squamous cell carcinomas and adenocarcinomas) anti-PD-1 pembrolizumab (1st line PD-L1 IHC ≥50%, 2nd line PD-L1 IHC >1%) anti-PD-1 nivolumab (2nd line, irrespective of biomarker PD-L1 IHC) anti-PD-L1 atezolizumab (2nd line, irrespective of biomarker PD-L1 IHC) 2015 nivolumab pembrolizumab PD-1 approved PD-L1+ 2016 atezolizumab PD-L1 Harnessing the immune system to treat lung cancer (PD-1 and PD-L1 antibodies [remove the breaks of the immune system]) Ribas A., et al. N Engl J Med 2012; 366:2417-2519. Harnessing the immune system to treat lung cancer (PD-1 and PD-L1 antibodies: early activity in NSCLC since 2012) effects of the anti-PD-L1 antibody BMS-936559 (example, drug discontinued) anti-PD-1 and anti-PD-L1 antibodies with FDA approval for NSCLC: Nivolumab (phase III trials – “positive” survival/FDA approved 2015) Pembrolizumab (phase III trials - “positive PD-L1-survival”/FDA approved 2015) Atezolizumab (phase III trial – “positive” survival/FDA approved 2016) Brahmer JR, et al. N Engl J Med 2012; 366:2455-2465. FDA approval of anti-PD-L1 atezolizumab for second line therapy of advanced NSCLC (POPLAR clinical trial) POPLAR The Lancet April 30 2016 atezolizumab – PD-L1 IHC score predictive of improved outcomes (not mandatory for selection) ORR 15% duration response 14.3 months median PFS 2.7 months median OS 12.6 months OS FDA approval of anti-PD-1 nivolumab for second line therapy of advanced NSCLC (CheckMate-057 clinical trial) CheckMate -057 Borghaei H NEJM 2015 nivolumab – PD-L1 IHC score predictive of improved outcomes (not mandatory for selection) ORR 19% duration response 17.2 months median PFS 2.3 months 12-month OS 51% OS FDA approval of anti-PD-1 pembrolizumab for second line therapy of advanced NSCLC (KEYNOTE-010 clinical trial) KEYNOTE -010 Herbst R et al. The Lancet 2016 pembrolizumab - PD-L1 >1% expression using the clone 22C3 pharmDx kit ORR 18% duration response NR (> 10-12 mths) median PFS 3.9 months PFS median OS 10.4 months OS FDA approval of anti-PD-1 pembrolizumab for first line therapy of advanced NSCLC (KEYNOTE-024 clinical trial) KEYNOTE -024 Reck M et al. NEJM 2016 pembrolizumab - PD-L1 ≥50% expression using the clone 22C3 pharmDx kit ORR 44.8% duration response NR (1.9-14.5 mths) median PFS 10.3 months PFS 6-month survival 80.2% OS New view of NSCLC (lung adenocarcinoma) in 2016-2017 (oncogene driven, immune evasion enhanced or none) [1] PD-L1 <50% EGFR or ALK or ROS1 positive PD-L1 <50% EGFR/ALK/ROS1 neg. [~20%] TKI 1st line [~50%] cytotoxic chemotherapy 1st line PD-L1 ≥50% EGFR/ALK/ROS1 neg. [~30%] anti-PD-1 pembrolizumab 1st line Adapted from Costa DB, et al. 2016 (manuscript in preparation) New view of NSCLC (lung adenocarcinoma) in 2016-2017 (oncogene driven, immune evasion enhanced or none) [2] advanced lung adenocarcinoma subtype classic driver oncogene enriched (EGFR/ALK/ROS1 pos.) immune checkpoint inhibitor enriched 1st line therapy 2nd line therapy 3rd line therapy approved TKI approved matched TKI (EGFR-T790M+ or ALK) (EGFR-T790M- or ROS1) cytotoxic chemotherapy or anti PD-1 or anti-PD-L1 cytotoxic chemotherapy cytotoxic chemotherapy anti-PD-1 (pembrolizumab) or cytotoxic chemotherapy (PD-L1 ≥50%) non-oncogene non-immune enriched (EGFR/ALK/ROS1 neg.) (PD-L1 <50%) cytotoxic chemotherapy anti-PD-1 (nivolumab or pembrolizumab) or anti-PD-L1 cytotoxic chemotherapy (atezolizumab) Adapted from Costa DB, et al. 2016 (manuscript in preparation) Avanços 2016: um ano em análise