EGFR and ALK Fadlo R. Khuri, MD President, American University of Beirut Professor of Medicine July 26, 2018
A great year end! Targeted Therapy for NSCLC:
Evolving Landscape of Lung Adenocarcinoma NSCLC was once considered a single disease, until distinct subtypes and characteristics were revealed Characteristics of NSCLS subtypes are clinically relevant for treatment planning from the point of diagnosis Figure adapted from Pao W, et al. Lancet Oncol. 2011;12(2):175-180
Treatment Algorithm for Advanced NSCLC Stage IV NSCLC Molecular testing for EGFR, ALK, ROS1, BRAF IHC for PD-L1 Expression EGFR, ALK, ROS1, OR BRAF PD-L1 > 50% No targetable mutation PD-L1 < 50% No Targetable mutation Targeted therapy 1. Pembrolizumab 2. Pembro Plus Chemo (Non-sq) 1. Platinum-based chemotherapy* 2. Chemo plus Pembro (Non-sq) * Bevacizumab/ necitumumab added when appropriate
Tsao AS, et al. J Thorac Oncol. 2016;11(5):613-638. Lung Adenocarcinoma in 2018 Targeted Therapy for NSCLC:
EGFR MT NSCLC: A Distinct Molecular Subset
EGFR Tyrosine Kinase Inhibitors Targeted Therapy for NSCLC: Agents Indication Salient aspects 1 st Generation TKI Gefitinib Erlotinib 1 st line therapy Reversible inhibition 2 nd Generation TKI Afatinib Dacomitinib 1 st line therapy Irreversible inhibition 3 rd Generation TKI Osimertinib 1 st line therapy 2 nd line therapy for T790M+ NSCLC Irreversible inhibition
TKI Vs. Chemotherapy in EGFR MT NSCLC Author Study Agent N (EGFR mut+) RR Median PFS (mo) OS (mo) Mok et al IPASS Gefitinib 261 71.2% vs 47.3% 9.8 vs 6.4 21.6 vs 21.9 Han et al First-SIGNAL Gefitinib 42 84.6% vs 37.5% 8.0 vs 6.3 27.2 vs 25.6 Mitsudomi et al WJTOG 3405 Gefitinib 172 62.1% vs 32.2% 9.2 vs 6.3 30.9 vs NR Maemondo et al NEJGSG002 Gefitinib 230 73.7% vs 30.7% 10.8 vs 5.4 30.5 vs 23.6 Zhou et al OPTIMAL Erlotinib 154 83% vs 36% 13.7 vs 4.6 22.7 vs 28.9 Rosell et al EURTAC Erlotinib 174 58% vs 15% 9.7 vs 5.2 19.3 vs 19.5 Wu et al ENSURE Erlotinib 217 62.7% vs 33.6% 11.0 vs 5.5 26.3 vs 25.5 Sequist et al LUX-Lung 3 Afatinib 345 56% vs 23% 13.6 vs 6.9 30.3 vs 26.2 Wu et al LUX-Lung 6 Afatinib 364 67% vs 23% 11.0 vs 5.6 22.1 vs 22.2 EGFR, epidermal growth factor receptor; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; RR, response rate; TKI, tyrosine kinase inhibitor. Mok TS, et al. N Engl J Med. 2009;361(10):947-957. Han JY, et al. J Clin Oncol. 2012;30(10):1122-1128. Mitsudomi T, et al. Lancet Oncol. 2010;11(2):121-128. Maemondo M, et al. N Engl J Med. 2010;362(25):2380-2388. Zhou C, et al. Lancet Oncol. 2011;12(8):735-742. Zhou C, et al. J Clin Oncol. 2012;30(Suppl): Abstract 7520. Rosell R, et al. Lancet Oncol. 2012;13(3):239-246. Wu YL, et al. Ann Oncol. 2015;26:1883-1889. Sequist LV, et al. J Clin Oncol. 2013;31(27):3327-3334. Wu YL, et al. Lancet Oncol. 2014;15(2):213-222.
We humans can agree on one overriding and universal theme: our good health is a precious and fragile gift. No wonder it is said that yesterday is history, tomorrow is a mystery, today is a gift, that is why they call it---present. Howard Koh
T790M is the Most Common Mechanism of Resistance to EGFR TKI Sequist LV, et al. Sci Transl Med. 2011;3(75):75ra26. Yu H, et al. Clin Cancer Res. 2013 Apr 15;19(8):2240-7. Piotrowska Z, et al. Cancer J. 2015;21(5):371-377. Camidge DR, et al. Nat Rev Clin Oncol. 2014;11(8):473-481.
Inspiring supporters of the AUB Mission What's so special about AUB? Everything... starting from the Main Gate, College Hall, Jafet's Library, the Chapel (now Assembly Hall), Marquand House and West Hall, the ground and the trees and my love, the Green Field Ramzi Alamuddin But I believe that children are born with empathy, and without discrimination they have to be taught to hate. Which means they can also be taught to respect others, use reason, be ethical, embrace diversity, challenge orthodoxy, and fight injustice. As a new parent I think that such lessons are the most important education a child can receive, a gift that top universities like AUB can provide them. Amal Clooney
World Cup 2018 with the boys ready to watch and play!
Osimertinib is Superior to Chemotherapy (AURA 3) Mok TS, et al. N Engl J Med, 2017;376(7):629-640.
Progression-free Survival Mok TS, et al. N Engl J Med, 2017;376(7):629-640.
FLAURA: Osimertinib Vs. Gefitinib/Erlotinib Ramalingam S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA2_PR. Soria JC, et al. N Engl J Med. 2018;378(2):113-125.
FLAURA: PFS Body Ramalingam S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA2_PR.
Conclusions- Gotterdamerung! Targeted Therapy for NSCLC:
FLAURA: Efficacy Against Brain Metastases Ramalingam S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA2_PR.
FLAURA: Overall Survival Ramalingam S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA2_PR.
Conclusions - Take that first generation TKI s (and Brazil!)
FLAURA: Adverse Events Ramalingam S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract LBA2_PR.
Evolution of Resistance Costa DB, et al. Transl Lung Cancer Res. 2015;4(6)809-815.
Dacomitinib Vs. Gefitinib Skin rash (G3/4) Diarrhea (G3/4) Dose reduction Dacomitinib Gefitinib 14% - 8% 1% 66% 8% Wu YL, et al. Lancet Oncol. 2017;18(11):1454-1466.
Study Period Design : NEJ 026 (Phase III study) Furuya N, et al. J Clin Oncol. 2018;36(suppl): Abstract 9006.
Primary endpoint: PFS by independent review Furuya N, et al. J Clin Oncol. 2018;36(suppl): Abstract 9006.
What Is a Role of Immunotherapy in EGFR-Mutant NSCLC? Meta-analysis of randomized clinical trials comparing OS benefit of second-line immune checkpoint inhibitors vs chemotherapy Lee CK, et al. J Thorac Oncol. 2016;12(2):403-407.
Present in 3-7% of NSCLC. ALK Rearrangements in Lung Cancer Typically adenocarcinoma histology. Typically (but not always!) never smokers or light former smokers. Detection methods: FISH IHC Next Generation Sequencing (NGS) Confusing nomenclature: ALK rearrangement, ALK fusion, ALK+ All mean the same thing for this purpose. Multiple studies have now shown that tumors harboring ALK rearrangements are sensitive to ALK inhibition. Shaw AT, et al. J Clin Oncol. 200927(26):4247-4253. Soda M, et al. Nature. 2007;448(7153):561-566. Sasaki T, et al. Eur J Cancer. 2010;46(10):1773-1780.
Pharmacol Res. 2017 Mar;117:343-356. ALK TKI Landscape of ALK inhibitors ADDITIONAL TARGETS 1 st generation Crizotinib MET, ROS1 FDA-approved (11/2013) Targeted Therapy for NSCLC: STATUS 2 nd generation Alectinib RET, LTK FDA accelerated approved, post crizotinib (12/2015) FDA breakthrough-therapy designation, first line (10/2016) Brigatinib Mutant EGFR, ROS1 FDA accelerated approval, post crizotinib (4/2017) Ceritinib IGF-R1, IR, ROS1 FDA-approved, post crizotinib (4/2014) FDA-approved, first line (5/2017) Ensartinib MET, ABL, AXL Investigational Entrectinib NTRKs, ROS1 Investigational 3 rd generation Lorlatinib ROS1 FDA breakthrough-therapy designation, in patients who have received 1 or more ALK inhibitors (4/2017) Awad MM, et al. Clin Adv Hematol Oncol. 2014;12(7):429-439. Roskoski R, et al. Pharmacol Res. 2017;117;343-356. The USA FDA. https://www.fda.gov/default.htm. Accessed July 11, 2018.
ALEX Study Design Targeted Therapy for NSCLC: N Engl J Med. 2017 Aug 31;377(9):829-838. Peters S, et al. N Engl J Med. 2017;377(9):829-838.
ALEX: PFS Peters S, et al. N Engl J Med. 2017;377(9):829-838.
First line therapy for ALK+ lung cancer Patient with metastatic ALK+ lung cancer First line ALK TKI therapy Second line ALK TKI therapy Third line (+beyond) ALK TKI therapy Crizotinib FDA approved Ceritinib FDA approved Alectinib FDA breakthrough therapy designation, final decision pending 11/30/17/ Brigatinib vs. Crizotinib (ALTA-1L, NCT02737501) accrual completed Ensartinib vs. Crizotinib (exalt3, NCT02767804) Lorlatinib vs. Crizotinib (NCT03052608)
Second line therapy for ALK+ lung cancer Patient with metastatic ALK+ lung cancer First line ALK TKI therapy Second line ALK TKI therapy Third line (+beyond) ALK TKI therapy Ceritinib* Brigatinib* Entrectinib Alectinib* Ensartinib Lorlatinib * = FDA approved post crizotinib
ALK Inhibitors: Activity Against Gatekeeper Mutations Camidge DR, et al. Presented at: 17 th World Congress on Lung Cancer. December 4-7, 2016. Vienna, Austria.
Other Treatable Mutations Target Treatment Results Status RET gene rearrangement LOXO-292 RR 75% In development MET exon 14 mutation Crizotinib RR 44% In development NTRK Fusion Larotrectinib RR- 70% In development
RET is activated by two major mechanisms in cancer Presented By Alexander Drilon at 2018 ASCO Annual Meeting
Clinical activity of LOXO-292 in RET-altered cancers Presented By Alexander Drilon at 2018 ASCO Annual Meeting
Conclusions Targeted therapy provides superior outcomes for a number of molecular subset of NSCLC EGFR - Osimertinib emerges as the most efficacious agent in class ALK - Alectinib is associated with mpfs > 2 yrs Options for other rare targets continue to improve Molecular testing is a must for patients with lung adenocarcinoma And a nod to our sponsors
Thank you, and that s all, folks! July 26, 2018 American University of Beirut