PD-1 Inhibitors on the Horizon for NSCLC: Current Knowledge, Future Possibilities

touchSATELLITE SYMPOSIUM

PD-1 inhibitors on the horizon for NSCLC: Current knowledge, future possibilities

This activity is an independently supported Satellite Symposium, not included in the ESMO Virtual Congress 2020 accredited program.

Funded by an independent medical education request from BeiGene. This activity is provided by touchIME. Disclaimer

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Prof. Tony Mok Prof. Giorgio V Scagliotti Dr Raffaele Califano Prof. Anne-Marie C Dingemans Co-chair Co-chair

Department of Clinical Oncology, Department of Oncology, Department of Medical Oncology, Department of Pulmonology, Chinese University of Hong Kong, University of Torino, The Christie NHS Foundation Trust, Erasmus Medical Center, Hong Kong, China Turin, Italy Manchester, UK Rotterdam, The Netherlands Agenda

Welcome and Introduction (5 mins) Tony Mok (Co-chair) PD-1 inhibitors for NSCLC: Where are we now? (10 mins) Tony Mok One molecule, many mechanisms of action: Why all PD-1 inhibitors are not the same (15 mins) Raffaele Califano How will the new wave of PD-1 inhibitors change the treatment landscape in NSCLC? (15 mins) Anne-Marie C Dingemans What is the impact of PD-1 inhibitors for NSCLC in your clinic? A case study discussion (10 mins) Tony Mok and Anne-Marie C Dingemans PD-1 inhibitors for NSCLC: Future challenges, future potential (20 mins) Giorgio V Scagliotti (Co-chair)

NSCLC, non-small cell lung cancer; PD-1, programmed death-1. Learning objectives

Review the latest clinical and pre-clinical data for anti-PD-1 agents in NSCLC

Discuss how current and emerging anti-PD-1 agents may be incorporated into the treatment landscape for NSCLC

Summarize how to identify the patients most suitable for anti-PD-1 blockade PD-1 inhibitors for NSCLC: Where are we now?

Prof. Tony Mok Department of Clinical Oncology Chinese University of Hong Kong Hong Kong, China Disclosures

AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eisai, Merck Sharp & Grant/research support Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Taiho.

AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Speaker’s fees Pfizer, Roche/Genentech, Taiho.

Stock Shareholder Hutchinson Chi-Med, Sanomics Ltd.

ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cirina, Clovis Advisory board Oncology, Eli Lilly, geneDecode, Ignyta, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, Roche/Genentech, SFJ Pharmaceutical, Vertex Pharmaceuticals.

AstraZeneca, Hutchinson Chi-Med, Sanomics. Board of Directors Chinese Lung Cancer Research Foundation Ltd., Hong Kong Cancer Therapy Society (HKCTS), International Association for the Study of Lung Cancer (IASLC). A positive report card: Reduction of lung cancer mortality in USA

50 Death-certificate mortality Improvement is 40 Death in 2006 attributed to Death in 2001 among patients with development of targeted among patients therapy 30 cancer diagnosed in Incidence-based mortality

adjusted with cancer 2002–2006 - diagnosed in 2001

Age 20 Death in 2016 among patients 2006–2013 2013–2016 with cancer 5-year burn-in period: Annual reduction of 3.2% Annual reduction ofdiagnosed 6.3% in 10 sufficient follow-back 2012–2016

number of deaths per 100,000 per deaths of number time to capture death Valid incidence-based mortality allowing partition of from lung cancer subtype-specific mortality trends in 2006–2016 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year of death

Howlader N, et al. New Engl J Med. 2020;383:640–9. List of FDA approved immune checkpoint inhibitors CTLA-4 Cancer cell escapes inhibitors immune system Ipilimumab Treg Tremelimumab • Nivolumab Cancer cell CTLA-4

• Ipilimumab MHC peptide TCR • Pembrolizumab Anergy CTL Signalling • Atezolizumab PD-L1 PD-1

CD28 • Durvalumab PD-L1 CTLA-4 TCR • Avelumab PD-L1 MHC peptide inhibitors • B7 Cemiplimab Cancer growth and B7 PD-L1 Pembrolizumab proliferation inhibitors Nivolumab Atezolizumab Avelumab Durvalumab DC

CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; DC, dendritic cell; FDA, Food and Drug Administration; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TCR, T cell receptor; Treg, regulatory T cell. Rapid growth in global ICI market

The market will be ACCELERATING growing at a CAGR of more than One of the KEY DRIVERS for this market will be the high-target affinity 19% $24.14 bn and specificity INCREMENTAL GROWTH

The market is EXTREMELY CONCENTRATED 49% with a few players occupying The year-over-year growth the market share of the growth will come rate for 2019 is estimated from the at AMERICAS 18.79% region

CAGR, compound annual growth rate; ICI, immune checkpoint inhibitor. How can we transform the rapid growth of the ICI market into a reduction in lung cancer mortality? Summary of our ICI strategy for advanced NSCLC

Biomarker as navigator First-line therapy

• PD-L1 expression • Single agent IO • TMB • Chemo + IO • Gene signature • Chemo + IO + bevacizumab • TIL infiltrate • IO + IO

IO, immunotherapy; NSCLC, non-small cell lung cancer; TIL, tumour infiltrating lymphocyte; TMB, tumour mutational burden. Summary of our ICI strategy for advanced NSCLC

Biomarker as navigator First-line therapy

• PD-L1 expression • Single agent IO • TMB • Chemo + IO • Gene signature • Chemo + IO + bevacizumab • TIL infiltrate • IO + IO

<1% 1–49% >50% List of selective randomized studies Study Selection Design PFS (months) OS (months) KEYN0TE-0241,2 PD-L1>50% PEMBRO vs chemo 10.3 vs 6.0 HR 0.501 30.2 vs 14.2 HR 0.632 KEYN0TE-0423 PD-L1>1% PEMBRO vs chemo 5.4 vs 6.5 HR 1.07 16.7 vs 12.1 HR 0.81 KEYN0TE-1894 PD-L1 0-100% chemo/PEMBRO vs chemo 8.8 vs 4.9 HR 0.52 NR vs 11.3 HR 0.49

KEYN0TE-4075 SCC; PD-L1 0-100% chemo/PEMBRO vs chemo 6.4 vs 4.8 HR 0.56 15.9 vs 11.3 HR 0.64

IMpower1506 PD-L1 0-100% chemo/BEV/ATEZO vs chemo/BEV 8.3 vs 6.8 HR 0.62 19.2 vs 14.7 HR 0.78 IMpower1317,8 SCC; PD-L1 0-100% chemo/ATEZO vs ATEZO 6.3 vs 5.6 HR 0.717 14.0 vs 13.9 HR 0.968 IMpower1329 PD-L1 0-100% PEMBRO/Pt/ATEZO vs PEMBRO/Pt 7.6 vs 5.2 HR 0.60 18.1 vs 13.6 HR 0.81

IMpower13010 PD-L1 0-100% nab-pacli/ATEZO vs nab-pacli 7.0 vs 5.5 HR 0.64 18.6 vs 13.9 HR 0.79

CheckMate-22711 PD-L1 <1% vs >100% IPI/NIVO vs NIVO vs chemo 6.7 vs 5.6 HR 0.62 21.2 vs 14.0 HR 0.70 CheckMate-9LA12 PD-L1 <1% vs >100% chemo x2 + IPI/NIVO vs chemo 6.7 vs 5.0 HR 0.68 15.6 vs 10.9 HR 0.66

ATEZO, atezolizumab; BEV, bevacizumab; chemo, chemotherapy; HR, hazard ratio; IPI, ipilimumab; nab-pacli; nab-paclitaxel; NIVO, nivolumab; NR, not reached; PEMBRO, pembrolizumab; PFS, progression-free survival; Pt, platinum-based chemotherapy; OS, overall survival; SCC, squamous cell carcinoma (lung). 1. Reck M, et al. N Engl J Med. 2016;375:1823–33; 2. Reck M, et al. J Clin Oncol. 2019;37:1537–46; 3. Mok TSK, et al. Lancet. 2019;393:P1819-30; 4. Gandhi L, et al. N Engl J Med. 2018:2078–92; 5. Paz-Ares L, et al. N Engl J Med. 2018;379:2040–51; 6. Socinski MA, et al. N Engl J Med. 2018;378:2288-301; 7. Jotte R, et al. J Thorac Oncol. 2020;15:1351–60; 8. Jotte R, et al. J Clin Oncol. 2018;36:LBA9000; 9. Papadimitrakopoulou V, et al. J Thorac Oncol. 2018;13:S332–3; 10. West H, et al. Lancet Oncol. 2019;20:924–37; 11. Hellmann MD, et al. N Engl J Med. 2019;381:2020–31; 12. Reck M, et al. J Clin Oncol. 2020;38:9501. KEYNOTE-024: Progression-free survival

100 Events, n Median, mo HR (95% CI) P 90 Pembro 73 10.3 0.50 80 <0.001 Chemo 116 6.0 (0.37–0.68) 70 62% 60 48% 50

PFS, % PFS, 40 30 RR 45% vs 28% 20 50% 10 15% 0 0 3 6 9 12 15 18 No. at risk Time, months pembro 154 104 89 44 22 3 1 chemo 151 99 70 18 9 1 0 Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016. CI, confidence interval; RECIST, Response Evaluation Criteria in Solid Tumours; RR, relative risk. Reck M, et al. N Engl J Med. 2016;375:1823–33. KEYNOTE-024: Overall survival

100 90 80 70 60 50

PFS, % PFS, 40 30

20 Median OS, months (95% CI) 10 30.0 (18.3–NR) vs 14.2 months (9.8–19.0) 0 0 3 6 9 12 15 18 21 24 27 30 33 No. at risk Time, months pembro 154 136 121 112 106 96 89 83 52 22 5 0 chemo 154 123 107 88 80 70 61 55 31 16 5 0

Reck M, et al. J Clin Oncol. 2019;37:537–46. PD-L1>20% KEYNOTE-042: Overall survival

A 100 PD-L1 tumour proportion score B 100 HR (95% CI) P value 90 90 80 80 70 70 60 ≥50% 60 0.69 (0.56–0.85) 0.0003 50 50 40 40 30 ≥20% 30 0.77 (0.64–0.92) 0.0020 20 20 10 10 % survival,Overall HR 0.77 (95% CI 0.64-0.92) p=0.0020 Overall survival, % survival,Overall HR 0.69 (95% CI 0.56-0.85) p=0.0003 0 0 No. at risk ≥1% No. at risk 0.81 (0.71–0.93) 0.0018 (censored) 0 6 12 18 24 30 36 42 (censored) 0 6 12 18 24 30 36 42 Pembro 299 (0) 224 (0) 189 (1) 107 (55) 59 (91) 22 (122) 2 (140) 0(142) Pembro 413 (0) 305 (0) 251 (2) 144 (70) 73 (120) 24 (161) 2 (181) 183) Chemo 300 (0) 231 (2) 149 (4) 175– 49%(46) 40 (67) 11 (90) 1 (100) 0 (100) Chemo 405 (0)0.92313 (6) (0.77210 (8)–1.11)106 (64) 53 (94) 14 (125) 1 (138)– 0 (139)

C 100 D 100 90 90 80 80 PD-L1 1–49% 70 PD-L1 >1% 70 60 Tumour RR 60 50 50 40 16.5% 40 30 30 20 20 10 10 % survival,Overall HR 0.92 (95% CI 0.77–1.11) Overall survival, % survival,Overall HR 0.81 (95% CI 0.71–0.93) P=0.0018 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 No. at risk No. at risk (censored) Time, months (censored) Time, months pembro 637 (0) 463 (0) 365 (3) 214 (104) 112 (174) 35 (235) 2 (264) 2 (264) Pembro 338 (0) 239 (0) 176 (2) 107 (49) 53 (83) 13 (113) 0 (124) 0 (124) chemo 637 (0) 485 (6) 316 (10) 166 (88) 88 (128) 24 (175) 1 (198) 0 (199) Chemo 337 (0) 254 (4) 167 (6) 91 (42) 48 (61) 13 (85) 0 (98) 0 (98)

Mok TSK, et al. Lancet. 2019;393:P1819–30. The benefit observed in the PD-L1 >1% group could be driven by the major benefit from the PD-L1 >50% subgroup PD-L1 PD-L1 PD-L1 <1% 1–49% >50% KEYNOTE-189: chemo/PEMBRO in PD-L1 1–49%

100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30

20 20

progression or death, % death, or progression Patients without disease without Patients Patients who survived, % survived, who Patients 10 10 HR (for death) 0.55 (95% CI 0.34–0.90) HR (for death) 0.55 (95% CI 0.37–0.81) 0 0 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 No. at risk Time, months No. at risk Time, months pembro 128 119 108 84 52 21 5 0 Pembro 128 101 84 47 21 6 2 0 placebo 58 54 47 32 17 5 2 0 Placebo 58 44 23 11 6 1 0 0 OS: HR 0.55 PFS: HR 0.55

Gandhi L, et al. N Engl J Med. 2018:2078–92. IMpower150 (TC 1/2 IC 1/2): Overall survival

Landmark OS rate, % (95% CI) 100 12-month 18-month 24-month 90 ABCP 70.0 (62.1–77.9) 57.0 (47.8–66.1) 48.4 (37.7–59.0) 80 BCP 59.6 (50.9–68.3) 47.9 (38.6–57.1) 38.3 (27.6–49.1) 70 60 50 40 30 Overall survival, % survival, Overall 20 10 Median, 16.7 months Median, 22.5 months HR, 0.76 (95% CI: 0.54–1.08) (95% CI: 12.5–22.9) (95% CI: 17.0–26.2) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 No. at risk Time, months ABCP 135 121 118 113 106 100 90 71 56 41 33 24 11 6 BCP 127 120 109 101 92 81 72 56 47 36 26 16 13 2 1 ABCP, atezolizumab plus bevacizumab and chemotherapy [carboplatin plus paclitaxel]; BCP, bevacizumab and chemotherapy [carboplatin plus paclitaxel]; IC, tumour-infiltrating immune cell; TC, tumour cell. Supplementary data to: Reck M, et al. Lancet Respir Med. 2019;7:387–401. CheckMate-227 Part 1: First-line NIVO + IPI vs chemotherapy for advanced NSCLC – 3-year update1–3

NIVO + IPIa Part 1a n=396 PD-L1 R Chemob Key eligibility criteria expression 1:1:1 n=397 • Stage IV or recurrent NSCLC ≥1% NIVOc Independent primary • e No prior systemic therapy N=1,189 n=396 endpoints: NIVO + IPI vs chemo • No sensitizing EGFR mutations or • PFS in high TMB known ALK alterations NIVO + IPIa (≥10 mut/Mb) population1 • No untreated CNS metastases Part 1b n=187 • OS in PD-L1 ≥1% population2 • ECOGPS 0–1 PD-L1 R Chemob expression • Stratified by SQ vs NSQ 1:1:1 n=186 <1% NIVOd + chemob N=550 n=177 Minimum/median follow-up for OS: 37.7 months/43.1 months. Treatment was continued until disease progression, unacceptable toxicity or for 2 years for immunotherapy; aNIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W); bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemo or NIVO + pemetrexed maintenance following NIVO + chemo; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cNIVO (240 mg Q2W); dNIVO (360 mg Q3W); eBoth endpoints were met; results were previously reported.

ALK, anaplastic lymphoma kinase; CNS, central nervous system; ECOGPS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; mut/Mb, mutations per megabase; NSQ, non-squamous NSCLC; Q2W, every 2 weeks; Q3W, every 3 weeks; Q6W, every 6 weeks; R, randomization; SQ, squamous NSCLC. 1. Hellmann MD, et al. N Engl J Med. 2018;378:2093–104; 2. Hellmann MD, et al. N Engl J Med. 2019;381:2020–31; 3. Ramalingam SS, et al. J Clin Oncol. 2020;38:9500. CheckMate-227: OS tumour PD-L1 expression and TMB status1,2

Median OS, months NIVO + IPI Chemo HR HR (95% CI) n=583 n=583 Randomized groups Stratified Stratified All randomized (N=1,166) 17.1 13.9 0.73 PD-L1 PD-L1 <1% (n=373) 17.2 12.2 0.62 PD-L1 ≥1% (n=793) 17.1 14.9 0.79a Additional exploratory subgroup analysesb,c Unstratified Unstratified 1–49% (n=396) 15.1 15.1 0.94 PD-L1 ≥50% (n=397) 21.2 14.0 0.70 TMBd low, <10 (n=380) 16.2 12.6 0.75 (mut/Mb) high, ≥10 (n=299) 23.0 16.4 0.68 0.25 0.5 1 2 • No consistent correlation was observed between survival outcomes NIVO + IPI Chemo with NIVO + IPI vs chemo and PD-L1 or TMB alone or in combination1

aStratifiedHR (97.72% CI); bPatients were not stratified by TMB or PD-L1 ≥ or <50% – subgroup analyses therefore may be impacted by imbalances and should be interpreted with caution; cNot controlled by randomization; dUnstratifiedHR for NIVO + IPI vs chemo in TMB-evaluable (n=679) and non-evaluable (n=487) patients was 0.74 (95% CI, 0.61–0.88) and 0.74 (95% CI 0.60–0.92), respectively.

1. Hellmann MD, et al. N Engl J Med. 2019;381:2020–31; 2. Hellman MD, et al. N Engl J Med. 2018;378:2093–104. CheckMate 9LA study design: NIVO + IPI + 2 cycles of chemo vs 4 cycles chemo

Key eligibility criteria NIVO 360 mg Q3W + IPI 1 mg/kg Q6W • Stage IV or recurrent NSCLC + • No prior systemic therapy n=361 Chemoc Q3W (2 cycles) Until disease • No sensitizing EGFR mutations progression, or known ALK alterations R unacceptable toxicity, 1:1 • ECOG PS 0–1 or for 2 years Stratified by n=358 Chemoc Q3W (4 cycles) for immunotherapy a b PD-L1 (<1% vs ≥1%), with optional pemetrexed maintenance (NSQ) sex, and histology (SQ vs NSQ

Primary endpoint Secondary endpoints • OS • PFS by BICRf • ORR by BICRf • Efficacy by tumor PD-L1 expression

Interim database lock: October 3, 2019; minimum follow-up: 8.1 months for OS and 6.5 months for all other endpoints. Updated database lock: March 9, 2020; minimum follow-up: 12.7 months for OS and 12.2 months for all other endpoints. aDetermined by the PD-L1 immunohistochemistry (IHC) 28-8 pharmDx assay (Dako); bPatients unevaluable for PD-L1 were stratified to PD-L1 < 1% and capped to 10% of all randomized patients; cNSQ: pemetrexed + cisplatin or carboplatin; SQ: paclitaxel + carboplatin; dCalculated as a percentage of quantifiable patients;. e6% and 7% of patients in the NIVO + IPI + chemo and chemo arms, respectively, were unevaluable for PD-L1; fHierarchically statistically tested; BICR, blinded independent central review. Reck M, et al. J Clin Oncol. 2020;38:9501. First-line option for patients with PD-L1 1–49%

KEYNOTE 189 nivolumab + ipilimumab

pembrolizumab atezolizumab IMpower150 chemo x2 and nivolumab + ipilimumab IMpower130

Single-agent IO only for patients who cannot receive chemotherapy PD-L1 PD-L1 PD-L1 <1% 1–49% >50%

Should we routinely use ICI in combination? KEYNOTE-189: OS, RR and PFS of the TPS 0%

Overall survival Progression-free survival 100 TPS <1% 100 TPS <1% 90 90 80 80 70 70 60 60 50 50 40 40 30 30

20 20

Patients who disease who Patients progression or death, % death, or progression Patients who survived, % survived, who Patients 10 10 HR (for death) 0.59 (95% CI 0.38–0.92) HR (for death) 0.75 (95% CI 0.53–1.05) 0 0 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 21 No. at risk Time, months No. at risk Time, months pembro 127 113 104 79 42 20 6 0 pembro 127 88 60 31 12 3 2 0 placebo 63 54 45 32 21 6 1 0 placebo 63 44 27 16 4 0 0 0 OS: HR 0.59 PFS: HR 0.75 95% CI 0.38-0.902 p=0.0095 RR: 32.3% vs 14.3% 95% CI 0.53-1.05 p=0.0476 Med OS: 15.2 mo vs 12.0 mo TPS, tumour proportion score. Med PFS: 6.1 mo vs 5.1 mo Gandhi L, et al. N Engl J Med. 2018;378:2078–92. Summary

• PD-L1 expression is the standard biomarker for clinical selection of patients for anti-PD-L1 therapy • Multiple options including single agent IO, chemo/IO, chemo/bev/IO and IO/IO • For patients with PD-L1 >50% - KEYNOTE-024, KEYNOTE-042, IMpower110 • For patients with PD-L1 1–49% - KEYNOTE-189, IMpower 150, IMpower130, CheckMate 9LA, CheckMate-227 • For patients with PD-L1 <1% - KEYNOTE-189, IMpower150 (liver metasteses), CheckMate 9LA, CheckMate-227 (high TMB?) One molecule, many mechanisms of action: Why all PD-1 inhibitors are not the same

Dr Raffaele Califano

Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK Presentation outline

• Introduction: PD-1 inhibitors approved in NSCLC

• Molecular structure and mechanism of action of ‘new’ PD-1 inhibitors

• New PD-1 inhibitors: preclinical and early phase data

NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein-1; rhPD-1, recombinant human PD-1; PD-L1, programmed death ligand-1 Agents approved in NSCLC engage PD-1 differently. . .

Nivolumab Pembrolizumab Property Nivolumab Pembrolizumab Ab subclass1 IgG4κ

2 Structural modifications S228P hinge modification (IgG4S288P) Glucose modifications1 None (CHO production)

Humanization3 Fully human Humanized

Epitope Flexible N-loop Flexible CD-loop (PD-1 engagement)1 TBS: 1487–1932.5 Å2 TBS: 1774–2126 Å2

1 Affinity for rhPD-1 SPR: KD=3.06 pM ELISA: KD=29 pmol/L

Differences in PD-1 engagement PD-1 • Pembrolizumab epitope shares greater overlap with PD-L1 1 Binding residues at PD-1 surface binding sites than nivolumab

PD-L1 • Almost no overlap between PD-L1 + nivolumab PD-L1 + pembrolizumab pembrolizumab and nivolumab Nivolumab Pembrolizumab PD-1 binding sites

Ab, antibody; CHO, Chinese hamster ovary cell; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; KD, equilibrium dissociation constant; rhPD-1, recombinant human PD-1; SPR, surface plasmon resonance; TBS, total buried surface. 1. Fessas P, et al. Semin Oncol. 2017;44:136–40; 2. Zhang T, et al. Cancer Immunol Immunother. 2018;67:1079–90; 3. Chen Y, et al. Frontiers Immunol. 2020;11:1088. Figure adapted from 1. Fessas P, et al. Semin Oncol. 2017;44:136–40. . . .and off-target effects leading to toxicities are known

1 IgG4S228P mAbs retain high affinity for FcγRI . . .

PD-1 binding sites In vivo activities of PD-1 inhibitors are FcγR independent2 FcγR engagement: • Compromises efficacy of PD-1 inhibitors2

2 VH • Increases anti-tumour activity of PD-L1 inhibitors V Fab L C region H . . .inducing FcγRI cross-linking and off-target effects1,2 . . . CL

Myeloid cells Hinge T cells • PD-1+ T cell/MΦ clustering C Disulphide bond H + • ADCP induction Fc region • Activating FcγR-engaging MΦ IL-10 secretion CH • TME modification IgG4S288P PD-1 inhibitor • Effector T cell inhibition Tumour cells FcγR† effector cells

ADCP, antibody-dependent cellular phagocytosis; C, constant domain; Fab, antigen binding fragment; Fc, constant fragment; FcγRI, Fcγ receptor-1; H, heavy chain; IL-10, interleukin-10; L, light chain; mAb, monoclonal antibody; MΦ , macrophage; TME, tumour microenvironment; V, variable domain. 1. Zhang T, et al. Cancer Immunol Immunother. 2018;67:1079–90; 2. Dahan R, et al. Cancer Cell. 2015;28:285–95. A new generation of PD-1 inhibitors is emerging

Camrelizumab1,2 Cemiplimab1,3 Sintilimab1,4 Tislelizumab1,5

Humanized IgG4 Fully human IgG4 Fully human IgG4 Humanized IgG4mut

PD-1 engagement PD-1 engagement PD-1 engagement PD-1 engagement

High-affinity binding to unique PD- VHCDR3 interacts with PD-1 1 epitopes (not specified) Hinge-stabilized IgG4S228P Hinge-stabilized IgG4S228P High-affinity interaction: Engages PD-1 via mechanisms • Binds via PD-1 front β-sheet, Mechanism not fully characterized Mechanism not fully characterized comparable to pembrolizumab comparable mechanism to and nivolumab PD-L1/PD-1 engagement Immunogenicity Immunogenicity Immunogenicity Immunogenicity Potent VEGFR2 agonist Not yet characterized Not yet characterized Fc region modifications 1 (IgG4mut FcγR-null) abrogate FcγRI binding + activation6

Camrelizumab engages PD-1 Cemiplimab binds PD-1 with but is associated with high affinity and potently Sintilimab binds PD-1 Tislelizumab binds PD-1 unique toxicity and blocks PD-1/PD-L1 with high affinity with high affinity, requires paratope refinement functional interaction via unique epitopes and mimics PD-L1 engagement

CDR, complementarity determining region; FcγRI, Fcγ receptor-1; IgG4mut, IgG4 mutantVEGFR2, vascular endothelial growth factor receptor-2; VH, variable heavy chain. 1. Chen X, et al. Front Immuonl. 2018;10:292; 2. Finlay WJJ, et al. MABS. 2019;11:26–44; 3. Burova E, et al. Mol Cancer. 2017;861–70; 4. Wang J, et al. MABS. 2019;11:1443–51; 5. Lee SH, et al. Biochem Phys Res Commun. 2020;527:226–31; 6. Zhang T, et al. Cancer Immunol Immunother. 2018;7:1079–90. Translational data driving PD-1 inhibitor development

in vitro activity in vitro activity • Specific high-affinity PD-1 binding in vitro studies characterized • Slow receptor dissociation kinetics mechanism underlying RCH TRAE • Blocks PD-L1/PD-L2 binding • Induces T cell CK secretion (IFN-γ; IL-2) 3 Camrelizumab (SHR-1210)1 Sintilimab (IBI308) in vitro blockade in vitro activity Off-target polyspecificity in vivo activity highly specific, low-affinity binding to: • Reverses PD-1-dependent • Engages humanized PD-1 Functional dissection of • VEGFR2 • † attenuation of T cell signalling Potent anti-tumour activity IgG4S228P hinge variants: • FZD5 • • Enhances human T cell responses High doses well tolerated IgG4mut FcγR-null Fc region modifications • ULBP2 in PK/PD studies with no signs do not affect PD-1 engagement4,5 of drug-related toxicity Cemiplumabin vitro studies(REGN2810)2 Tislelizumab (BGBA317)4

in vivo activity in vivo activity • Binds humanized PD-1 • BGBA317 inhibits murine • Inhibits tumourigenesis† tumourigenesis, unlike • High doses well tolerated BGBA317S228P without immune-related • BGBA317S228P induced effects in PK/PD studies unfavourable TME †in models of murine colon carcinoma

CK, cytokine; FZD5, frizzled class receptor 5; IFN-γ, interferon gamma; IL-2, interleukin-2; PD, pharmacodynamic; PK, pharmacokinetic; RCH, reactive capillary hemangioma; TME, tumour microenvironment; TRAE, treatment-related adverse event; ULBP2, UL16 binding protein 2; VEGFR2, vascular endothelial growth factor receptor-2. 1. Finlay WJJ, et al. MABS. 2019;11:26-44; 2. Burova E, et al. Mol Ther Cancer. 2017;2051–62; 3. Zhang S, et al. Antibody Ther. 2018;1:65–73; 4. Zhang T, et al. Cancer Immunol Immunother. 2018;7:1079–90; 5.Chen X, et al. Front Immuonl. 2018;10:292. Camrelizumab: Phase I data

Advanced solid tumours Most frequent TRAEs (any grade) • Advanced solid tumours (N=36) occurring in ≥10% patients • OSCC (38.9%) • NASOP (8.3%) 100 • Gastric cancer (13.9%) • HCC (5.6%) • TNBC (11.1%) • Bladder cancer (2.8%) • CRC (8.3%) • Cervical cancer (2.8%) • NSCLC (8.3%)

Dose escalation: 50 • 60 mg to 200 mg or 400 mg Q2W

Objective response by tumour type (%)Patients 000 100 n=1 0

50 n=3 n=3 n=3

n=14 n=5 Patients (%)Patients 0 Immunogenicity

RCH is a frequent TRAE, unique to camrelizumab Camrelizumab showed anti-tumour activity and amongst anti-PD-1 inhibitory antibody drug class manageable safety in advanced solid tumours

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRC, colorectal cancer; HCC, hepatocellular carcinoma; NASOP, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; OSCC, oesophageal squamous cell carcinoma; Q2W, every 2 weeks; TNBC, triple negative breast cancer. Mo H, et al. Br J Cancer. 2018;119:538–45. Camrelizumab: Phase I data

Advanced gastric + GOJ cancer Most frequent TRAEs (any grade) • Recurrent or metastatic gastric/GOJ cancer occurring in ≥10% patients 100 • Previous chemotherapy: refractory/intolerant (N=30) Dose escalation: • 60 mg to 200 mg or 400 mg Q2W

50 Response by tumour cell PD-L1 expression 000 100

26.7% 23.1% 26.1% 50 20.0% 0 n=15 n=23

n=13 n=5 Patients (%)Patients 0 Immunogenicity <1% ≥1% <5% ≥5% N=30

Camrelizumab showed encouraging efficacy RCH is a frequent TRAE, unique to camrelizumab in a Chinese cohort of patients amongst anti-PD-1 inhibitory antibody drug class with advanced gastric/GOJ cancer

GOJ, gastro-oesophageal junction. Huang J, et al. Cancer. 2019;125:742-749. Cemiplimab: Phase I data

Advanced solid tumours Most frequent TRAEs (any grade) • CRC (11.7%) • Prostate (5.0%) occurring in ≥10% patients • Head + neck (10.0%) • Salivary gland (5.0%) 100 • Breast (8.3%) • Uterus (5.0%) • Skin cancer • Oesophageal (3.3%) (non-melanoma) (8.3%) • Ovary (3.3) • Sarcoma (8.3%) • Pancreas (3.3%) • Cervix (5.0%) • Other (23.3%) (N=60) 50 Dose escalation: • 1 mg/kg or 2 mg/kg or 10 mg/kg Q2W • Monotherapy 000 • Combination therapy with CPA or hfRT (%)Patients Objective response 0 100 ORR, % (95% CI): 15.0 (7.1–26.6)

50 40.0% Immunogenicity

Patients (%)Patients 11.7% 3.3% 0 CR PR SD N=60 Cemiplimab has a manageable safety profile comparable with other PD-1 inhibitors and can be safely administered with hfRT and/or CPA Cemiplimab showed anti-tumour activity

CI, confidence interval; CPA, cyclophosphamide; CR, complete response; CRC, colorectal cancer; hfRT, hypofractionated radiotherapy; PR, partial response; ORR, objective response rate; SD, stable disease. Papadopoulos KP, et al. Clin Cancer Res. 2020;26:1025–33. Cemiplimab: Phase I expansion data

Advanced CSCC Most frequent TRAEs (any grade) Advanced CSCC: occurring in ≥10% patients 100 • Prior therapy permitted • Systemic therapy (58%) • Radiotherapy (77%) (N=26) Dose escalation + expansion study: • 3 mg/kg Q2W 50 000 Objective response (%)Patients ORR, % (95% CI): 50 (30–70) 0 100

50% 50 23% Immunogenicity Patients (%)Patients 0 0 CR PR SD N=26 Cemiplimab has a manageable safety profile Cemiplimab showed anti-tumour activity, eliciting comparable with other PD-1 inhibitors a response in approximately half of patients

CI, confidence interval; CPA, cyclophosphamide; CR, complete response; CSCC, cutaneous squamous cell carcinoma; PR, partial response; ORR, objective response rate; TRAE, treatment-related adverse event; UTI, urinary tract infection. Migden MR, et al. N Engl J Med 2018;379:341–51. Sintilimab: Phase I data

Advanced solid tumours PK profile

• Linear PK profile • >95% PD-1 receptor occupancy • Patients with advanced solid tumours (N=12) (1 – 10 mg/kg) (across all dose levels)

Dose escalation by ‘3+3’ method: • 1 mg/kg or 3 mg/kg or 10 mg/kg Q2W Most frequent TRAEs or 200 mg Q3W (n=3 per dose level) (any grade) occurring in ≥10% patients 50

36.6% 36.6% 36.6% 36.6% ≥Grade 3 TRAEs 11 patients evaluated for response Reported in 4 patients: 000 • Lung infection DoR • Pneumonitis 1 HCC 9.5 months • Respiratory failure • Elevated lipase + amylase PR = 2 1 NET 5.7 months 0 Immunogenicity Pyrexia Thyroid Elevatated Pneumonitis dysfunction bilirubin (serum) Sintilimab showed promising preliminary efficacy Sintilimab was well tolerated and 200mg Q3W dosing schedule was data in this first in-human study recommended for further studies

DoR, duration of response; HCC, hepatocellular carcinoma; NET, neuroendocrine tumour; PR, partial response; SD, stable disease; Q3W, every 3 weeks. Xu J-M, et al. J Clin Oncol. 2018;36 :e15125. Sintilimab: Phase IB data

Advanced gastric + GOJ cancer Most frequent TRAEs (any grade) • Locally adv. or metastatic gastric/GOJ cancer occurring in >10% patients 100 • Systemic treatment naïve (N=20)

Combination 1st-line therapy: • 200 mg sintilimab + CapeOx 21 days/6 cycles followed by • Maintenance 200 mg sintilimab Q2W PFS 7.5 mo (95% CI 6.2–9.4) OS NR 50 1.0 1.0 Censored Censored 000 0.8 0.8

0.6 0.6

0.4 0.4 0

PFS (rate) PFS (rate) OS probability OS

PFS probability PFS 0.2 0.2 6 months 88% (59%, 97%) 6 months 100% (100%, 100%) Immunogenicity 12 months NA (NA, NA) 12 months 68% (24%, 90%) 0.0 0.0 0 50 100 150 200 250 300 350 0 50 100 150 200 250 300 350 400 No. at risk Time, days No. at risk Time, days 20 20 18 13 8 3 1 0 20 20 20 20 16 8 3 2 0 Sintilimab in combination with CapeOx demonstrated an acceptable safety profile Sintilimab combined with CapeOx shows promising efficacy as 1st-line therapy in advanced gastric/GOJ cancer CapeOx, 1000 mg/m2 capecitabine orally BID; D1–14 and 130 mg/m2 oxaliplatin IV D1

Adv., advanced; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; NR, not reached; OS, overall survival; PFS, progression-free survival. Jiang H, et al. BMC Cancer. 2020;20:760. Tislelizumab: Phase IB data

Advanced solid tumours Phase IB: most frequent TRAEs (any grade) Advanced solid tumours, including in Phase IB: 100 • NSCLC (n=50) • HNSCC (n=20) 9.3 %: AE leading to treatment discontinuation • Ovarian cancer (n=20) • Oesophageal cancer (n=50) 26.6 %: AE leading to treatment interruption • Gastric cancer (n=50) • TNBC (n=20) • HCC (n=50) • Cholangiocarcinoma (n=20) 50 Following dose-escalation studies: • Phase IA: 200 mg Q3W (fixed-dose expansion)

• Phase IB: 5 mg/kg Q3W 000 Patients (%)Patients

Phase IB: objective response 0 50 ORR: 11.6 (95% CI 8.41–15.57) 29.6% 25 Immunogenicity 11.0% Patients (%)Patients 0.6% 0 CR PR SD N=335 Tislelizumab demonstrated an acceptable safety profile Tislelizumab showed anti-tumour activity 200 mg Q3W recommended as dosing schedule for further studies Durable responses were observed in some patients

CI, confidence interval; CRC, colorectal cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; TNBC, triple negative breast cancer. 1. Desai J, et al. J Immunother Cancer. 2020;8:e000453 including associated supplementary data available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC7295442/bin/jitc-2019-000453supp001.pdf [accessed 27 August 2020]. Tislelizumab: Phase I/II data

Advanced solid tumours Most frequent TRAEs (any grade) occurring in ≥10% patients Advanced solid tumours including: 100 • NSCLC (n=56) • ESCC (n=22) • Melanoma (n=34) • UC (n=22) 8% : TRAE leading to treatment discontinuation N=300 • Gastric cancer (n=24) • RCC (n=21) • HCC (n=18) • NASOP (n=21) 50 Dosing schedule: 200 mg Q3W

Objective response in NSCLC cohort 000 Patients (%)Patients ORR, % (95% CI): 18 (8.9–30.4) PFS, months (95% CI): 4.0 (2.1–8.1) 0 50 38%

18% Immunogenicity Patients (%)Patients 0 0 N=300 CR PR SD n=56 Tislelizumab was well tolerated in Tislelizumab showed anti-tumour activity in a cohort of Chinese patients with advanced solid tumours multiple solid tumours, including NSCLC

CR, complete response; CRC, colorectal cancer; ESCC, oesophageal squamous cell carcinoma; HCC, hepatocellular carcinoma; PR, partial response; NASOP, nasopharyngeal carcinoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; UC, urothelial cell bladder carcinoma. Shen L, et al. J Immunother Cancer. 2020;8:e000437. Summary and concluding remarks

• Structural differences of PD-1 inhibitors may influence clinical activity and toxicity profile • Several new PD-1 inhibitors are in development • Promising ‘early phase’ activity with emerging novel toxicities How will the new wave of PD-1 inhibitors change the treatment landscape in NSCLC?

Prof. Anne-Marie C Dingemans

Department of Pulmonology, Erasmus Medical Center, Rotterdam, The Netherlands A new wave of PD-1 inhibitors: Potential in NSCLC?

Tislelizumab Cemiplimab Sintilimab Camrelizumab

FDA Dec 20182,3 Approval NMPA Dec 20191 NMPA Dec 20185 NMPA May 20196 status EMA Dec 20194

HL: Relapsed/refractory following ≥2 prior lines of chemotherapy1

UC: Locally advanced or CSCC: Metastatic or locally HL: Relapsed/refractory HL: Relapsed/refractory Indications metastatic PD-L1+hi UC advanced in patients classical HL following ≥2 classical HL following ≥2 ineligible for curative prior lines of prior lines of surgery or curative chemotherapy5 chemotherapy6 NSCLC: CDE reviewing radiation2 application for tislelizumab + chemo as 1st-line in NSCLC (NCT03594747)

Dosing i.v 200 mg Q3W1 i.v 350 mg Q3W3,4 i.v 200 mg Q3W5 i.v 200 mg Q2W6 schedule

CDE, Center for Drug Evaluation; CSCC, cutaneous squamous cell carcinoma; EMA, European Medicines Agency; FDA, Food and Drug Administration; HL, Hodgkin lymphoma; i.v, intravenous infusion; NMPA, National Medicinal Products Administration; NSCLC, non-small cell lung cancer; PD-1, programmed death-1; PD-L1, programmed death ligand-1; UC, urothelial carcinoma. 1. Lee A. and Keam SJ. Drugs. 2020;80:617–24; 2. Markham A. and Duggan S. Drugs. 2018;78:1841–46; 3. FDA Prescribing Information: Cemiplimab. Sept 2020; 4. EMA Summary of Product Characteristics: Cemiplimab. July 2020; 5. Hoy SM. Drugs. 2019;79:341–6; 6. Markham A and Keam SJ. Drugs. 2019;79:1355–61. New PD-1 inhibitors have shown efficacy in Phase II studies. . .

Camrelizumab1 Cemiplimab2 Sintilimab3 Tislelizumab4 single-arm, multicentre single-arm, multicentre single-arm, multicentre single-arm, multicentre

HL: R/R (n=75) CSCC: Locally adv. (n=78) HL: R/R (n=96) HL: R/R (n=70)

200 mg Q2W i.v 3 mg/kg Q2W i.v 200 mg Q3W i.v 200 mg Q3W i.v

Objective response Objective response Objective response Objective response 100 76% 100 100 100 80.4% 87.1% 62.9% 44% 50 50 50 50 28% 34.0% 13% 0 0 0 0

ORR* CR ORR* CR ORR* CR ORR* CR

Patients with response (%) response with Patients

Patients with response (%) response with Patients Patients with response (%) response with Patients *95% CI 64.7–85.1 *95% CI 32–55 *95% CI 70.9–88.0 *95% CI 77.0–93.9; p<0.0001 analysis set (n=75) analysis set (n=78) analysis set (n=92) analysis set (n=70) Camrelizumab elicits high Cemiplimab shows anti-tumour Sintilimab is well-tolerated + Tislelizumab is well-tolerated response rates + tolerable safety activity with acceptable safety shows favourable activity with high ORR + CR rates

adv., advanced; CI, confidence interval; CR, complete response; CSCC, cutaneous squamous cell carcinoma; HL, Hodgkin lymphoma; i.v, intravenous; ORR, objective response rate; Q2W, every 2 weeks; Q3W, every 3 weeks; R/R, relapsed refractory. 1. Song Y, et al. Clin Cancer Res. 2019;25:7363–69; 2. Migden et al. Lancet Oncol. 2020;21:294–305; 3. Shi Y, et al. Lancet Haematol. 2019;6:e12–9; 4. Song Y, et al. Leukaemia. 2020;34:533–42. . . .and a manageable safety profile

Camrelizumab1 Cemiplimab2 Sintilimab3 Tislelizumab4

most frequent AEs most frequent AEs most frequent AEs most frequent AEs • cutaneous RCCEP • fatigue (27.0%) • pyrexia (45.8%) • pyrexia (54.3%) (97.3%) • diarrhoea (23.5%) • hypothyroidism (22%) • hypothyroidism (32.9%) • pyrexia (42.7%) • nausea (20.9%) • URTI (19.8%) • URTI (30.0%) • URTI (42.7%) • rash (16.5%) • leukopenia (14.6%) • leukopenia (18.6%) • leukopenia (26.7%) AE profile AE profile AE profile 100% AE profile 98.3% 100% 92.9% 100 100 100 100

62.6% 54.0% 50 50 38.6% 32.0% 50 45.2% 50 38.6% 25.0% 21.4%

Patients (%)Patients 14.7% Patients (%)Patients

Patients (%)Patients 12.5% Patients (%)Patients 0 0 0 0

Cutaneous RCCEP is an Discontinuations: 3 (3%) Discontinuations: 4 (5.7%) AE unique to camrelizumab Discontinuations: 9 (7.8%) pneumonitis [2]; liver injury [1] pneumonitis [3]; renal injury [1] amongst PD-1 inhibitors

AE, adverse event; irAE, immune-related AE; RCCEP, reactive cutaneous capillary endothelial proliferation [also referred to as RCH, reactive capillary hemangioma]; URTI, upper respiratory tract infection. 1. Song Y, et al. Clin Cancer Res. 2019;25:7363–69; 2. Rischin D, et al. J Immunother Cancer. 2020;8:e000775; 3. Shi Y, et al. Lancet Haematol. 2019;6:e12–9; 4. Song Y, et al. Leukaemia. 2020;34:533–42. Tislelizumab + chemo in advanced lung cancer: Ph II study design

54 patients with locally advanced or metastatic lung cancer: • Histologically confirmed stage III or IV • Treatment naïve (no prior systemic therapy)

NSQ (n=16) SQ-A (n=15) SQ-B (n=6) SCLC (n=17) Non-squamous NSCLC Squamous NSCLC (cohort A) Squamous NSCLC (cohort B) Small cell lung cancer Tislelizumab 200 mg + pemetrexed + Tislelizumab 200 mg + paclitaxel + Tislelizumab 200 mg + gemcitabine + Tislelizumab 200 mg + etoposide + cisplatin/carboplatin Q3W 4–6 cycles cisplatin/carboplatin Q3W 4–6 cycles cisplatin/carboplatin Q3W 4–6 cycles cisplatin/carboplatin Q3W 4–6 cycles

Response stratified by gene expression profiles + tumour cell PD-L1 expression

Efficacy and safety

ORR per RECISTv1.1* *Investigator-assessed confirmed CR + confirmed PR

CR, complete response; NSCLC, non-small cell lung cancer; NSQ, non-squamous NSCLC; ORR, objective response rate; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SCLC, squamous cell carcinoma; SQ- A, squamous NSCLC [cohort A]; SQ-B, squamous NSCLC [cohort B]. Wang Z, et al. Lung Cancer. 2020;259–68. Tislelizumab + chemo in advanced lung cancer: Ph II results

Efficacy: best confirmed overall response Safety profile: TRAEs

100 CR PR Any grade Grade ≥3 100 100 100 100 100 % % % % 86.7% 80 77% % 76.5% 67 68.8% % 50 50 50%

44 33.3% Patients (%) Patients %

Patients (%) Patients 0 17 13 % 12 NSQ SQ-A SQ-B SCLC % % n=16 n=15 n=6 n=17 0 0 0 0 0 NSQ SQ-A SQ-B SCLC n=16 n=15 n=6 n=17 Tumour cell PD-L1 expression correlated with increased ORR in NSQ cohort but showed no ORR, % 44% 80% 67% 77% (95% CI) (19.8–70.1) (51.9–95.7) (22.3–95.7) (50.1–93.2) correlation in SQ or SCLC cohorts

CR, complete response; NSQ, non-squamous NSCLC cohort; ORR, objective response rate; PR, partial response; SCLC, small-cell lung cancer; SD, stable disease; SQ [-A; -B], squamous NSCLC [cohort A; cohort B]; TRAE, treatment-related adverse event. Wang Z, et al. Lung Cancer. 2020;259–68. First-line tislelizumab in NSCLC: Phase III study design1,2

360 patients with locally advanced or metastatic squamous NSCLC: • Histologically confirmed stage IIIB or IV • Treatment naïve (for locally advanced or metastatic squamous NSCLC) • Sensitizing EGFR mutation or ALK translocation negative

1:1:1

Arm A (n=120) Arm B (n=119) Arm C (n=121) Tislelizumab 200 mg + paclitaxel + Tislelizumab 200 mg + nab-paclitaxel paclitaxel + carboplatin carboplatin Q3W 4–6 cycles + carboplatin Q3W 4–6 cycles Q3W 4–6 cycles

Patients stratified by tumour stage and PD-L1 expression for analyses

Efficacy and safety

PFS by IRRC

ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; IRRC, independent radiologic review committee; PFS, progression free survival. 1. Wang J, et al. J Clin Oncol. 2020;38:9554; 2. https://clinicaltrials.gov/ct2/show/NCT03594747 [accessed 18 Aug 2020]. First-line tislelizumab in NSCLC: Preliminary results (efficacy)

Arm A (n=120) Arm B (n=119) Arm C (n=121) Tislelizumab+paclitaxel+carboplatin Tislelizumab+nab-paclitaxel+carboplatin paclitaxel+carboplatin PFS, months 7.6 7.6 5.5 (95% CI) (6.0–9.8) (5.8–11.0) (4.2–5.7) strat. HR, 0.48 0.52 NA (95% CI; p-value) (0.4–0.7; p=0.0001) (0.3–0.7; p<0.0001) ORR, % 72.5 74.8 49.6 (95% CI) (63.6–80.3) (66.0–82.3) (40.4–58.8)

DoR, % 8.2 8.6 4.2 (95% CI) (5.0–NE) (6.3–NE) (2.8–4.9)

Tislelizumab in addition to chemotherapy improved PFS, achieved higher ORR and longer DoR than chemotherapy alone.

DoR, duration of response; HR, hazard ratio; NE, not evaluable; strat. HR, stratified HR. Wang J, et al. J Clin Oncol. 2020;38:9554. First-line tislelizumab in NSCLC: preliminary results (safety)

Arm A (n=120) Arm B (n=119) Arm C (n=121) Tislelizumab+paclitaxel+carboplatin Tislelizumab+nab-paclitaxel+carboplatin paclitaxel+carboplatin AE leading to 29.7 15.4 discontinuation, % 12.5

† Serious TRAEs , % 37.5 38.9 23.6

TRAEs leading to death*, n 1 2 3

†serious TRAEs reported in 72 patients *no deaths solely attributed to tislelizumab

Safety profile in line with known profiles of tislelizumab, chemotherapy and underlying NSCLC.

No new safety signals detected with addition of tislelizumab to chemotherapy.

AE, adverse event; CI, confidence interval; TRAE, treatment-related adverse event. Wang J, et al. J Clin Oncol. 2020;38:9554. Sintilimab in NSCLC (ORIENT-11): Phase III study design1,2

397 patients with locally advanced or metastatic non-squamous NSCLC: • Treatment naïve • Sensitizing EGFR or ALK mutation negative

2:1

Placebo (n=131) Sintilimab 200 mg (n=266) plus pemetrexed + platinum plus pemetrexed + platinum Q3W x 4 cycles Q3W x 4 cycles

Maintenance therapy: sintilimab or placebo plus pemetrexed Cross-over or treatment beyond progression permitted

Efficacy and safety

PFS by IRRC

1. Yang Y, et al. J Thorac Oncol. 2020; S1556-0864(20)30595-5 [online ahead of print]; 2. Zhang L, et al. 2020; presented at IASLC Presidential Symposium. https://wclc2020.iaslc.org/wp-content/uploads/2020/08/Abstracts-Virtual- Presidential-Symposium.pdf Sintilimab in NSCLC (ORIENT-11): Interim results1,2

Placebo (n=131) Sintilimab 200 mg (n=266) + pemetrexed + platinum + pemetrexed + platinum

PFS, months 5.0 8.9 HR 0.482; 95% CI 0.362–0.643; p<0.00001

29.8 51.9 ORR, % (95% CI) (22.1–38.4) (45.7–58.0)

Grade ≥3 AEs, 58.8 61.7 %

irAEs*, % 36.6 43.2

*investigator-assessed prior to unblinding

Sintilimab + combination therapy: • Median OS NR but showed nominal improvement: HR 0.609; 95% CI 0.400–0.926; p=0.01921

• PFS benefit observed across all PD-L1 TPS subgroups

AE, adverse event; CI, confidence interval; HR, hazard ratio; irAE, immune-related AE; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression free survival; TPS, tumour proportion score. 1. Yang Y, et al. J Thorac Oncol. 2020; S1556-0864(20)30595-5 [online ahead of print]; 2. Zhang L, et al. 2020; presented at IASLC Presidential Symposium. https://wclc2020.iaslc.org/wp-content/uploads/2020/08/Abstracts-Virtual- Presidential-Symposium.pdf ORIENT-11 versus KEYNOTE 189: Same chemotherapy backbone

1,2 3,4 Both studies evaluated: ORIENT-11 KEYNOTE 189 Sintilimab Placebo Pembrolizumab Placebo Non-squamous NSCLC cohorts without sensitizing ALK or N 266 131 410 206 EGFR alterations Male, % 76.7 75.6 62 52.9 East Asian, % 100 100 1 2.9 PD-1 inhibition in combination Never smokers, % 35.7 33.6 11.7 12.1 with pemetrexed and platinum Results -based chemotherapy backbone ORR, % 51.9 29.8 47.6 18.9 Median PFS, 8.9 (NR) 5.0 (NR) 9.0 (8.1–9.9) 4.9 (4.7–5.5) months (95% CI) HR (95% CI) 0.482 (0.362–0.643) p<0.00001 0.48 (0.40–0.58)

NR, not reported. 1. Yang Y, et al. J Thorac Oncol. 2020; S1556-0864(20)30595-5 [online ahead of print]; 2. Zhang L, et al. Journal Thorac Oncol. 2020;https://doi.org/10.1016/j.jtho.2020.07.014 [journal pre-proof] presented at IASLC Presidential Symposium: https://wclc2020.iaslc.org/wp-content/uploads/2020/08/Abstracts-Virtual-Presidential-Symposium.pdf; 3. Gadgeel J, et al. Clin Oncol. 2020;1505–17; 4. Gandhi L, et al. N Engl J Med. 2018;378:2078–92. Camrelizumab: Real-world use and effectiveness in NSCLC

Camrelizumab Real-world use 100 Camrelizumab-based treatment regimen prospective, multicentre study 80 Advanced lung cancer: 60 52.6% (n=97; Aug – Dec 2019, enrolment ongoing) 40 Eligible for camrelizumab-based regimens 24.7%

Patients (%)Patients 13.4% 20 Treatment setting 0 100

80 n=72 60 44.4% Real-world effectiveness

Patients (%)Patients 40 30.9% 100 24.7% Objective response 20 80 71% 0 60

40 21.2% 21% n=72 (%)Patients 20 Real-world data providing insights into 0 camrelizumab therapy in advanced lung cancer n=52

Wang R, et al. J Clin Oncol. 2020;38:e21650. Camrelizumab: Real-world safety in NSCLC

Camrelizumab

Most frequent AEs1 Apatinib salvage therapy for RCCEP in • cutaneous RCCEP (27.8%) NSCLC3 • neutropenia (19.4%) Patients experiencing RCCEP TRAE . . . • nausea (16.7%) 28.6% (n/N=8/28) • fatigue (15.3%) • leukopenia (13.9%) 9.3% achieved rapid regression with apatinib (n/N=4/28) RCCEP2 Combination of camrelizumab and Prevalent and unique TRAE associated with camrelizumab therapy apatinib in patients with NSCLC may reduce incidence of RCCEP • Median time to onset: 23 days • Typically Grade 1 severity • No RCCEP TRAE discontinuations to date

RCCEP, reactive cutaneous capillary endothelial proliferation [also referred to as RCH, reactive capillary hemangioma]. 1. Wang R, et al. J Clin Oncol. 2020;38:e21650; 2. Mo H, et al. Br J Cancer. 2018;119:538–45; 3. Li W, et al. J Cancer Res Ther. 2019;15:1624–28. Camrelizumab-associated RCCEP and improved outcome in HCC

Morphological classification of RCCEP Occurrence of RCCEP associated with improved OS in HCC

red-nevus-like pearl-like mulberry-like 100 With RCCEP 17.0 months (95% CI, 14.4–NR) Without RCCEP 5.8 months (95% CI, 4.0–7.3)

50 patch-like tumour-like

25 HR: 0.33 (95% CI, 0.22–0.47) Log-rank p<0.0001

Probability of overall survival (%) survival overall of Probability 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

No. at risk With RCCEP 145 145 144 141 136 130 126 121 117 111 105 98 95 84 68 56 40 23 18 11 7 2 1 1 0 Without RCCEP 72 68 56 49 44 39 32 27 25 24 23 21 20 17 16 9 3 2 1 1 0

HCC, hepatocellulair carcinoma; RCCEP, reactive cutaneaous capillary endothelial proliferation [also referred to as RCH, reactive capillary hemangioma]. Wang F, et al. J Hematol Oncol. 2020,13:47. Figure 1 reproduced with permission from: Wang F, et al. J Hematol Oncol. 2020,13:47. Ongoing trials in NSCLC: Impact for future practice?

Tislelizumab Camrelizumab Novel PD-1 7 active trials 11 active trials inhibitors following 1st- or 2nd-generation following 1st-line EGFR TKI failure1,2 ALK TKI failure16 in combination regimens3–5 neoadjuvant setting in stage II/III17–20

neoadjuvant setting in stage II/III6,7 in combination regimens21–25

Cemiplimab Sintilimab in NSCLC 8 active trials 27 active trials

in combination regimens8–14 in EGFR-positive NSCLC26,27 in combination regimens28 neoadjuvant setting15 Data pending . . . neoadjuvant setting in stage II/III29

ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-1, programmed death-1; TKI, tyrosine kinase inhibitor. All trials listed on ClinicalTrials.gov; accessed 10 August 2020 1. NCT04405674; 2. NCT04310943; 3. NCT03663205; 4. NCT04379635; 5. NCT04282018; 6, NCT04379635; 7. NCT03745222; 8. NCT03367819; 9. NCT03409614; 10. NCT03580694; 11. NCT03430063; 12. NCT03088540; 13. NCT03515629; 14. NCT03367819; 15. NCT03916627; 16. NCT04425135; 17. NCT04506242; 18. NCT04338620; 19. NCT04379739; 20. NCT04133337; 21. NCT04239443; 22. NCT04211090; 23. NCT04167774; 24. NCT04303130; 25. NCT04203485; 26. NCT03765775; 27. NCT03802240; 28. NCT04144582; 29. NCT04459611. Emerging data in NSCLC: Neoadjuvant sintilimab

AJCC stage IA – IIIB NSCLC A decrease in SUVmax of primary tumour may be predictive of pathologic response for neoadjuvant PD-1 therapy in NSCLC Surgically resectable (1o tumour diameter: ≥2 cm) Histology: S S S S A S S A S A S S S S S MA S S S A S S S S S S S S S S S S S S S S • Treatment naïve RECIST: D S S S S S S S S S S S D S S S S S S P D S S P S P P S S P P S S S P S P N=40 • No EGFR sensitizing mutation Gender: MMF F F MMMM F MMMMM F MMMMMMMMMMMMMM F MMMMMM Preliminary results: Response rates Smoker: Y Y NN N Y Y Y Y N Y Y Y Y Y N Y Y Y Y Y Y Y Y Y Y Y Y Y Y N Y Y Y Y Y Y PD-L1: - U - U U + + - + - - + + + + + + + U + + + - + + U + - + - U - + + U U + Response % (95% CI) n/N 0 10 ORR 20.0 (9.1–35.6) 8/40 20 MPR 40.5 (24.8–57.9) 15/37 30 40 50 pCR 16.2 (6.2–32.0) 6/37 SUVmax reduction ≥ 30% 60 SUVmax reduction < 30% o pCR (1 + 8.1 (1.7–21.9) 3/37 70 SUVmax NA LNs) 80 Safety 90

Pathologic regression (%) regressionPathologic Major pathologic response ≥ 90% 100 • 80% patients experiencing AEs Histology: (S)quamous, (A)denocarcinoma, (M)ixed RECIST: P(R), (S)D, P(D) ChiCTR-OIC-17013726 • 4 patients (10%) experienced Grade ≥3 TRAE Gender: M(ale), (F)emale • predominantly pneumonitis (5%) Smoker:(Y)es, (N)o Stromal PD-L1: -<1%,+≥1%,U = NA

AJCC, American Joint Committee on Cancer; MPR, major pathologic response; ORR, objective response rate; pCR, pathologic complete response; SUVmax, standardized uptake values. Gao S, et al. J Thorac Oncol. 2020;15:816–26. Other agents targeting PD-1 are in development

Spartalizumab AMP-224

• Humanized IgG4κ monoclonal antibody PD-1 inhibitors • In pilot studies in metastatic bowel • In Phase I / II studies in solid tumours1 cancer4 • In Phase III for melanoma2

Dostarlimab AMP-514 • Humanized IgG4 monoclonal antibody • In Phase II / III studies in ovarian cancer • In development and endometrial cancer2 in development

Toripalimab INCMGA00012 • In Phase I studies in solid tumours3 • In development Clinical trial investigations ongoing . . .

1. Naing A, et al. J Immunother Cancer. 2020; 8: e000530.; 2. Kaplon H, et al. MABS. 2020;12:1703531; 3. Wei X-L, et al. Cancer Commun (Lond);2020 40:345–54; 4. Flouda CS, et al. Clin Colorectal Cancer. 2019 Dec;18:e349–60. Summary statements and concluding remarks

How will the new wave of PD-1 inhibitors change the treatment landscape in NSCLC? • Promising (and expected?) results with new PD-1 inhibitors

Will the new wave of PD-1 inhibitors change the treatment landscape in NSCLC? • Structural differences impact on toxicity profile • Structural difference might have impact on efficacy • Do we need head-to-head comparison? Case discussion

Prof. Anne-Marie C Dingemans

Department of Pulmonology, Erasmus Medical Center, Rotterdam, The Netherlands Case discussion

Prof. Tony Mok

Prof. Anne-Marie C Dingemans PD-1 inhibitors in NSCLC: A case discussion

75-year-old male patient

Patient history Clinical findings

SMOKER PRESENTATION • 15 pack-year • Right upper lobe mass history

RENAL FUNCTION IMAGING • Mildly impaired • Bone + adrenal metastases

HISTORY OF DIABETES ImmunogenicityBIOPSY • Adenocarcinoma • Tumour PD-L1 expression ~40%

Optimal first-line therapy?

NSCLC, non-small cell lung cancer; PD-1, programmed death-1; PD-L1, programmed death ligand-1. PD-1 inhibitors for NSCLC: Future challenges, future potential

Prof. Giorgio V Scagliotti Department of Oncology, University of Torino, Turin, Italy

Treatment regimens evaluated in first-line NSCLC immunotherapy studies

- Non

ALK+, anaplastic lymphoma kinase positive; EGFRmut, epidermal growth factor receptor mutant variant-positive; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand-1; TMB, tumour mutational burden. Martinez P, et al. Clin Cancer Res. 2019;25:2691–8. Current paradigm for immunotherapy in advanced NSCLC without an actionable mutation

PD-L1 low PD-L1 high (1–49%) or negative (≥50%) (<1%) • For PD-L1 low (1–49%) or negative (<1%), SoC is combination ICI + CT • For ≥50% PD-L1, choice of single-agent ICI or PD-(L)1 inhibitor ICI + CT Squamous Non-squamous • or CT + Single-agent ICI approved for ≥1% PD-L1 histology histology but not broadly recommended by experts PD-(L)1 inhibitor • Nivolumab/ipilimumab approved for first-line treatment of advanced NSCLC with ≥1% PD-L1 on May 15, 2020 CT + CT + PD-1 inhibitor PD-(L)1 inhibitor

CT, chemotherapy; ICI, immune checkpoint inhibitor; PD-1, programmed death-1; PD-L1, programmed death ligand-1; SoC, standard of care. Lim SM, et al. Immune Netw. 2020;20:e10. Outcomes to first-line pembrolizumab in patients with NSCLC and very high PD-L1 expression

150 PD-L1 TPS 50–89% PD-L1 TPS 90–100% P<0.001 70

60 100 50

40 50 30

0 20 Response rate (%) Responserate 10

–50 0 50–89% 90–100%

PD-L1 level Change in target lesions lesions target in Change baseline from(%) –100

TPS, tumour proportion score. Aguilar EJ, et al. Ann Oncol. 2019;30:1653–9. Outcomes of first-line pembrolizumab in patients with NSCLC and very high PD-L1 expression

100 N Median PFS (95% CI) 100 PD-L1 90–100% 80 14.5 months (6.0–NR) PD-L1 50–89% 107 4.1 months (1.7–6.6) 80 80 HR: 0.50 (95% CI: 0.33–0.74), p<0.01

60 60 free free survival (%) - 40 40

Overall Overall survival (%) N Median OS (95% CI) 20 20 PD-L1 90–100% 80 Not reached (NR–NR) Progression PD-L1 50–9% 107 15.9 months (11.2–20.7) HR: 0.39 (95% CI: 0.21–0.70), p=0.002 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 27 30 Months Months No. at risk No. at risk PD-L1 90–100% 80 58 44 34 27 12 3 0 0 PD-L1 90–100% 80 73 66 57 38 22 10 0 0 0 0 PD-L1 50–89% 107 59 42 25 13 6 2 2 0 PD-L1 50–89% 107 92 75 51 33 18 8 4 1 1 0

CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival. Aguilar EJ, et al. Ann Oncol. 2019;30:1653–9. Atezolizumab improves OS regardless of PD-L1 expression levels Improved OS for atezolizumab vs. docetaxel was observed regardless of PD-L1 expression

Median OS, months On-study prevalence1 atezolizumab docetaxel Subgroup2 n=425 n=425 TC3 or IC3 0.41 20.5 8.9 TC3 or IC3 16% TC2/3 or IC2/3 0.67 16.3 10.8 31% TC2/3 or IC2/3 TC1/2/3 or IC1/2/3a 0.74 15.7 10.3 TC1/2/3 or IC1/2/3 55% TC0 and IC0 0.75 12.6 8.9

TC0 and IC0 45% ITTa 0.73 13.8 9.6 0% 20% 40% 60% 80% 100% 0.2 1 2 HRa 100% Favours atezolizumab Favours docetaxel

aStratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for subgroups. IC, tumour infiltrating immune cell; ITT, intention-to-treat; TC, tumour cell. 1. Rittmeyer A, et al. Lancet. 2017;389:255–65; 2. Park K, et al. Ann Oncol. 2016;27:4380. PD-L1 immunohistochemistry is not going to disappear1–4

• It works, it is relatively simple, quick and cheap

• Discussions continue over cut points (assay dependant) but also tumour cells vs. immune cells, location of expression, intensity, % positivity, distribution Issues • Reporting TPS is important • Heterogeneity – multiple tumours and multiple passes within a tumour

• Interval between biopsy and treatment

• Primary vs. metastatic disease

• Antibody and staining conditions

TPS, tumour proportion score. 1. Peters S, et al. Ann Oncol. 2019;30:884–96; 2. Mountzios G, et al. Ann Oncol. 2019;30:1686–8; 3. Aguilar EJ, et al. Ann Oncol. 2019;30:1653–9; 4. McLaughlin J, et al. JAMA Oncology. 2016;1:46–54. Blueprint Phase IIb data showed that aspirates compare well with other sample types Matched samples (FNA, biopsy, large block) from the same tumour shows good comparability between TPS scores

Agreement: aspirate and biopsy Agreement: aspirate and resection Agreement: biopsy and resection

22c3 22c3 22c3 28-8 28-8 28-8 ≥1% 73-10 ≥1% 73-10 ≥1% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

22c3 22c3 22c3 28-8 28-8 28-8 ≥5% 73-10 ≥5% 73-10 ≥5% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

22c3 22c3 22c3 28-8 28-8 28-8 ≥10% 73-10 ≥10% 73-10 ≥10% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

22c3 22c3 22c3 28-8 28-8 28-8 ≥25% 73-10 ≥25% 73-10 ≥25% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

22c3 22c3 22c3 28-8 28-8 28-8 ≥50% 73-10 ≥50% 73-10 ≥50% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

22c3 22c3 22c3 28-8 28-8 28-8 ≥80% 73-10 ≥80% 73-10 ≥80% 73-10 SP142 SP142 SP142 SP263 SP263 SP263

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 None Weak Strong None Weak Strong None Weak Strong Minimal Moderate Near perfect Minimal Moderate Near perfect Minimal Moderate Near perfect Sample preparation is vitally important to replicate these outcomes

FNA, fine needle aspirate. Data presented by Kerr KM, et al at IASLC 2018;late-breaking abstract_OAO3.O3 2018. Data provided by presenting faculty. Mechanism of immune checkpoint inhibitors

IFNγR IFNγ-mediated PD-L1/PD-1-mediated upregulation of tumour PD-L1 inhibition of tumour cell killing

Complexity of the immune microenvironment PI3K

Tumour-

PD-L2-mediated inhibition of TH2 T cells

IFNγ, interferon gamma; IFNγR, interferon gamma receptor; MHC, major histocompatibility complex; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells ; PD-L2, programmed death ligand-2; PI3K, phosphoinositide 3-kinase; Shp-2, SH2 domain-containing protein tyrosine phosphatase-2; TCR, T cell receptor; TGF-β, transforming growth factor beta; TH, helper T cell; Treg, regulatory T cell. Herbst RS, et al. J Clin Oncol. 2013;31:3000. Schematic provided by presenting faculty. Four categories of tumours based on presence of PD-L1 and TILs1,2

PD-L1-/TIL- PD-L1+/TIL+ PD-L1-/TIL+ PD-L1+/TIL- 450 samples analyzed

PD-L1=B7-H1 45% Type I 17% Type II 26% Type III 12% Type IV

Initial response to anti-PD-1 therapy No response to anti-PD-1 therapy

TIL, tumour infiltrating lymphocyte. 1. Velcheti V, et al. Lab Invest. 2014;94:107–16; 2. Kim TK, et al. Trends Immunol. 2018;39:624–31. Data and schematics shared by presenting faculty. Biomarker analyses: Defining the profile of non-responders1–4

Immunological Non-functional Excluded ignorance immune response infiltrate

CD8 CD8 CD8

treatment treatment treatment

- - -

Pre Pre Pre

Immune desert Immune excluded

CD8 CD8 CD8

week week 9 week 6 week 6

– – –

On treatment treatment On treatment On treatment On

• Three distinct patterns of non-response were observed • Most patients who progressed failed to show up-regulation of PD-L1 or evidence of activated T cells • These results provide evidence for the “inflamed tumour” hypothesis

Adapted from: Chen DS and Mellman I. Immunity. 2013;39:P1–10.

1. Herbst RS, et al. Nature. 2014;515:563–7; 2. Hegde PS, et al. Clin Cancer Res. 2016;22:1865–74; Kim JM and Chen DS. Ann Oncol 2016;27:1492–504; 4. Chen DS and Mellman I. Nature. 2017;541:321–30. Biomarkers for immunotherapy

Surrogates of immune response PD-L1 IHC • Immune cells • Gene signature T-effector and IFNᵧ gene 1 100 All tumours signature subgroups2

100

free (%) free - 50 Tumour 80 High nonsynonymous burden Mutational burden 60 T Low nonsynonymous burden HR 0·43 (95% CI 40 0·24–0·77)

Progression 0

Atezolizumab (T T Overall survival (%) survival Overall 0 4 8 12 16 20 24 20 Atezolizumab (T HR 1·10 Months Docetaxel (T (95% CI Docetaxel (T 0·68–1·76) 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up (months)

Other factors Microbiome

Metabolism TMB surrogates

1. Adapted from Rizvi NA, et al. Science. 2015;348:124–8. 2. Adapted from Fehrenbacher L, et al. Lancet. 2016;387:1837–46. 3. Adapted from McGranahan N, et al. Science. 2016;351:1463–9. Tumour mutational load predicts survival after immunotherapy across multiple cancer types

100 a Top 10% TMB within histology Top 10–20% TMB within histology No. of patients Cut-off p-value Bottom 80% TMB within histology All samples in cohort 1,662 - 1.59 x 10-6

50 Cancer type Bladder 214 17.6 0.040 Breast 45 5.9 0.605

Overall Overall survival (%) ER+ 24 6.8 0.287 p<0.0001 ER- 21 4.4 0.731 Unknown primary 0 90 14.2 0.155 Colorectal 110 52.2 0.031 0 12 24 36 48 Oesophagogastric 126 8.8 0.221 No. at risk Time (months) Glioma 117 5.9 0.465 Bottom 80% 1,305 586 231 85 33 Head and neck -3 Top 10–20% 184 100 39 16 5 138 10.3 7.42 x 10 Top 10% 173 101 43 16 6 Melanoma 321 30.7 0.067 NSCLC -4 1.0 350 13.8 2.30 x 10 b RCC 151 5.9 0.569 Drug class Combo 260 - 0.018 CTLA-4 146 - 1.89 x 10-3

0.5 PD-1/PD-L1 1,256 - 6.95 x 10-4 Hazardratio 0.12 0.25 0.50 1.0 2.0 4.0 Better OS------HR------Worse OS→ 0 0 20 40 60 TMB cutoff CTLA-4, cytotoxic T lymphocyte-associated antigen-4; ER, oestrogen receptor; RCC, renal cell carcinoma. Samstein MR, et al. Nature Genetics. 2019;51:202–6. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade A systematic review and meta-analysis Weighted Unweighted 1.0 1.0

0.9 0.9

0.8 0.8 TMB + GEP + PD-L1 IHC TMB + GEP 0.7 0.7 TMB + GEP + 0.6 0.6 PD-L1 IHC

TMB + PD-L1 HC

positive positive rate) positive rate) - - 0.5 0.5 TMB + PD-L1 HC 0.4 0.4

GEP + CD8 IHC Sensitivity (trueSensitivity Sensitivity (trueSensitivity 0.3 0.3

Modality AUC Dot size represents 50 patients 0.2 PD-L1 IHC 0.657 0.2 TMB (DNA) 0.710 Modality Weighted AUC mlHC/IF 0.790 1.0 GEP (RNA) 0.687 1.0 mlHC/IF 0.872a Multimodality 0.736

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

1 –Specificity (False-Positive Rate) 1 –Specificity (False-Positive Rate) aIndicates statistical significance (p<0.05), Hanley and McNeil method. AUC, area under the curve; GEP, gene expression profiling; IF, immunofluorescence; mIHC, multiplex immunohistochemistry. Lu S, et al. JAMA Oncol. 2019;5:1195–204. Multiomics prediction of response rates to therapies that inhibit PD-1 and PD-L1 Neoantigen hydrophobicity Tumour IFNγ signature Tumour immune neoantigen Neoantigen burden microenvironment

Tumour mutational CD8 T cell abundance burden R=0.72 R=0.68 Intratumour T cell exhaustion signature heterogeneity 0.4 0.6 WES and RNA sequencing of 7,187 0.8 The three key variables (R=0.90) can patients from the publicly available Correlation explain most of the observed cross- TCGA, and the ORR data of 21 cancer coefficient cancer response variability, but their types, obtained from a collection of relative explanatory roles may vary in clinical trials. A total of 36 variables of CPS PD-L1 protein expression specific cancer types. three distinct classes. Fraction of high PD-1 mRNA samples

R=0.68 Checkpoint targets

CPS, combined positive score; ORR, objective response rate; PD, progressive disease; TCGA, The Cancer Genome Atlas; WES, whole-exome sequencing. Lee JS, Ruppin E. JAMA Oncol. 2019;5:1614–8. What is hyper-progressive disease? ICI cohort 100 Log-rank P=0.003 80

Reference Period (REF) Experimental Period (EXP) 60

40 Progressive disease without

Overall Overall survival (%) hyperprogression 20 Hyperprogressive disease 0 0 6 12 18 24 Time from start of immunotherapy (months) Chemotherapy cohort Before Baseline IO 1° evaluation (8 weeks) 100 Log-rank p=0.60 80

60 ✓ ICI specific (PD-1/PD-L1 monoclonal antibody specific) phenomenon 40 Progressive disease without

✓ ICI treatment accelerate the tumor growth speed Overall survival (%) hyperprogression 20 Hyperprogressive disease 0 0 6 12 18 24 Time from start of immunotherapy (months)

IO, immunotherapy. Champiat S, et al. Clin Cancer Res. 2017;23:1920–8; Ferrara R, et al. JAMA Oncol. 2018;4:1543–52. Ferrara R, et al. ESMO R,et 2017.Ferrara 1306PD; R,et al. Abstract Ferrara hypercompleteHPD,CR, response; HPD can occur in ~16% immuno of IO drug type IO Line Performancestatus N Stage (advanceddisease) PD Histology Smoking history Age ° 0 ≥65 years - – met sitesIO baseline PD PD ≥2 (range 2 >2 IVA or IVB Unknown PD PD Squamous Non Current Former Non Patients characteristicsPatients L1 status 1 - - - - L1 inhibitor 1 inhibitor L1 positive L1 negative - - squamous smoker – 7) - progressive disease; SD, stable disease; TGR,stable disease; tumourgrowth SD, rate. disease; progressive N=242 (%) 235 (97%) 238 (98%) 217 (90%) 108 (45%) 204 (85%) 186 (77%) 172 (71%) 123 (51%) 101 (42%) 118 (49%) 30 (12%) 26 (11%) 70 (29%) 18 (7%) 7 (3%) JAMA Oncol. Oncol. JAMA 2018;4:1543

- TGR-IO (%) 100 200 300 400 500 Under treatmen100 t percent change in tumor volume per month – 0 - 52. 1 1 2 3 4 5 - 0 0 0 0 0 0 100 0 0 0 0 0 0 0 - 1 0 0 Deleterious effect effect Deleterious IO of Blue Blue 0 0 = HPD = P r e - b a s oncology patients treated with NSCLC 100 1 spot= 1 patient e 1 l 0 i 0 TGR pre TGR n e

p e r c e n t

c h a n g 200 2 e response to IO response patterns 0

- i 0 n IO (%)

t Typical and and atypicalTypical u Status m o r S

v t a o t l Black u u t m e

300 p 3 e 0 r 0

m o n d t = not HPD = not e h l t a

T G R > = Delta TGR ≥50% ≥50% (HPD) TGR Delta 5 4 0 400 0 % 0

( Delta TGR <50% TGR Delta H d e y l p t a e

r T p G r o R g r

< e s 5 s 0 o % 5 500 r ) 0 0 Delta TGR >50% (HPD) Delta TGR ≤50% Delta TGR >0 (not regressing tumours) tumours Delta TGR ≤0 (regressing/stable 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% ) 15% TRG VariationTRG Response by 39% 45% 1.2% delta 16% TGR N=242 (%) 202 (84%) 155 (64%) 40 (16%) 87 (36%) Definition of hyper-progressive disease

TGKR<0 0> TGKR<2 0 1. Time to treatment failure <2 months TGKR> 2 0 2. ≥50% increase in tumor burden compared with

volume pre-treatment imaging 3. ≥2-fold increase in progression speed (EXP/REF) 0 Evaluation of tumour growth speed before and after ICI

Tumour treatment might be difficult Is only definition of 1 and 2 is enough for 10 hyperprogressive disease? 0 Time (months) 0 ✓ TGR = Log(Dt/D0)/t ※ Dt: Tumour size at Time t

0 D0: Tumour size at baseline

0 Before ICI On ICI therapy

Saâda-Bouzid E, et.al. Ann Oncol .2017;28:1605–11. What is the mechanism of hyper-progressive disease?

Intratumour T cells unleashed by PD-1/PD-L1 blockade

✓ Hyper-progression cases showed tumor infiltration by M2-like CD163+ CD33+ PD-L1+ clustered epithelioid macrophages

✓ M2 immunosuppressive macrophages reprogramming, via FcR engagement by ICI, inducing hyper-progressive disease

FcR , Fc receptor. Lo Russo P. et al. Clin Canc Res. 2019;25:989–99. Can we identify patients at risk of hyper-progression?

35 Overall survival (months) Comprehensive Clinical and Genetic Characterization 0 Response of Hyper-progression Based on Volumetry in Advanced Number of prior ICI treatment Non-Small Cell Lung Cancer Treated With Immune Age Checkpoint Inhibitor Gender Youjin Kim, Chu Hyun Kim, Ho Yun Lee, Se-hoon Lee, Hong Sook Kim, Sook Lee, Smoking Hongui Cha, Sungjun Hong, Kyunga Kim, Sang Won Seo, Jong-Mu Sun, Myung-Ju Histology Ahn, Jin Seok Ahn, Keunchil Park PD-L1 TMB EGFR KRAS RAF1 CDKN2A STK11 Hyper-progressive disease is associated with: JAK2 MDM2 B2M Concurrent KRAS and STK11 mutations NFE2L2 JAK1 NLR >4 BACH1 MDM4 LDH >upper limit of normal

Status Response Alteration type PDL 1 Gender Smoking Histology TMB/sCNA z-core Dead HPD AMP DEL Possitive Male Ever ADC Alive non-HPD loss gain Negative Female Never SQCC -1 5 SD nonsynonymus SNV Negative etc Number of prior ICI treatment PR Truncation 0 7 Age

30 80

ADC, adenocarcinoma; LDH, lactate dehydrogenase; NLR, neutrophil to lymphocyte ratio; STK11, serine/threonine kinase 11; SQCC, squamous cell carcinoma. Kim Y, et al. J Thorac Oncol. 2019;14:1608–18. Pre-treatment CD4 senescent T cells in NSCLC: Correlation with hyper-progression and non-response to PD-L1/PD-1 inhibitors

Change in target lesions

Red: G2 profile 100 Black: G1 profile • ORR in G2 patients was 0%, ORR in G1 patients was 50% Progression by 80 non-measurable 60 disease 40 New lesions • The CD4 THD (CD28-/CD27-) core (using 40% as a 20 cut-off point) is an intriguing novel biomarker of IO 0 efficacy 2 4 6 8 20 • Questions remain about the 40% cut-off point and 40 the reproducibility in a larger sample lesion diameters (%) lesion diameters 60 • THD phenotype seems independent of PD-L1 but Change from baseline in target baselinetarget in from Change 80 those with PD-L1 and G1 phenotype of THD were 100 Months very intriguing

THD, highly differentiated T cells. Zuazo M, et al. ESMO 2018. Abstract 54PD; Arasanz H, et al. Cancers. 2020;12:E344. Pre-treatment CD4 senescent T cells in NSCLC: PFS by baseline CD4+ THD profile

PFS in patients receiving checkpoint PFS in patients receiving checkpoint inhibitor therapy stratified by baseline CD4+ inhibitor therapy stratified by baseline CD4+ THD, G1 and G2 profiles THD, G1 and G2 profiles and PD-L1

Median PFS 12-wk PFS wk (95% CI) % patients 100 100 +++ + + G1+ PD-L1+ patients (n=9) Negative profile 6 (4–8) 8 80 Positive profile 36 (17–34) 60 80 p=0.0001 by log-rank test + + 60 ++++ 60 Median PFS 12-wk PFS + + +

wk (95% CI) % patients PFS (%) PFS 40 + + (%) PFS 40 Negative profile 7 (5–10) 12 Positive profile 42 (37–48) 100 20 20 p=0.0001 by log-rank test G2 patients (n=24) Remaining (n=25) 0 0 0 10 20 30 40 50 0 10 20 30 40 50 Weeks since treatment initiation Weeks since treatment initiation

wk, week. Zuazo M, et al. ESMO 2018. Abstract 54PD; Arasanz H, et al. Cancers. 2020;12:E344. Clinical factors associated with HPD

✓ Older age (>65 years of age)1 and a higher number of metastatic lesions at baseline (>2)2

✓ They have not been consistently observed across different studies3

✓ PD-L1 expression on tumour cell was not associated with the occurrence of HPD1,2

✓ EGFR mutation and MDM2/4 amplification (p53 suppressor gene) were associated with HPD in one report.4 However, disease flare after stopping TKI is well known

✓ NLR and high LDH5

✓ Large scale multivariable analyses of the clinical factors underpinning HPD are warranted

EGFR, epidermal growth factor receptor; MDM2, Mouse double minute; homologue-2; TKI, tyrosine kinase inhibitor. 1. Champiat S, et al. Clin Canc Res. 2017;23:1920–8; 2. Ferrara R, et al. JAMA Oncol. 2018;4:1543–52; 3. Champiat S, et al. Nat Rev Clin Oncol. 2018;12:748–62; 4. Forschner A, et al. Cancers. 2020;12:540; 5. Onesti CE, et al. J Thorac Dis. 2019;11:35–8. The next steps for immunotherapy

• Treatment duration • Sequencing chemotherapy & immunotherapy • Combinations ✓ Established therapies that are of benefit should increase ORR and PFS if not impeded by toxicity concerns ✓ Survival advantage should be seen under one of two conditions ✓ Synergy ✓ Avoidance of a lack of opportunity to receive the second drug ✓ It is not likely that any agent is “Just what a PD-(L)1 inhibitor needs to make everyone respond” ✓ It will be hard to evaluate combinations without knowing what the agent does ✓ If benefits of addition of a second agent are seen, it will be in a definable subset • Early Stages How do we optimize adjuvant therapy to increase the cure rate?

Efficacious systemic therapies Patient selection

Immunotherapy Many patients are cured with surgery alone Molecularly targeted therapies Chemotherapy has significant acute and late Number of drugs onset side effects 1? 2? 3? 4? Identify biomarkers of relapse Drug sequence 1. Clinical/pathological/immune criteria 1. Concurrent versus sequential 2. Tumour gene signatures 2. Incorporation of neoadjuvant therapies 3. Molecular residual disease (MRD)

Identify predictive biomarkers of response to adjuvant therapy Neoadjuvant immunotherapy in lung cancer

Therapies N MPR pCR ORR • Several neo-adjuvant Phase II/III 1 clinical trials of IO and IO + Nivolumab 21 9 (43%) NR 9.5% chemotherapy have been Nivolumab or nivolumab 44 11/41 (25%) 8 (18%) 9 (20) completed or are in progress + ipilimumab2

• The clinical trial endpoints consider Atezolizumab (LCMC3)3 82 15 (18%) 4 (5%) 6 (7%) either ≤10% MPR or recurrence/disease-free survival Sintilimab4 22 10 (45%) 3 (14%) NR • However, there is no standardized and validated pathology Total IO alone 169 45 (27%) 15/148 (10%) 24/147 (16%) methodology to process surgically Nivolumab + 30 24 (80%) 18 (60%) NR resected lung tumour specimens chemotherapy5 and to evaluate MPR in this setting Atezolizumab + 14 7 (50%) 3 (21%) 8 (57%) chemotherapy6

Total IO + chemotherapy 44 31 (70%) 21 (48%) 8/14 (57%)

MPR, major pathological response; pCR, pathologic complete response. 1. Reuss JE, et al. J Clin Oncol. 2019 37:15_suppl,8524-8524; 2. Cascone T, et al. J Clin Oncol. 2019:37:15_suppl,8504-8504; 3. Kwiatkowski DJ, et al. J Clin Oncol. 2019;37:15_suppl,8503-8503; Gao S, et al. J Thorac Oncol. 2020;15:816–26; 5. Provencio-Pulla M, et al. J Clin Oncol. 2018 36:15_suppl,8521-8521 ; 6. Shu CA, et al. J Clin Oncol. 2018 36:15_suppl,8532-8532. Select Phase III adjuvant trials with PD-1/PD-L1 and other immune-targeting therapy in NSCLC

Primary Drug/Trial Description Stages Selection endpoint N Update

IB (≥4 cm)–IIIA Estimated US NCI, Nivolumab After adjuvant accrual observation Unselected OS/DFS 903 ALCHEMIST/ANVIL1 chemotherapy and/or completion control arm radiation fall 2019 IB (≥4 cm)–IIIA Atezolizumab Global, BSC Completed After adjuvant Unselected DFS 1,280 IMpower0102 controlled accrual chemotherapy IB (≥4 cm)–IIIA Durvalumab Global, placebo Completed After adjuvant Unselected DFS 1,360 BR313 controlled accrual chemotherapy ETOP/EORTC, IB (≥4 cm)–IIIA Pembrolizumab placebo After adjuvant Unselected DFS 1,080 Recruiting KEYNOTE-0914 controlled chemotherapy Global, Canakinumab* II–IIIA placebo NA DFS 1,500 Recruiting CANOPY-A5 IIIB (T>5 cm N2) controlled

*Human monoclonal antibody to interleukin-1 beta. BSC, best supportive care; DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; ETOP, European Thoracic Oncology Platform; NA, not applicable; NCI, National Cancer Institute. 1. https://clinicaltrials.gov/ct2/show/NCT02595944; 2. https://clinicaltrials.gov/ct2/show/NCT02486718; 3. https://clinicaltrials.gov/ct2/show/NCT02273375; 4. https://www.clinicaltrials.gov/ct2/show/NCT02504372; 5. https://clinicaltrials.gov/ct2/show/NCT03447769. Proposed Phase III adjuvant trial of chemotherapy + immune checkpoint inhibitor (ALCHEMIST CHEMO-IO)1 KEYNOTE-1892 100 12-mo rate 90 69.2% 80 49.4% 70 60 Surgical resection 50

(R0) and eligibility +/- PORT Unblinding 40 OS OS (%) criteria consistent 30 OS: Median (95% CI) with ongoing 20 HR 0.49 (95% CI: 0.38–0.64) NR (NE-NE) ALCHEMIST trials 10 p<0.00001 11.3 mo (8.7–15.1) Platinum doublet* Pembrolizumab* 0 + pembrolizumab (x13 more cycles) 0 3 6 9 12 15 18 21 Months KEYNOTE-4073 Events HR (95% CI) p Enrollment Randomization/ Platinum doublet* Pembrolizumab** Pembro + Chemo 30.6% 0.64 0.0008 on A151216 blinding + placebo (x17 cycles) (0.49-0.85) 100 Placebo + Chemo 42.7% 90 80 70 Platinum doublet* 60 Observation 50 *Acceptable regimes: + placebo Cisplatin (or carbo) pemetrexed 40 Cisplatin (or carbo) gemcitabine OS (%) 30 Median (95% CI) Carboplatin paclitaxel 20 NR (NE-NE) x4 cycles 10 **Each experimental arm includes a (as tolerated) 11.3 mo (8.7–15.1) total of 17 doses of pembrolizumab 0 0 3 6 9 12 15 18 21 Months

PORT, post-operative radiotherapy. 1. Sand J, et al. J Clin Oncol. 38:15_suppl; 2. Gandh L, et al. N Engl J Med. 2018;378:2078–92; 3. Paz-Ares L, et al. N Eng J Med. 2018;379:2040–51. Conclusions

• No individual biomarker will provide the “ideal” solution to select patients benefiting most from ICIs

• Understanding the role of the tumour microenvironment will be critical

• Combination of biomarkers may be more powerful

• HPD is occurring in a minority of patients and some molecular and clinical factors are more likely associated with its detection

• Future treatment avenues will be represented by the integration of immune-checkpoint inhibitors in the management of early stage NSCLC Summary and concluding remarks

• How can we translate the latest developments in IO, including PD-1 inhibitors, into reduction of mortality for patients with NSCLC? o Interpretation and application of PD-L1 expression thresholds o Options for single-agent and combination regimens incorporating PD-1 blockade

• A ‘new wave’ of PD-1 inhibitors are on the horizon o Structural differences may influence clinical activity and toxicity profiles o Promising ‘early phase’ clinical data but novel toxicities are emerging

• Will this new wave of PD-1 inhibitors impact the treatment landscape in NSCLC? o Appraisal of recently published Phase II/III data of new PD-1 inhibitors in NSCLC provide valuable insights

• What is needed to further optimize PD-1 inhibitor-based regimens in future? o Characterization of the complex network of biomarkers required to tailor treatment schedules to the individual patient o Greater understanding of hyper-progressive disease, and how best to robustly define this phenotype with objective clinical and molecular parameters PD-1 inhibitors on the horizon for NSCLC: Current knowledge, future possibilities

Live Q&A Session Phase III studies of new PD-1 inhibitors

Sintilimab1,2 Cemiplimab3

Locally advanced or metastatic non-squamous Advanced NSCLC (n=710) NSCLC (n=397) Sintilimab 200 mg plus pemetrexed + platinum vs Cemiplimab 350 mg monotherapy vs placebo plus pemetrexed + platinum platinum-doublet chemotherapy

PFS, months 8.9 HR 0.482 5.0 mOS, months HR 0.68 p<0.00001 22.1 p=0.002 14.3

ORR, 51.9 29.8 mPFS, 6.2 HR 0.59 5.6 % (95% CI) (45.7–58.0) (22.1–38.4) months p<0.0001

Grade ≥3 61.7 58.8 PD-L1 ≥50% NR HR 0.57 14.2 AEs, % mOS, months p=0.0002 PD-L1 ≥50% HR 0.54 43.2 36.6 8.2 irAEs, % mPFS, months p<0.0001 5.7

PFS benefit observed across all PD-L1 TPS subgroups Significantly improved OS and PFS with PD-L1 ≥50%

AE, adverse event; CI, confidence interval; HR, hazard ratio; irAE, immune-related AE; mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate; OS, overall survival; NR, not reached; NSCLC, non-small cell lung cancer; PD-1, programmed death 1; PD-L1, programmed death ligand-1; PFS, progression-free survival; TPS, tumour proportion score. 1. Yang Y, et al. J Thorac Oncol. 2020;15:1636–46; 2. Zhang L, et al. J Thorac Oncol. 2020;15(Suppl.):E41; 3. Sezer A, et al. Ann Oncol. 2020;31:S1182–3. EMPOWER-Lung 1 study design (NCT03088540)

710 patients with advanced NSCLC • No EGFR, ALK or ROS1 mutations • Treatment naïve (no prior systemic therapy) • ECOG PS 0 or 1

Randomize d 1:1 Cemiplimab (n=356) Investigator’s choice of IV monotherapy 350 mg Q3W chemotherapy (n=354) Treat until progression or 108 weeks 4–6 cycles OS and PFS Progressive disease Progressive disease ORR, DOR, HRQoL and safety Optional continuation of Optional crossover to cemiplimab + four cycles of Patients stratified by PD-L1 expression cemiplimab monotherapy chemotherapy for analyses

ALK, anaplastic lymphoma kinase; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; HRQoL, health-related quality of life; PS, performance status; Q3W, every three weeks; ROS1, ROS proto-oncogene 1 receptor tyrosine kinase. Sezer A, et al. Ann Oncol. 2020;31:S1182–3. Biomarker analysis of ORIENT-11

Genes associated with MHC-II antigen-presenting pathway P-value Hazard ratio

HLA-DMA, HLA-DMB, HLA-DOA, Sintilimab 0.0041 0.41 HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA- (95% CI, 0.23–0.76) DQB1, HLA-DQB2, HLA-DRA, HLA- DRB1, HLA-DRB3, HLA-DRB4 Chemotherapy 0.9030 0.96 and HLA-DRB5 (95% CI, 0.52–1.79)

MHC-II antigen presentation was significantly associated with longer PFS in patients receiving sintilimab 200 mg plus pemetrexed + platinum

HLA, human leucocyte antigen; MHC, major histocompatibility complex. Yang Y, et al. Ann Oncol. 2020;31:S1186. Examining adverse event profiles: Insights from Phase III studies of first-line tislelizumab with chemotherapy RATIONALE 3041 RATIONALE 3072 Locally advanced or metastatic non-squamous NSCLC (n=334) Advanced squamous NSCLC (n=360)

Tislelizumab 200 mg plus platinum chemotherapy Tislelizumab 200 mg plus paclitaxel + carboplatin + pemetrexed vs platinum chemotherapy vs tislelizumab 200 mg plus nab-paclitaxel + + pemetrexed carboplatin vs paclitaxel + carboplatin

Grade ≥3 Grade ≥3 67.6 53.6 88.3 86.4 83.8 AEs, % TRAEs, %

ORR, 57.4 36.9 PD-L1 TC <1% 68.8 68.1 51.0 % (95% CI) (50.6–64.0) (28.0–46.6) ORR, %

mPFS, months 9.7 HR 0.645 7.6 PD-L1 TC 1– 70.0 66.7 41.9 p<0.0044 49% DoR, months 8.5 6.0 ORRPD-L1, % TC ≥50% 78.6 88.1 53.7 (95% CI) (6.80–10.58) (4.99–NE) ORR, % The addition of tislelizumab resulted in significantly improved PFS as Tislelizumab plus chemotherapy resulted in significantly improved well as higher ORR and longer DoR than observed with PFS, higher ORR and longer DoR compared with chemotherapy chemotherapy alone alone

DoR, duration of response; NE, not evaluable; TC, tumour cell; TRAE, treatment-related adverse event. 1. Lu S, et al. Ann Oncol. 2020;31:S816–7; 2. Wang J, et al. Ann Oncol. 2020;31:S817. PD-1 inhibitors on the horizon for NSCLC: Current knowledge, future possibilities

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