Recent Advances in Lung Cancer: Updates from ASCO Updates from ESMO, AACR and ASCO

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1 Recent Advances in Lung Cancer: Updates from ASCO 2018 Updates from ESMO, AACR and ASCO Charu Aggarwal, MD, MPH Assistant Professor of Medicine Division of Hematology-Oncology Abramson Cancer Center University of Pennsylvania 6/14/2018

2 Please note that some of the studies reported in this presentation were published as abstracts only and/or presented at a conference. These data and conclusions are included because expert faculty found them to be important scientific contributions but should be considered to be preliminary until published in a peer-reviewed journal.

3 Outline Immunotherapy for NSCLC Front line Immunotherapy - Results from Keynote 189, 42 Squamous NSCLC - Results from Keynote 407, IMpower 131 Biomarkers Role of TMB - ready for primetime? EGFR Mutant NSCLC Osimertinib: Results from FLAURA Dacomitinib: Results from ARCHER Role of Chemo + EGFR TKI in front line setting

4 Outline Immunotherapy for NSCLC Front line Immunotherapy - Results from Keynote 189, 42 Squamous NSCLC - Results from Keynote 407, IMpower 131 Biomarkers Role of TMB - ready for primetime? EGFR Mutant NSCLC Osimertinib: Results from FLAURA Dacomitinib: Results from ARCHER Role of Chemo + EGFR TKI in front line setting

5 KEYNOTE 24: Pembrolizumab vs. Chemotherapy Reck et al, NEJM 2016

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

7 KEYNOTE 189: ChemoIO vs. Chemotherapy Gandhi et al, NEJM 2018

8 KEYNOTE 189: Results N= 410 vs. 206 PDL1 expression categories balanced Mirroring the prevalence of 33-34% HR 0.49!! Benefit seen across all subgroups HR 0.42 for High PDL1 Similar Benefit for PFS RR highest in PDL1 high (61.4%) Gandhi et al, NEJM 2018

9 Cross Trial Comparison ORR = 61.4% Longer follow-up required ORR = 44.8% HR 0.63 Median 30 vs 14.2 months 2 year landmark survival 51% vs 34.5%

10 KEYNOTE 42: Pembro vs. Chemotherapy All histologies Squamous ALLOWED Lopes et al, ASCO 2018

11 KEYNOTE 42: Results Overall Survival: TPS 50% Trial did not allow crossover Only 19.8% in chemo arm rec d Pembro!! ~ 47% PDL1>50% (usual prevalence 33%) OS being driven by high PDL1 RR 27% similar to chemo! (>1%) HR 0.8 for OS (>1%) HR 0.9 for OS (1-49%) Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

12 Cross Trial Comparison KEYNOTE-042, TPS>50% HR = 0.69 Median 20 vs months 2 year landmark survival 44.7% vs 30.1% ORR 39.5%

13 KEYNOTE 407: ChemoIO vs. Chemotherapy Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

14 KEYNOTE 407: Results N=559 PDL1 expression categories balanced Mirroring the prevalence of 33-34% HR 0.64 in SQUAMOUS!! Benefit seen across all subgroups Similar Benefit for PFS Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

15 Cross Trial Comparison KEYNOTE-407 SQUAMOUS IMPOWER-131 SQUAMOUS

16 My Takeaways STILL important to look for PDL1 Non-Squamous patients KEYNOTE-189 shows us that triplet is better irrespective of PDL1 level KEYNOTE-42 confirms patients with High PDL1 do well with single agent Pembro No clear role of Pembro alone for PDL1 intermediate (1-49%) Squamous patients KEYNOTE-407 shows us that triplet is potentially the new standard I would still prefer to use Pembro alone for PDL1 high in this population (need longer follow up) Role of Atezolizumab less clear

17 Outline Immunotherapy for NSCLC Front line Immunotherapy - Results from Keynote 189, 42 Squamous NSCLC - Results from Keynote 407, IMpower 131 Biomarkers Role of TMB - ready for primetime? EGFR Mutant NSCLC Osimertinib: Results from FLAURA Dacomitinib: Results from ARCHER Role of Chemo + EGFR TKI in front line setting

18 CheckMate 227: Ipi/Nivo vs. Chemotherapy Patients for PD-L1 co-primary analysis N = 1189 Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W n = 396 Nivolumab + ipilimumab n = 396 1% PD-L1 expression R 1:1:1 Histology-based chemotherapy b n = 397 Chemotherapy b n = 397 Key Eligibility Criteria Stage IV or recurrent NSCLC No prior systemic therapy No known sensitizing EGFR/ALK alterations ECOG PS 0 1 Stratified by SQ vs NSQ Nivolumab 240 mg Q2W n = 396 Patients for TMB co-primary analysis c Nivolumab + ipilimumab n = 139 Chemotherapy b n = 160 N = 550 Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W n = 187 <1% PD-L1 expression R 1:1:1 Histology-based chemotherapy b n = 186 Nivolumab 360 mg Q3W + histology-based chemotherapy b n = 177 Co-primary endpoints: Nivolumab + ipilimumab vs chemotherapy OS in PD-L1 selected populations PFS in TMB-selected populations Database lock: January 24, 2018; minimum follow-up: 11.2 months Hellman et al, AACR 2018

19 CheckMate 227: Patients With High TMB ( 10 mut/mb) a Hellman et al, AACR 2018

20 CheckMate 227: Ipi/Nivo vs. ChemoIO vs. Chemo

21 CheckMate 227: Ipi/Nivo vs. ChemoIO vs. Chemo Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

22 CheckMate 227: Ipi/Nivo vs. ChemoIO vs. Chemo Presented By Hossein Borghaei at 2018 ASCO Annual Meeting

23 Proposed Management Presented By Solange Peters at 2018 ASCO Annual Meeting

24 Proposed Management Presented By Solange Peters at 2018 ASCO Annual Meeting

25 My takeaways PDL1 is a crude, imperfect biomarker It is easy to obtain Most labs do it reflexly I would still recommend obtaining it TMB may be then used as an enrichment biomarker Currently difficult to obtain 2-4 week turnaround Interest in blood based biomarkers, esp. TMB analysis (Velcheti et al, Aggarwal + Carpenter ongoing) Others: HLA, Microbiome (and more!)

26 Outline Immunotherapy for NSCLC Front line Immunotherapy - Results from Keynote 189, 42 Squamous NSCLC - Results from Keynote 407, IMpower 131 Biomarkers Role of TMB - ready for primetime? EGFR Mutant NSCLC Osimertinib: Results from FLAURA Dacomitinib: Results from ARCHER Role of Chemo + EGFR TKI in front line setting

27 FLAURA : Front Line OSI vs. Erlotinib/Gefitinib Primary Endpoint: PFS Secondary Endpoint: ORR, DoR, Disease Control Rate, Depth of Response, OS, PROs, Safety Soria et al, NEJM 2018

28 FLAURA Results Soria et al, NEJM 2018

29 Two NEW studies at ASCO

30 How should we sequence new EGFR therapies? T790M + Dacomitinib PFS 14.7 mo Osimertinib T790M - Chemo Chemo Osimertinib PFS 18.9 mo Chemo/IO T790M + Gefitinib/Carbo/Pem PFS 20.9 mo T790M - Osimertinib Chemo

31 My Takeaways OSI is available and should be the current standard Improved PFS OS not mature yet CNS penetration is a huge benefit Gefitnib + chemotherapy may be a reasonable approach PFS of 20 mos, still leaves potential of T790M directed therapy No clear role of Dacomitinib

32 Summary Immunotherapy is the established front line standard for metastatic NSCLC PDL1 High may be able to get treated with IO alone For PDL1 <50%, triplet remains standard for non-squamous AND new data to support it for SQUAMOUS TMB is an emerging biomarker Targeted therapy is still the standard of care therapy for EGFR MT therapy Osimertinib is the current standard Chemo + TKI may have a role under special circumstances Chemo + OSI

33 Thank you! Charu Aggarwal, MD,