LATEST DEVELOPMENT IN LUNG CANCER IMUNOTHERAPY & INSIGHTS TO THE DAILY CLINICAL PRACTICE

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1 LATEST DEVELOPMENT IN LUNG CANCER IMUNOTHERAPY & INSIGHTS TO THE DAILY CLINICAL PRACTICE Solange Peters MD-PhD Head Medical Oncology and Thoracic Clinic Oncology Department Lausanne University Hospital

2 DISCLOSURE SLIDE I have received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: Amgen, AstraZeneca, Boehringer- Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, Janssen, Merck Sharp and Dohme, and Merck Serono, Pfizer, Regeneron and Takeda. I declare no conflict of interest.

3 NSCLC Outcome: 8th TNM

4 Lung cancer facts Lung cancer is characterized by a strongly immunosuppressive environment We have been enrolling thousands of patients in strictly negative vaccine trials Lung tumors display ~200 nonsynonymous mutations per tumor. Lung cancers from smokers have 10 times as many somatic mutations as those from non smokers. Vogelstein, Science 2013 Lawrence, Nature 2013

5 Barriers to T-cell activity in solid tumors

6 Approvals in NSCLC Nivo (2L SQ) 1 Nivo (2L SQ) 2 Checkpoint Inhibitors in Thoracic Cancers: Nivo (2L NSQ) Nivo ± ipi (SCLC) Checkmate 032 Pembro (SCLC) KEYNOTE-028 Pembro (Meso) KEYNOTE-028 Nivo (2L) 3 Pembro (2L PD-L1+) 1 Pembro (2L PD-L1+) 2 Nivo (2L NSQ) 2 Key Milestones Pembro (1L PD-L1+) Nivo (Meso) NivoMes Avel (Meso) JAVELIN Solid Tumor Pembro (Thymic) NCT Atezo (2L) 1 Atezo (SCLC) NCT U.S. Food and Drug Administration. 2. European Medicines Agency. 3. ONO Pharmaceutical Co., Ltd. 4. Merck [press release]. December 19, Pembro (1L PD-L1+) 4 Pembro (2L PD-L1+) 4 Pembro (1L PD-L1+) 2 Pembro + chemo (1L) 1 Atezo (2L) Nivo ± ipi (Meso) MAPS2 Durva (Stage IIIB) 1 Nivo ± ipi TMB (SCLC) Checkmate 032 Nivo + ipi (Meso) INITIATE Clinical data in other thoracic tumors 6

7 NIVO+IPI Lung-MAP DURVA + Treme Arctic AVEL + utomilumab JAVELIN Medley OX40 agonists + utomilumab NCT DURVA + AZD9291 CAURAL NIVO+IPI Checkmate 722 Lung-MAP AVEL + utomilumab JAVELIN Medley OX40 agonists + utomilumab NCT NIVO + Cx Checkmate 722 DURVA + AZD9291 CAURAL Later lines Second line First line NIVO Checkmate 077 Checkmate 078 Checkmate 870 Checkmate 153 DURVA ATLANTIC NIVO Checkmate 017 Checkmate 057 Checkmate 077 ( 2L) Checkmate 078 ( 2L) Checkmate 870 ( 2L) Checkmate 384 Checkmate 153 ( 2L) Checkmate 907 PEMBRO KEYNOTE-010 ATEZO POPLAR OAK FIR ATEZO + Cx IMpower 130 IMpower 131 IMpower 132 IMpower 150 PEMBRO + Cx KEYNOTE-021 KEYNOTE-189 KEYNOTE-407 NIVO+Cx Checkmate 012 Checkmate 227 Checkmate 568 Checkmate 722* ONO PEMBRO KEYNOTE-024 KEYNOTE-042 NIVO Checkmate 026 DURVA + TREME + Cx POSEIDON NCT NIVO + erlo or Cx or NIVO+Ipi in EGFR M+ Checkmate 012 Checkmate 370 ATEZO + erlo or alectinib NCT PEMBRO + crizotinib NCT PEMBRO + MK-1308 NCT DURVA+ Treme MYSTIC NEPTUNE NCT NIVI/PEMBRO+ epacadostat ECHO202 ECHO204 NIVO+Ipi Checkmate 012 Checkmate 227 Checkmate 817 Checkmate 592 Checkmate 955 Checkmate 568

8 Data show a consistent OS benefit in 2 nd line

9 Our lessons from late lines clinical trials Histological subtype does not matter, but smoking does Anti PD(L)-1 response is rapid and rarely non conventional PD-L1 positivity allows enrichment Observed OS effect is stronger than PFS : non-proportional HRs Activity is present in the brain Anti PD(L)-1 has manageable toxicities Anti PD(L)-1 is better tolerated than docetaxel Anti PD(L)-1 results in better PROs than chemotherapy In NSCLC, a plateau and long term survival are observed

10 OS (%) y OS, 42% 5-Year Estimates of OS Phase 1 Nivolumab Median OS (95% CI), mo Overall (N = 129) 9.9 (7.8, 12.4) 2 y OS, 24% 3 y OS, 18% 5 y OS, 16% Years No. at Risk Brahmer, AACR 2017 Leigh, ASCO 2017 Plateau and long term survival 3-Year Estimates of OS Phase 1 pembrolizumab

11 Are we treating NSCLC patients as in clinical trials? Treatment patterns for a population of Canadian patients with metastatic NSCLC (Ontario, through multiple linked provincial databases) Sacher, Cancer 2015 Stinchcombe and Socinski. Oncologist 2008

12 First line platinum doublet chemotherapy is a challenging Treatment N PD-L1+ % competitor RR % PFS (median) months OS (median) PARAMOUNT (NSCC) 359? E4599 (NSCC) 434? Squire (SCC) 545?

13 ORR (%) PD-L1 Cutoffs: ORR by PD-L1 expression levels in 1L NSCLC 50 CheckMate 012 KN-001 BIRCH Durva JAVELIN Solid Tumor 58,3 (NCT ) , ,4 21, , ,2

14 Key eligibility criteria: Stage IV or recurrent NSCLC CheckMate 026: Nivolumab vs Chemotherapy No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression a CNS metastases permitted if adequately treated at least 2 weeks prior to randomization Randomize 1:1 Stratification factors at randomization: PD-L1 expression (<5% vs 5%) a Histology (squamous vs non-squamous) Nivolumab 3 mg/kg IV Q2W n = 271 Chemotherapy (histology dependent) b Maximum of 6 cycles n = 270 Tumor scans Q6W until wk 48 then Q12W Disease progression Primary endpoint: PFS ( 5% PD-L1+) d Secondary endpoints: PFS ( 1% PD-L1+) d a Dako 28-8 validated; archival tumor samples obtained 6 months before enrollment were permitted; PD-L1 testing was centralized b Squamous: gemcitabine 1250 mg/m 2 + cisplatin 75 mg/m 2 ; gemcitabine 1000 mg/m 2 + carboplatin AUC 5; paclitaxel 200 mg/m 2 + carboplatin AUC 6; Non-squamous: pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 ; pemetrexed 500 mg/m 2 + carboplatin AUC 6; option for pemetrexed maintenance therapy c Permitted 14 if crossover eligibility criteria met, including progression confirmed by independent radiology review d Tumor response assessment for PFS and ORR per RECIST v1.1 as determined by independent central review OS ORR d Disease progression or unacceptable toxicity Crossover nivolumab c (optional)

15 PFS (%) PD-L1 >5% CheckMate 026 Median PFS, months (95% CI) Months Nivolumab n = (3.0, 5.6) Nivolumab Chemotherapy Chemotherapy n = (5.4, 6.9) 1-year PFS rate, % No. of patients at risk: Nivolumab Chemotherapy Socinsky, ESMO 2016 HR = 1.15 (95% CI: 0.91, 1.45), P = All randomized patients ( 1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)

16 KEYNOTE-024 Pembrolizumab vs chemo in high PD-L1 Key Eligibility Criteria Untreated stage IV NSCLC PD-L1 TPS 50% ECOG PS 0-1 No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy Key End Points Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, safety Exploratory: DOR R (1:1) N = 305 Pembrolizumab 200 mg IV Q3W (2 years) Platinum-Doublet Chemotherapy (4-6 cycles) PD a Pembrolizumab 200 mg Q3W for 2 years

17 P F S, % Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, Events, n Median, mo HR (95% CI) % 70 50% 48% 60 15% No. at risk PD-L1 >50%: Keynote 024 Time, months Pembro Chemo ( ) Brahmer, ASCO 2017 P <0.00 1

18 PD-L1 >50%: Keynote 024: updated OS Brahmer, WCLC 2017

19 EMA approval: 12/2016 Pembrolizumab frontline

20 Do we have good biomarkers in hands for NSCLC? Tissue is strongly limited in NSCLC Almost all trials so far in NSCLC have shown a positive relationship between clinical benefit from PD1 or PD-L1 inhibitors and PD-L1 expression Most data are presented for a cut off value rather than by cohorts determined by ranges of expression.

21 The dilemma of predictive PD-L1 IHC 5 drugs, each with its own PD-L1 IHC assay Drug Antibody Platform TC IC Nivolumab 28-8 clone Dako + Pembrolizumab 22C3 clone Dako + Atezolizumab SP142 clone Ventana + + Durvalumab SP263 clone Ventana + Avelumab - Dako + 4 antibodies 2 immunostainer platforms Different cut-offs (<1%, 5%, 10%, 25%, 50%) Different scoring: Tumor cells +/- Immune cells

22 Comparison studies using trial-validated assays German Ring study NCCN Study AZ500 study IASLC Blueprint study Scheel et al. Mod Pathol 2016; Rimm D et al (in press), Ratcliffe MJ et al, CCR 2017 epub, Hirsch FR et al, JTO 2017; The 28-8, 22C3 and SP263 assays are technically similar The SP142 assay is different We can use ONE assay and read it for prescription of multiple drugs. This defines a need for harmonization! Cave: about 50% of 27 LDTs showed discordant results - Kappa < 0.75

23 High TMB May Influence the Immune-Mediated Tumor cells with high TMB 1,2 Tumor cell Anti-Tumor Response may have high neoantigen load 1,2 which can lead to increased immune and anti-tumor response 2-5 NK cell CD8+ T cell 1. Schumacher TN, Schreiber RD. Science. 2015;348(6230): Kim JM, Chen DS. Ann Oncol. 2016;27(8): Liontos M et al. Ann Transl Med. 2016; 4(14): Sharma P, Allison JP. Science. 2015;348(6230): Giannakis M et al. Cell Rep. 2016;15: Tumor The hypothesis that high TMB increases the immunogenicity of tumors makes them a rational target for treatment with I-O therapies 1,2

24 PFS (%) High TMB Median PFS, months (95% CI) No. at Risk by Time Months Nivolumab Chemotherapy PFS by TMB Subgroup Nivolumab Chemotherapy n = 47 n = (5.5, NA) 5.8 (4.4, 9.1) HR = 0.62 (95% CI: 0.38, 1.00) Nivolumab Chemotherapy Low/Medium TMB Median PFS, months (95% CI) Nivolumab Chemotherapy n = 111 n = (2.8, 5.4) 6.9 (5.6, 8.8) HR = 1.82 (95% CI: 1.30, 2.55) Chemotherapy Nivolumab Months

25 TMB by F1 (somatic mutations per Mb) TMB by WES (missense mutations) How to assess TMB? TMB Concordance Between F1 and WES There was no association between TMB and PD-L1 expression (in these patients with 1% PD-L1 tumor expression) TMB WES median 148 WES bridged to F In silico/vitro F1 panel simulation correlates with WES (n=312) - TMB calculated from WES was highly correlated with TMB outputs from F1 (Spearman s r = 0.9) (n=44)

26 Can it be performed in liquid biopsies?

27 Comparing TMB across matched tumor tissue and ctdna? TMB TMB (including potentially functional variant) Median (muts/mb) TMB<15 (n) TMB>15 (n) Median (muts/mb) TMB<15 (n) TMB>15 (n) Matched-Paired Concordance Tissue ctdna Test Mean of Differences 95% CI P [-15.2, -5.0] < [-0.4, -0.0] Paired T-test [-19.6, -10.0] < Andrew A. Davis, et al. JCO , no. 15_suppl - published online before print [-0.4, -0.1] <0.001 Correlation Coefficient Pearson Correlation P Coefficient of Determination R= R 2 = R= R 2 = patients with NSCLC (53), breast cancer (34), and other solid tumors (10) with paired tissue (FoundationOne) and ctdna (Guardant360) Tissue coverage ~ million bp; ctdna coverage 78, ,000 bp P

28 OAK (atezolizumab) serum TMB

29 Plasma ctdna release: affected by many factors n=223 Tumor type Tumor stage Blood-brain barrier These can all impact plasma ctdna release Sci Transl Med. Feb 19, 2014; 6(224): 224ra24 frequency of cases with detectable ctdna (%) 100% 80% 60% 40% 20% 0% n=355 P<0.001 n=218 Brain 单纯脑转移 metastasis Other 其它转移部位 metastasis

30 Yarchoan, NEJM 2017 Mutation burden across diseases

31 Biomarkers signatures applied for frontline IO? PD-L1 IHC Mutational burden or surrogate Microsatellite instability Surrogates of immune response Immune cells Gene signature Rizvi NA, et al. Science. 2015;348: Fehrenbacher L, et al. Lancet 2016;387: McGranahan N, et al. Science. 2016;351:

32 Routy et al., Science 359, (2018) 5 January 2018

33 PFS by fecal diversity

34 Maximal heterozygosity at HLA-I loci improved overall survival on immunotherapy compared with patients who were homozygous for at least one HLA locus.

35 Therapeutic Approaches to engage the immune system Activation/priming of T cells mab against PD-1, PD-L1, CTLA-4 IL-2 IL-12 Agonists for CD137, OX40, CD27 Presentation of tumorassociated antigens by APC Vaccines IFN-α GM-CSF Release of tumor-associated antigens Chemotherapy Radiotherapy Targeted therapy Lymph node Tumor Blood vessel Migration of activated T cells to the tumor via blood vessels Infiltration of T cells into the tumor mab against VEGF/VEGFR Recognition and killing of tumor cells mab against PD-1, PD-L1, IDO, LAG-3 Combinations across modalities might allow to drive tumour immunogenicity

36 Combining immunotherapy and chemotherapy Immunotherapy can modify tumor micro-environment increasing sensitivity to chemotherapy Reduced support to cancer cells (effect on MDSC and macrophages) Reprogrammed tumor vasculature Chemotherapy can boost the immune response Immunogenic cell death Depletion of myeloid cells & Tregs, influx of TILs, inflammation Leisha A. Emens, and Gary Middleton Cancer Immunol Res 2015;3: Lorenzo Galluzzi et al. Cancer Immunol Res 2016 Peters, ASCO 2017

37 Rational for Anti-angiogenesis & Immunomodulation combination c n O y g o l o l a c i Angiogenic factors play in influencing lymphocyte trafficking nacross endothelia into i l C tumor deposits n i s s a l VEGF has profound effects on immune regulatory cell function c r e t By inhibiting dendritic cell maturation and antigen presentation s a By inhibiting T-cell responses (upregulation PD-L1, PD-L2, IDO-1, IL-6, IL-10 ) M O By inducing proliferation of regulatory T cells M S By favoring accumulation of myeloid-derived suppressor cells E O S E h t 17

38 38 Stage IV or recurrent metastatic Non-squamous NSCLC Chemotherapy-naive a Tumour tissue available for PD-L1 & Teff testing Any PD-L1 IHC Stratification factors: Sex PD-L1 IHC expression Liver metastases N = 1202 IMpower150 study design IMpower150 evaluates the addition of atezolizumab to chemotherapy ± bevacizumab in chemotherapy-naive patients with non-squamous NSCLC R 1:1:1 Arm A Atezolizumab b + Carboplatin c + Paclitaxel d 4 or 6 cycles Arm B Atezolizumab b + Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Arm C Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Maintenance therapy (no crossover permitted) Atezolizumab b Atezolizumab b + Bevacizumab e Bevacizumab e Treated with atezolizumab until PD by RECIST v1.1 or loss of clinical benefit AND/OR Treated with bevacizumab until PD by RECIST v1.1 Teff, T-effector; WT, wild-type. a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m 2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w. Reck M, et al. IMpower150 PFS analysis. Survival follow-up

39 4 cycles of platin? Median, 6.8 mo (95% CI: 6.0, 7.1) PFS in EGFR and ALK WT Landmark PFS, % Median, 8.3 mo (95% CI: 7.7, 9.8) Arm C: bev + CP Arm B: atezo + bev + CP 6-month 56% 67% 12-month 18% 37% HR, (95% CI: 0.517, 0.737) P < Minimum follow-up: 9.5 mo

40 Keynote-024 PD-L1 > 50%: pembrolizumab mpfs 10m 1yr PFS 48% Did we define new IO standards for all advanced untreated NSCLC patients? Monotherapy IO/IO IO/chemo Phase 1/2 Ipi/Nivo Terme/Durva (Mystic PFS negative) Frontline therapy for naive Advanced NSCLC IMPower 150 All PD-L1 non-squamous, bevacizumab eligible pembrolizumab + chemo + bev mpfs 8m 1yr PFS 37% 20-30% 40% Squamous PD-L1 0-49%? 20-80%?

41 Mystic phase 3 trial

42 Keynote 189

43 Checkmate 227

44 Impower 131

45 The pace of clinical trials in NSCLC has clearly outstripped our understanding of specific immunogenicity and our ability for a rational selection of patients

46 Target Overview of the PD-1/L1 combo trials in lung cancer Numbers of Trials Using Common Combo Strategies: 1. Anti-CTLA-4 agents: Chemotherapies: Radiotherapies: 15 THERAPIES AGAINST 61 DIFFERENT TARGETS ARE BEING COMBINED WITH ANTI-PD1/L1 AGENTS 4. Chemoradiotherapy combos: 10 Chemotherapy 48 Chemoradiothera py 10 Radiotherapy 15 CTLA-4 48 Courtesy of Cancer Research Institute Part 3

47 Resistance mechanisms Impaired recognition, insensitivity to T cell effectors and trafficking

48 Thanks for your attention