Recent Advances in Lung Cancer: Updates from ASCO PDF Free Download

Recent Advances in Lung Cancer: Updates from ASCO 2017 Charu Aggarwal, MD, MPH Assistant Professor of Medicine Division of Hematology-Oncology Abramson Cancer Center University of Pennsylvania 6/15/2017

Outline Immunotherapy for NSCLC Front line Immunotherapy - updated results from Keynote 024 EGFR Mutant NSCLC ARCHER: Dacomitinib vs. Gefitinib ALK Rearranged NSCLC ALEX: Alectinib vs. Crizotinib Immunotherapy Combination for SCLC Nivolumab + Ipilimumab in SCLC

KEYNOTE 024 Front line, PDL 1 > 50% Pembro vs. Investigator choice chemotherapy Pembrolizumab was FDA approved in metastatic NSCLC expressing PD-L1 (TPS > 50%) and no previous chemotherapy Clear and Strong Signal of Activity ORR was improved PFS improved by 4.3 months (HR 0.5) Survival Benefit (HR 0.6) Strongest Signal seen in SCC (HR 0.35) Control Arm performed as expected Reck et al, NEJM 2016

KEYNOTE 024 - PFS 2 update What is PFS2? - To assess the impact of cross over therapy - Assess whether an investigational therapy positively or negatively affects the next line of therapy

KEYNOTE 024 Patient Disposition Enrolled patients N=305 Pembrolizumab N=154 Chemotherapy N=151 48 with PD 97 with PD Platinum Doublet 87.5% - Carbo/pem/bev 35.4% - Carbo/pac/bev 18.8% Pembrolizumab 81.4% Anti PD-1 12.4% Other 6% Non Platinum Doublet 12.5% Presented By Julie Brahmer at 2017 ASCO Annual Meeting

KEYNOTE 024 Results Median PFS2 18.3 vs. 8.4 months HR 0.54 P<0.001 Kaplan-Meier Estimate of PFS2 Median OS NR vs. 14.5 months HR 0.6 P=0.003 Presented By Julie Brahmer at 2017 ASCO Annual Meeting

Does this change practice? Practice affirming, not changing For patients with PDL-1> 50% Pembrolizumab continues to show survival benefit (median OS NR) Despite cross over of 60%, there was a high level of separation of survival curves Improved survival for patients that begin with Pembrolizumab Caveats Combination Carboplatin/Pemetrexed + Pembro vs. Carbo/Pem alone Superior PFS for combination, HR 0.5 (Langer et al, Lancet Oncology 2016) OS NR (p=0.13, HR 0.69) (Papadimitrakopoulou et al, ASCO 2017) sbla approval for Carbo/Pem/Pembro already in place Await Keynote 189 Data How will we choose between Pembro Monotherapy vs. Combination Chemo/IO

Current treatment of EGFR MT NSCLC EGFR Mutation Testing is standard of care at diagnosis We have FOUR FDA Approved oral TKIs: Erlotinib, Gefitinib, Afatinib Osimertinib Randomized studies have established oral TKI as superior therapy c/w chemotherapy Study Agent N (EGFR MT) RR (%) PFS (mos) OS (mos) IPASS Gefitinib 261 71.2 vs. 47.3 9.8 vs 6.4 21.6 vs 21.9 First-SIGNAL Gefitinib 42 84.6 vs. 37.5 8.4 vs 6.7 27.2 vs 25.6 WJTOG 3405 Gefitinib 177 62.1 vs. 32.2 9.2 vs 6.3 35.5 vs 38.8 NEJGSG002 Gefitinib 230 73.7 vs. 30.7 10.8 vs 5.4 30.0 vs 23.6 OPTIMAL Erlotinib 154 83 vs. 36 13.1 vs 4.6 22.6 vs 28.8 EURTAC Erlotinib 154 54.5 vs. 10.5 9.2 vs 5.4 19.3 vs 19.5 LUX-Lung 3 Afatinib 345 56 vs. 23 11.9 vs 6.9 HR 1.12 LUX-Lung 6 Afatinib 364 67 vs. 23 11.0 vs 5.6 HR 0.95 Mok et al NEJM 2009, Lee et al JCO, 2011, Mitsudomi et al Lancet Oncology, 2010, Maemondo NEJM 2010, Zhou et al Lancer Oncology, 2011, Rosell et al Lancet Oncology, 2012, Yang et al ASCO, 2012, Sequist et al JCO, 2012, Wu et al ASCO, 2013

ARCHER Trial ARCHER 1050: Study Design Presented By Tony Mok at 2017 ASCO Annual Meeting

ARCHER Trial - PFS PFS: Blinded Independent Review (ITT population) Presented By Tony Mok at 2017 ASCO Annual Meeting

Is this practice changing? Represents a potential new front line approach Not ready for primetime just yet Not yet FDA approved Compared to Gefitinib (even though approved in US, used only by a minority of practitioners) Different toxicity profile 66% patients required dose reduction with Dacomitinib c/w 8% with Gefitinib

How would we sequence new EGFR therapies? T790M + Dacomitinib Osimertinib Chemo/IO T790M - Dacomitinib Chemo/IO 1 st Line Osimertinib Chemo/IO

FLAURA: Phase III Osi vs. Gef or Erl.

Current treatment of ALK Rearranged NSCLC Testing for ALK rearrangement is standard of care at diagnosis We have FOUR FDA Approved oral TKIs: 1 st line: Crizotinib and Ceritinib 2 nd line: Alectinib and Brigatinib How do we sequence ALK therapies? Crizotinib Alectinib 3 rd gen/ Lorlatinib Chemo/IO Crizotinib Brigatinib 3 rd gen/ Lorlatinib Chemo/IO

ALEX Trial Study design Presented By Alice Shaw at 2017 ASCO Annual Meeting

Shaw et al, ALEX: PFS underpinned by CNS activity

Should we change our current first line? YES ALEX provides proof of superior PFS (> 2years!) With CNS mets improved efficacy Without CNS mets seems to be neuroprotective Caveats OS not mature enough Would sequencing be similar?

Slide 26 Presented By Shirish Gadgeel at 2016 ASCO Annual Meeting

How do we sequence new ALK therapies? Crizotinib Alectinib 3 rd gen/ Lorlatinib Chemo/IO Crizotinib Brigatinib 3 rd gen/ Lorlatinib Chemo/IO Alectinib Bx SPECIFIC ALK Inhibitor

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Phase I/II CheckMate 032 Study Design Presented By Matthew Hellmann at 2017 ASCO Annual Meeting

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC OS Non-Randomized Cohort

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC ORR by Subgroups Pooled Cohorts Presented By Matthew Hellmann at 2017 ASCO Annual Meeting

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC 3-month PFSa and OS Rates

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Summary of Safety Pooled Cohorts Presented By Matthew Hellmann at 2017 ASCO Annual Meeting

Does this change practice? Probably Response rate with Nivolumab plus Ipilimumab looks promising Caveats Selective presentation of 3 month PFS and OS rates Toxicity is substantial with this combination

Summary Immunotherapy for NSCLC Front line Immunotherapy with Pembrolizumab shows persistent survival benefit PFS2 improved with Pembrolizumab for patients with PDL-1>50% EGFR Mutant NSCLC Dacomitinib is superior to Gefitinib for front line therapy Sequencing of these oral agents is an important question - ongoing trials ALK Rearranged NSCLC PFS improved with Alectinib c/w Crizotinib in front line therapy CNS progression rates reduced Represents a new standard in front line treatment Immunotherapy combination for SCLC Nivolumab + Ipilimumab looks promising in SCLC Toxicity should be considered

And while I was at ASCO Mama, we know you are at a meeting but we MISS you!

Thank you