ESMO 2021 (Virtual) Congress Report - PowerPoint Presentation

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ESMO 2021 (Virtual) Congress Report - PPT Presentation

Lung and gastrointestinal cancers Slide numbers Study Author ESMO ID 5 12 RATIONALE 304 Tislelizumab chemotherapy vs chemotherapy alone as 1L treatment for nonsquamous NSCLC in patients who are smokers vs nonsmokers ID: 932019

chemo patients response pfs patients chemo pfs response 2021 months treatment esmo arm abstract presented median orr survival disease

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Slide1

ESMO 2021 (Virtual)Congress Report

Lung and gastrointestinal cancers

Slide2

Slide numbers

Study

AuthorESMO ID5 – 12RATIONALE 304: Tislelizumab + chemotherapy vs chemotherapy alone as 1L treatment for non-squamous NSCLC in patients who are smokers vs non-smokersShun Lu1290P 13 – 21RATIONALE 307: Tislelizumab + chemotherapy vs chemotherapy alone as 1L treatment for advanced squamous NSCLC in patients who were smokers vs non-smokersXinmin Yu1297P 22 – 28Sitravatinib + tislelizumab in patients with metastatic NSCLCQing Zhou1280P 29 – 35Sitravatinib + tislelizumab in patients with anti-PD-(L)1 refractory/resistant metastatic NSCLCBo Gao1284P 36 – 43MRTX-500: Sitravatinib + nivolumab in patients with non-squamous NSCLC progressing on or after prior checkpoint inhibitor therapyTiciana Leal1191O44 – 52COAST: Durvalumab alone or in combination with novel agents in patients with locally advanced, unresectable, Stage III NSCLCAlexandrei Martinez-MartiLBA4253 – 61GEMSTONE-301: Sugemalimab in patients with unresectable Stage III NSCLC who had not progressed after concurrent or sequential chemoradiotherapyYi Long WuLBA4362 – 72DESTINY-Lung01: Trastuzumab deruxtecan in patients with HER2-mutated metastatic NSCLC: Primary data Bob LiLBA45

1L, First line; NSCLC, non small cell lung cancer.

Contents: Lung Cancer Studies

Slide3

Contents: Gastrointestinal Cancer Studies

GI: Gastrointestinal. GC: Gastric cancer. GEJC: Gastroesophageal junction cancer. EAC: esophageal adenocarcinoma.1L: First line.

Slide numbersStudy AuthorESMO ID74 – 85CheckMate 649: Nivolumab + chemotherapy or ipilimumab vs chemotherapy as 1L treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC)Yelena JanjigianLBA786 – 93ORIENT-15: Sintilimab plus chemotherapy versus chemotherapy as 1L therapy in patients with advanced or metastatic esophageal squamous cell cancer (ESCC): First resultsLin ShenLBA5294 – 101ORIENT-16: Sintilimab plus chemotherapy vs chemotherapy as 1L treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: First resultsJianming XuLBA53102 – 107JUPITER-06: Toripalimab vs placebo in combination with 1L chemotherapy for treatment naive advanced or metastatic esophageal squamous cell carcinoma (ESCC)Ruihua Xu1373MO108 – 114DisTinGuish: DKN-01 + tislelizumab + chemotherapy as 1L therapy in unselected patients with advanced gastroesophageal adenocarcinoma (GEA)Samuel Klempnera1384P 115 – 121Effects of tislelizumab monotherapy on health-related quality of life in patients with previously treated unresectable hepatocellular carcinoma (HCC)Zhenggang Ren936P

Slide4

Lung Cancer

Slide5

Tislelizumab plus chemotherapy vs chemotherapy alone as 1L treatment for locally advanced/metastatic non-squamous NSCLC:

Sub-analysis of patients who were smokers or non-smokers

RATIONALE 304

Slide6

R 2:1

Stage IIIB/IV non-squamous NSCLC

Key eligibility criteriaHistologically confirmed, locally advanced (Stage IIIB) not amenable to curative surgery or radiotherapy, or metastatic (Stage IV) nsq-NSCLCNo prior systemic chemotherapy for advanced or metastatic disease*No EGFR-sensitizing mutations or known ALK gene translocationECOG ≤1At least 1 measurable lesion as per RECIST 1.1Fresh or archival tissue for PD-L1 assessment (Ventana SP263 assay)*Patients with prior neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a disease-free interval of ≥6 months from the last dose of chemotherapy and/or radiotherapy prior to randomization. † Investigator’s choice. DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, Independent Review Committee; nsqNSCLC, non-squamous non small cell lung cancer; NSCLC, non small cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; R, randomized; TC, tumor cell. 1. Lu S, et al. J Thorac Oncol 2021; doi:10.1016/j.jtho.2021.05.005. Online ahead of print.Lu S, et al. Abstract 1290P presented at ESMO 2021.N = 111N = 223Induction PhaseQ3W 4-6 cycles Tislelizumab 200 mg + Platinum chemotherapy† (cisplatin 75 mg/m² OR carboplatin AUC 5) + Pemetrexed 500 mg/m² Platinum chemotherapy†(cisplatin 75 mg/m² ORcarboplatin AUC 5) +

Pemetrexed 500 mg/m²

Stratification factors Primary endpoints:

PFS (IRC-assessed)

Disease Stage (IIIB vs IV)

Secondary endpoints:

ORR, DoR, OS, safety profile

PD-L1 TC expression (<1% vs 1%-49% vs ≥50%)

Upon PD

Maintenance Phase

Q3W

Tislelizumab 200 mg + Pemetrexed 500 mg/m²

Pemetrexed 500 mg/m²

Continue tislelizumab until:

• Loss of clinical benefit

• Intolerable toxicity

• Withdrawal of consent

Follow up

Optional crossover to tislelizumab

RATIONALE-304 Study design

Open-label Phase 3 trial comparing tislelizumab plus chemotherapy to chemotherapy alone as first-line treatment for

locally advanced/metastatic non-squamous NSCLC

Slide7

RATIONALE 304

Primary results from the Phase 3 RATIONALE 304 study showed that the addition of tislelizumab to chemotherapy compared with chemotherapy alone in the first-line treatment of advanced non-squamous NSCLC resulted in:

significantly improved progression-free survival (PFS)1consistent safety and tolerability profile compared with chemotherapy alone in the first-line treatment of advanced non-squamous NSCLC1The results of a sub-analysis of patients who were smokers or non-smokers from the RATIONALE 304 study are reported hereNSCLC, non small cell lung cancer 1. Lu S, et al. J Thorac Oncol 2021; doi:10.1016/j.jtho.2021.05.005. Online ahead of print.Lu S, et al. Abstract 1290P presented at ESMO 2021.

Slide8

Data cut-off: January 23, 2020.CI, confidence interval; HR, hazard ratio; IRC, Independent review committee; ITT, intention-to-treat; PFS, progression-free survival.

Lu S, et al. Abstract 1290P presented at ESMO 2021.

PFS by IRCSmokers (Arm A vs Arm B) in the ITT analysis setNon-smokers (Arm A vs Arm B) in the ITT analysis setIn patients who were smokers, PFS by IRC was longer in Arm A (Tislelizumab + Platinum chemotherapy + Pemetrexed) compared with Arm B (Platinum chemotherapy + Pemetrexed)Median PFS 9.7 months vs 4.6 months (HR: 0.466 [95% CI: 0.311, 0.697])

100

Time (

months

)

PFS probability (%)

Number at risk:

Arm A

Arm B

100

PFS probability (%)

Number at risk:

Arm A

147

116

Arm B

Arm A

Arm B

Arm A

Arm B

Time (

months

)

In patients who were

non-smokers

, PFS by IRC was similar between the two arms

Median PFS 8.5 months vs 7.7 months (HR: 1.075 [95% CI: 0.596, 1.940])

Slide9

Data cut-off: January 23, 2020.CI, confidence interval; DoR, duration of response; HR, hazard ratio; IRC, independent review committee; ITT, intention-to-treat; NE, not estimable; ORR, objective response rate; PP, pemetrexed + platinum; TIS, tislelizumab.

Lu S, et al. Abstract 1290P presented at ESMO 2021.

ORR and DoRORR and median DoR by IRC in patients who were smokers or non-smokers (ITT analysis set)ORR was higher with tislelizumab plus chemotherapy (Arm A) vs chemotherapy alone (Arm B) regardless of smoking statusSmokersNon-smokersArm ATIS + PP(n=147)Arm BPP(n=66)Arm ATIS + PP(n=76)Arm BPP(n=45)

ORR, % (95% CI)61.2 (52.8, 69.1)

31.8 (20.9, 44.4)

50.0 (38.3, 61.7)

44.4 (29.6, 60.0)

Complete response, n (%)

5 (3.4)

0 (0.0)

2 (2.6)

1 (2.2)

Partial response, n (%)

85 (57.8)

21 (31.8)

36 (47.4)

19 (42.2)

Median DoR,

months (95% CI)

8.5 (6.34, NE)

8.5 (5.98, NE)

7.4 (4.96, NE)

5.4 (4.44, NE)

HR, (95% CI)0.938 (0.389, 2.262)0.788 (0.354, 1.752)

Slide10

PP, pemetrexed + platinum; TEAE, treatment-emergent adverse event; TIS, tislelizumab; TRAE, treatment-related adverse event.

Lu S, et al. Abstract 1290P presented at ESMO 2021.

Overall summary of TEAEs and TRAEs in patients who were smokers or non-smokers (safety analysis set)SmokersNon-smokersn (%)Arm ATIS + PP(n=146)Arm BPP(n=66)Arm ATIS + PP(n=76)Arm BPP(n=44)Patients with ≥ 1 TEAE146 (100.0)66 (100.0)76 (100.0)43 (97.7)

≥ Grade 399 (67.8)36 (54.5)51 (67.1)

23 (52.3)

Serious

52 (35.6)

15 (22.7)

22 (28.9)

8 (18.2)

≥ Grade 3 serious

39 (26.7)

12 (18.2)

15 (19.7)

3 (6.8)

Leading to treatment discontinuation

39 (26.7)

6 (9.1)

18 (23.7)

4 (9.1)

Leading to death

5 (3.4)2 (3.0)2 (2.6)0 (0.0)

Patients with ≥ 1 TRAE145 (99.3)64 (97.0)76 (100.0)43 (97.7)

≥ Grade 390 (61.6)30 (45.5)50 (65.8)20 (45.5)

Serious34 (23.3)9 (13.6)15 (19.7)6 (13.6) Leading to death2 (1.4)1 (1.5)1 (1.3)0 (0.0)

Overall safety profile

Slide11

TRAEs (≥ 20%)

TRAEs (≥ 20%) in patients who were smokers or non-smokers (safety analysis set)

SmokersNon-smokersPreferred term, n (%)Arm ATIS + PP(n=146)Arm BPP(n=66)Arm ATIS + PP(n=76)Arm BPP(n=44)

Grades 1-2

≥ Grade 3

Grades 1-2

≥ Grade 3

Grades 1-2

≥ Grade 3

Grades 1-2

≥ Grade 3

Patients with ≥ 1 event

145 (99.3)

90 (61.6)

64 (97.0)

30 (45.5)

76 (100.0)

50 (65.8)

43 (97.7)

20 (45.5)

Anemia*

97 (66.4)

24 (16.4)

44 (66.7)

7 (10.6)

54 (71.1)

6 (7.9)

27 (61.4)

4 (9.1)

Leukopenia

†

86 (58.9)

34 (23.3)

38 (57.6)

9 (13.6)

49 (64.5)14 (18.4)27 (61.4)

7 (15.9) Thrombocytopenia

‡

67 (45.9)

32 (21.9)

28 (42.4)

9 (13.6)

45 (49.2)

11 (14.5)

27 (61.4)

6 (13.6)

Alanine aminotransferase increased

63 (43.2)

3 (2.1)

20 (30.3)

2 (3.0)

29 (38.2)

5 (6.6)

25 (56.8)

1 (2.3)

Neutropenia

61 (41.8)

60 (41.1)

25 (37.9)

24 (36.4)

22 (28.9)

39 (51.3)

17 (38.6)

15 (34.1)

Nausea

55 (37.7)

1 (0.7)

23 (34.8)

1 (1.5)

39 (51.3)

0 (0.0)

20 (45.5)

0 (0.0)

Aspartate aminotransferase increased

53 (36.3)

1 (0.7)

24 (36.4)

0 (0.0)

33 (3.4)

3 (3.9)

25 (56.8)

0 (0.0)

Decreased appetite

45 (30.8)

2 (1.4)

18 (27.3)

1 (1.5)

18 (23.7)

1 (1.3)

10 (22.7)

0 (0.0)

Fatigue

45 (30.8)

3 (2.1)

18 (27.3)

1 (1.5)

29 (38.2)

0 (0.0)

17 (38.6)

0 (0.0)

Vomiting

30 (20.5)

1 (0.7)

11 (16.7)

1 (1.5)25 (32.9)

0 (0.0)12 (27.3)

0 (0.0)

Data cut-off: January 23, 2020.*Anemia included: reports of anemia, hemoglobin decreased, and red blood cell count decreased. †Leukopenia included reports of white blood cell count decreased and leukopenia. ‡Thrombocytopenia included: reports of platelet count decreased and thrombocytopenia. §Neutropenia included: reports of neutrophil count decreased and neutropenia. ¶Fatigue included asthenia, fatigue, and malaise.

PP, pemetrexed + platinum; TIS, tislelizumab; TRAE, treatment-related adverse event.Lu S, et al. Abstract 1290P presented at ESMO 2021.

Slide12

Safety summary and conclusions

The safety profile in patients who were smokers or non-smokers was consistent with the overall patient population

1Regardless of smoking status, most patients (97.7%–100.0%) experienced ≥1 TEAEOf the patients who were smokers, 67.8% and 54.5% of patients experienced ≥3 Grade TEAEs in Arms A and B, respectivelyOf the patients who were non-smokers, 67.1% and 52.3% experienced ≥3 Grade TEAEs in Arms A and B, respectivelyIn patients who were smokers, five (3.4%) patients in Arm A and two (3.0%) patients in Arm B reported a TEAE leading to death. Two TEAEs leading to death in Arm A were reported to be related to tislelizumab treatment In patients who were non-smokers, two (2.6%) patients in Arm A and no (0.0%) patients in Arm B reported a TEAE leading to death. One TEAE leading to death in Arm A was reported to be related to tislelizumab treatmentThe most common immune-mediated TEAEs occurring in patients who were smokers or non-smokers were pneumonitis (11.0%) and hypothyroidism (10.5%), respectivelyEfficacy results in patients who were smokers with advanced non-squamous NSCLC were consistent with the overall population of the Phase 3 RATIONALE 304 study1Observed improvements in PFS and ORR suggest treatment benefits of tislelizumab plus chemotherapy in patients with advanced non-squamous NSCLC, regardless of smoking status1. Lu S, et al. J Thorac Oncol 2021; doi:10.1016/j.jtho.2021.05.005. Online ahead of print.NSCLC, non small cell lung cancer; ORR, overall response rate; PFS, progression-free survival; TEAE, treatment-emergent adverse event.Lu S, et al. Abstract 1290P presented at ESMO 2021.

Slide13

Tislelizumab plus chemotherapy vs chemotherapy alone as 1L treatment for advanced squamous NSCLC:

Sub-analysis of patients who were smokers or non-smokers

RATIONALE 307

Slide14

R 1:1:1

1. Wang J, et al.

JAMA Oncol 2021. doi: 10.1001/jamaoncol.2021.0366. Online ahead of print.*Patients receiving prior neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a disease-free interval of ≥6 months from the last dose of chemotherapy and/or radiotherapy prior to randomization.D, day; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; nab, nanoparticle albumin-bound; NSCLC, non small cell lungcancer; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; R, randomized; RECIST, response evaluation criteria insolid tumors; sq, squamous; TC, tumor cell. Yu X, et al. Abstract 1297P presented at ESMO 2021.Stage IIIB/IV Squamous NSCLCKey eligibility criteriaHistologically confirmed, locally advanced (Stage IIIB) not amenable to curative surgery or radiotherapy, or metastatic (Stage IV) sq-NSCLCNo prior systemic chemotherapy for advanced or metastatic disease*No EGFR-sensitizing mutations or known ALK gene translocationsECOG ≤1At least 1 measurable lesion as per RECIST v1.1Fresh or archival tissue for PD-L1 assessment (Ventana SP263 assay)Initial TreatmentQ3W 4–6 cyclesArm B (n=118)Tislelizumab 200 mg+nab-paclitaxel 100 mg/m2+carboplatin AUC 5Arm C (n=117)Paclitaxel 175 mg/m2 +carboplatin AUC 5Arm A (n=120)Tislelizumab 200 mg +paclitaxel 175 mg/m2 + carboplatin AUC 5Maintenance TreatmentQ3W

Tislelizumab 200 mg

Crossover allowed

upon disease

progression

Tislelizumab, carboplatin, and paclitaxel were administered on D1.

Nab-paclitaxel was administered on D1, D8, and D15.

RATIONALE-307 Study design

Open-label, randomized, multicenter Phase 3 study comparing the efficacy and safety of tislelizumab combined with chemotherapy vs chemotherapy only as first-line treatment in advanced squamous NSCLC

Stratification factors

Stage (IIIB vs IV)

PD-L1 TC (<1% vs 1%-49% vs ≥50%)

Primary endpoint:

PFS (IRC-assessed)

Secondary endpoints:

ORR, DoR, OS, and safety profile

Slide15

RATIONALE 307

Primary results from the Phase 3 RATIONALE 307 study showed that the addition of tislelizumab to chemotherapy

compared with chemotherapy alone in patients with locally advanced or metastatic squamous NSCLC resulted in a:significant PFS benefit1manageable safety/tolerability profile1Results of a sub analysis of patients who were smokers or non-smokers from the RATIONALE 307 study are reported here1. Wang J, et al. JAMA Oncol 2021. doi: 10.1001/jamaoncol.2021.0366. Online ahead of print.NSCLC, non small cell lung cancer; PFS, progression-free survival.Yu X, et al. Abstract 1297P presented at ESMO 2021.

Slide16

Data cutoff: December 6, 2019.CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committe; mo, months; nab-PC, nab-paclitaxel + carboplatin; PC, paclitaxel + carboplatin; PFS, progression-free survival; TIS, Tislelizumab.Yu X, et al. Abstract 1297P presented at ESMO 2021.PFS in smokersPFS by IRC in patients who were smokers (Arms A vs C) PFS by IRC in patients who were smokers (Arms B vs C)

100

PFS

probability

(%)

100

PFS probability (%)

Number

risk

Arm A

Arm C

Number

risk

Arm B

107

Arm C

Months

Arm A

Arm C

Months

Arm B

Arm C

PFS (by IRC) was longer in Arms A (TIS + PC) and B (TIS + nab-PC) compared with Arm C (PC), regardless of smoking status

In patients who were smokers, median PFS by

IRC was

7.6 months in Arm A vs

5.5 months in Arm C

7.6 months in Arm B vs

5.5 months in Arm C

Events (%)

Median PFS,

(95% CI)

Arm A

46 (47.9)

7.6 (5.6, 10.4)

0.534

(0.363, 0.786)

Arm C

61 (62.2)

5.5 (4.2, 5.8)

Events (%)

Median PFS,

(95% CI)

Arm B

54 (50.5)

7.6 (5.6, 9.9)

0.556

(0.384, 0.803)

Arm C

61 (62.2)

5.5 (4.2, 5.8)

Slide17

Data cutoff: December 6, 2019.

CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committe;

nab-PC, nab-paclitaxel + carboplatin; NE, non-evaluable; PC, paclitaxel + carboplatin; PFS, progression-free survival; TIS, Tislelizumab.Yu X, et al. Abstract 1297P presented at ESMO 2021.PFS in non-smokersPFS by IRC in patients who were non-smokers (Arms A vs C) PFS (by IRC) was longer in Arms A (TIS + PC) and B (TIS + nab-PC) compared with Arm C (PC), regardless of smoking statusIn patients who were non-smokers, median PFS by IRC was7.5 months in Arm A vs 5.4 months in Arm C Non evaluable in Arm B vs 5.4 months in Arm C036912

100

Arm A

Arm C

Arm A

Arm C

Months

PFS

probability

(%)

PFS

probability

(%)

Number

risk

Arm B

Arm C

Number

risk

Arm A

Arm C

Events (%)

Median PFS,

mo (95% CI)

(95% CI)

Arm A

14 (58.3)

7.5 (5.5, 7.8)

0.475

(0.226, 1.000)

Arm C

15 (65.2)

5.4 (2.8, 5.6)

Events (%)

Median PFS, mo (95% CI)

(95% CI)

Arm B

2 (16.7)

NE (4.2, NE)

0.119

(0.027, 0.533)

Arm C

15 (65.2)

5.4 (2.8, 5.6)

PFS by IRC in patients who were non-smokers (Arms B vs C)

Slide18

Data cutoff: December 6, 2019.CI, confidence interval; DoR, duration of response; HR, hazard ratio; NE, not estimable; ORR, objective response rate; nab, nanoparticle albumin-bound; PC, paclitaxel and carboplatin; TIS, tislelizumab.

Yu X, et al. Abstract 1297P presented at ESMO 2021.

ORR and DoR for patients who were smokers or non-smokersRegardless of smoking status, ORR was higher with tislelizumab plus chemotherapy vs chemotherapy aloneSmokersNon-smokersArm ATIS + PC(n=96)Arm BTIS + nab-PC(n=107)Arm CPC (n=98)Arm ATIS + PC(n=24)Arm BTIS + nab-PC(n=12)

Arm C

PC (n=23)

ORR, n (%)

72.0 (75.0)

79.0 (73.8)

49.0 (50.0)

15 (62.5)

10 (83.3)

11 (47.8)

95% CI

(65.1, 83.3)

(64.4, 81.9)

(39.7, 60.3)

(40.6, 81.2)

(51.6, 97.9)

(26.8, 69.4)

Odds ratio (95% CI)

3.30

(1.748, 6.221)

2.75

(1.520, 4.968)-

1.93(0.578, 6.448)8.19(1.157, 57.953)-ORR difference, % (95% CI)25.8(12.95, 38.61)23.0(10.04, 35.90)-15.6(-12.35, 43.51)

44.5(12.50, 76.55)-DoR, months, median (95% CI)NE(5.03, NE)

8.3(4.80 - NE)4.3(2.83, 5.55)5.2(2.99, NE)NE(2.76, NE)4.1 (1.91, 5.59)

HR, (95% CI)0.443(0.262, 0.748)0.505(0.308, 0.828)

-0.511(0.184, 1.422)0.099(0.012, 0.821)-

ORR and DoR

Slide19

Data cutoff: December 6, 2019.nab, nanoparticle albumin bound; PC, paclitaxel and carboplatin; TEAE, treatment-emergent adverse event; TIS, tislelizumab; TRAE, treatment-related adverse event.

Yu X, et al. Abstract 1297P presented at ESMO 2021.

Overall safety profileOverall summary of TEAEs in patients who were smokers or non-smokersSmokersNon-smokersn (%)Arm ATIS + PC(n=96)Arm BTIS + nab-PC(n=106)Arm CPC (n=94)Arm ATIS + PC(n=24)Arm BTIS + nab-PC(n=12)

Arm CPC (n=23)

Patients with ≥ 1 TEAE

96 (100.0)

105 (99.1)

94 (100.0)

24 (100.0)

12 (100.0)

23 (100.0)

≥ Grade 3

87 (90.6)

91 (85.8)

82 (87.2)

19 (79.2)

11 (91.7)

16 (69.6)

Serious

36 (37.5)

42 (39.6)

23 (24.5)

8 (33.3)

3 (25.0)

6 (26.1) ≥ Grade 3 serious26 (27.1)34 (32.1)14 (14.9)6 (25.0)3 (25.0)2 (8.7)

Leading to treatment discontinuation12 (12.5)32 (30.2)14 (14.9)3 (12.5)3 (25.0)

4 (17.4) Leading to death3 (3.1)5 (4.7)5 (5.3)

1 (4.2)0 (0.0)0 (0.0)Patients with ≥ 1 TRAE

95 (99.0)105 (99.1)94 (100.0)24 (100.0)

12 (100.0)23 (100.0) ≥ Grade 385 (88.5)

88 (83.0)79 (84.0)18 (75.0)11 (91.7)15 (65.2)

Serious22 (22.9)26 (24.5)

14 (14.9)5 (20.8)2 (16.7)3 (13.0)

Leding to death1 (1.0)2 (1.9)3 (3.2)0 (0.0)

0 (0.0)0 (0.0)

Slide20

Data cutoff: December 6, 2019.nab, nanoparticle albumin-bound; PC, paclitaxel and carboplatin; TIS, tislelizumab; TRAE, treatment-related adverse event.

Yu X, et al. Abstract 1297P presented at ESMO 2021.

TRAEs (≥ 20%) in patients who were smokers or non-smokers (safety analysis set)SmokersNon-smokersArm ATIS + PC(n=96)Arm BTIS + nab-PC(n=106)Arm CPC (n=94)Arm ATIS + PC(n=24)

Arm B

TIS + nab-PC

(n=12)

Arm C

PC (n=23)

All Grades

≥Grade 3

All Grades

≥Grade 3

All Grades

≥Grade 3

All Grades

≥Grade 3

All Grades

≥Grade 3

All Grades

≥Grade 3

Patients with at least one event

95 (99.0)

85 (88.5)

105 (99.1)

88 (83.0)

94 (100.0)

79 (84.0)

24 (100.0)

18 (75.0)

12 (100.0)

11 (91.7)

23 (100.0)

15 (65.2)

Anemia

78 (81.3)

5 (5.2)

93 (87.7)

19 (17.9)

70 (74.5)

9 (9.6)

21 (87.5)

1 (4.2)

11 (91.7)

5 (41.7)

17 (73.9)

2 (8.7)

Alopecia

60 (62.5)

72 (67.9)

58 (61.7)

17 (70.8)

9 (75.0)

14 (60.9)

Leukopenia

48 (50.0)

14 (14.6)

59 (55.7)

25 (23.6)

44 (46.8)

18 (19.1)

9 (37.5)

5 (20.8)

7 (58.3)

5 (41.7)

12 (52.2)

3 (13.0)

Neutropenia

43 (44.8)

35 (36.5)

47 (44.3)

30 (28.3)

44 (46.8)

38 (40.4)

8 (33.3)

5 (20.8)

3 (25.0)

2 (16.7)

11 (47.8)

9 (39.1)

Neutrophil count decreased

56 (58.3)

48 (50.

62 (58.5)

45 (28.3)

54 (57.4)

45 (47.9)

19 (79.2)

15 (58.3)

10 (83.3)

9 (75.0)

14 (60.9)

8 (34.8)

White blood cell count decreased

48 (50.0)

20 (20.8)

61 (57.5)

30 (28.3)

49 (52.1)

23 (24.5)

15 (62.5)

6 (25.0)

7 (58.3)

2 (16.7)

13 (56.5)

5 (21.7)

Alanine aminotransferase increased

37 (38.5)

1 (1.0)

34 (32.1)

2 (1.9)

23 (24.5)

11 (45.8)

1 (4.2)6 (50.0)04 (17.4)0Platelet count decreased32 (33.3)4 (4.2)46 (43.4)12 (11.3)24 (25.5)2 (2.1)

8 (33.3)1 (4.2)6 (50.0)4 (33.3)

4 (17.4)

0Aspartate aminotransferase increased28 (29.2)

033 (31.1)

1 (0.9)9 (9.6)0

11 (45.8)05 (41.7)04 (17.4)

0Blood bilirubin increased25 (26.0)

014 (13.2)

013 (13.8)02 (8.3)

000

2 (8.7)0Rash

18 (18.8)1 (1.0)21 (19.8)2 (1.9)

3 (3.2)05 (20.8)3 (12.5)

4 (33.3)01 (4.3)0

Decreased appetite45 (46.9)1 (1.0)

44 (41.5)

1 (0.9)

28 (29.8)

1 (1.1)

5 (20.8)

5 (41.7)

7 (30.4)

Hypokalemia

6 (6.3)

2 (2.1)

10 (9.4)

1 (0.9)

4 (4.3)

5 (20.8)

1 (4.3)

TRAEs

Slide21

Safety summary and conclusions

The safety profile of tislelizumab plus chemotherapy and chemotherapy alone in patients who were smokers or non-smokers was consistent with the overall patient population

1Regardless of smoking status, most patients experienced ≥1 TEAEOf the patients who were smokers, 90.6% and 85.8% experienced ≥Grade 3 TEAEs in Arms A and B, respectively, vs 87.2% in Arm COf the patients who were non-smokers 79.2 and 91.7 experienced ≥Grade 3 TEAEs in Arms A and B, respectively, vs 69.6% in Arm CConfirmed immune mediated TEAEs were reported in 30 (31.3%) patients in Arm A and 34 (32.1%) patients in Arm B for smokers, and 7 (29.2%) patients in Arm A and 1 (8.3%) patients in Arm B for non-smokersMost were mild or moderate, and did not lead to discontinuation of any treatment componentThe most common immune mediated TEAE of any grade was hypothyroidism (11 patients [11.5% in Arm A; 14 patients [13.2%] in Arm B) in the smoker population, and rash (3 patients [12.5%] in Arm A; 0 patients [0.0%] in Arm B) in the non-smoker populationIn this sub analysis, improvements in PFS and ORR suggest that the observed treatment benefits of tislelizumab plus paclitaxel/nab-paclitaxel and carboplatin in patients with advanced squamous NSCLC are consistent with the ITT population, irrespective of smoking status1. Wang J, et al. JAMA Oncol 2021. doi: 10.1001/jamaoncol.2021.0366. Online ahead of print.ITT, intention to treat; NSCLC, non small cell lung cancer; ORR, objective response rate; PFS, progression-free survival; TEAE, treatment0emergent adverse event.Yu X, et al. Abstract 1297P presented at ESMO 2021.

Slide22

Sitravatinib + tislelizumab in metastatic NSCLC

Slide23

Study design

NSCLC cohorts reported here:

Cohort A/B/F: Anti-PD-1/PD-L1 Ab naïve or refractory/resistant metastatic non-sq or sq NSCLCOther cohorts (not reported here):Cohort C: Anti-PD-1/PD-L1 Ab refractory/resistant advanced/metastatic RCCCohort D (China only): Treatment naïve metastatic/advanced RCCCohort E:Anti-PD-1/PD-L1 Ab naïve recurrent and platinum-resistant OCCohort G: Anti-PD-1/PD-L1 Ab refractory/resistant unresectable or metastatic melanomaCohorts H and I: PD-L1 positive (≥1%) locally advanced/metastatic non-sq (cohort H) or sq (cohort I) NSCLC; treatment naïve in metastatic settingKey eligibility criteria (all tumor types)Age ≥18 years Histologically or cytologically confirmed advanced or metastatic, unresectable solid tumorsECOG PS 0 or 1Adequate end organ functionAdditional key eligibility criteria for cohorts A, B, and FStage IV non-squamous (cohorts A and B) or squamous (cohort F) NSCLCDisease progression after 1–3 lines of systemic therapy, with (cohorts A and F) or without (cohort B) prior anti-PD-(L)1 therapyNo known EGFR/BRAF mutations or ALK/ROS1 rearrangementsTreatment for all cohorts:Sitravatinib 120 mg PO QD + tislelizumab 200 mg IV Q3WPrimary endpoint: Safety and tolerability*Secondary endpoints:Investigator-assessed ORR†, DCR†, DoR† and, PFS*Exploratory analysis:OS*, retrospective analysis of

PD-L1 expression†

Treatment until:

Progressive disease

Unacceptable toxicity

Death

Withdrawal of consent

Study termination by sponsor

Open-label, multicenter, non-randomized, multi-cohort, Phase 1b trial assessing the safety, tolerability, and antitumor activity of

sitravatinib

+ tislelizumab in various solid tumors: Results from metastatic NSCLC cohorts including both anti-PD-(L)1-naïve patients and those with tumors refractory/resistant (R/R) to anti-PD-(L)1 therapy are reported here

*Safety, tolerability, PFS, and OS were assessed using the safety analysis set (all patients receiving ≥1 dose of study drug); †Tumor responses were assessed using the efficacy evaluable analysis set (all dosed patients who had measurable disease at baseline per RECIST v1.1 and who had ≥1 evaluable post-baseline tumor assessment unless treatment was discontinued due to disease progression or death before tumor assessment)

Ab, antibody; ALK, anaplastic lymphoma kinase; BRAF, v-

raf

murine sarcoma viral oncogene homolog B1; DCR, disease control rate;

DoR

, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IV, intravenously; NSCLC, non-small cell lung cancer;

Nsq

, non-squamous; OC, ovarian cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed cell protein-1; PD-L1, programmed death ligand-1; PFS, progression-free survival; PO, orally; QD, once-daily; Q3W, once every three weeks; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; ROS1, c-

ros

oncogene 1; Sq, squamous.

Zhou Q, et al. Abstract 1280P presented at ESMO 2021.

Slide24

*Includes two patients who died early with no post-baseline tumor assessment and one patient with an NE tumor response; †DCR = complete response + partial response + stable disease.

**Two patients with no post-baseline tumor assessment due to early death were not included in this figure; Tumor responses assessed by investigators per RECIST v1.1.

DCR, disease control rate; DoR, duration of response; NE, non-evaluable; ORR, objective response rate; PD, disease progression; PD-(L)1, programmed death protein (ligand)-1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.Zhou Q, et al. Abstract 1280P presented at ESMO 2021.Efficacy: Tumor response Analysis of confirmed disease response per RECIST v1.1 (efficacy evaluable analysis set)Best change in target lesion size from baseline by confirmed best overall response (efficacy evaluable analysis set)Total (N=71)ORR, % (95% CI)16.9 (9.1, 27.7)Best overall response, n (%) Complete response0 (0.0) Partial response12 (16.9) Stable disease48 (67.6) Progressive disease8 (11.3) Non-evaluable3 (4.2)*DCR†, % (95% CI)84.5 (74.0, 92.0)Median DoR, months (95% CI)7.0 (2.9, NE)In the overall population, ORR was 16.9%ORR was numerically higher in patients naïve to anti-PD-(L)1 therapy (22.2%) vs patients with anti-PD-(L)1 R/R disease (13.6%)Median DoR was 7.0 months; this did not differ between patients naïve to anti-PD-(L)1 therapy and patients with anti-PD-(L)1 R/R diseaseConfirmed PR and SD reported in 12 (16.9%) and 48 (67.6%) patients, respectively, in the overall patient population. Few patients (n=8 [11.3%]) had PDDisease control was achieved in >80% of patients in both anti-PD-(L)1 pretreated and naïve groups50403020100-10

-20

-30

-40

-50

-60

-70

-80

-90

PR (n=12)

PD (n=8)

SD (n=48)

NE (

=1)**

Best

overall

response

Best

change

target

lesion

size

from

baseline

(%)

Slide25

CI, confidence interval; NSCLC, non small cell lung cancer; OS, overall survival; PD-(L)1, programmed death protein (ligand)-1;

PFS, progression-free survival; R/R, refractory/resistant

Zhou Q, et al. Abstract 1280P presented at ESMO 2021.PFS (safety analysis set)OS (safety analysis set)In the overall population, median PFS was 5.5 months (95% CI: 4.1, 7.0) Median PFS was numerically longer in patients naïve to anti-PD(L)1 therapy (7.0 months [95% CI: 2.7, 11.2]) vs those with anti-PD-(L)1 R/R disease (5.2 months [95% CI: 4.1, 5.9])Median OS was 11.9 months (95% CI: 10.1, 18.8) in the overall population,15.3 months (95% CI: 11.5, 18.8) in anti-PD-(L)1-naïve patients, and 10.1 months (95% CI: 6.1, 18.1) in those with anti-PD-(L)1 R/R diseaseOS data are not mature (median follow-up duration: 14.1 months)Number of patients at risk:NSCLC7553402315632100Number of patients at risk:

NSCLC7573

Efficacy: Survival

Censored

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Probability

PFS

Time (

months

)

Censored

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Probability

Time (

months

)

Slide26

*Two patients with no post-baseline tumor assessment due to early death were not included; †Patients without evaluable PD-L1 expression data; PD-L1 expression was assessed using the Ventana SP263 assay.

CI, confidence interval; IC, immune cell; NA, not applicable; ORR, objective response rate; PD-L1, programmed death ligand-1; TC, tumor cell.

Zhou Q, et al. Abstract 1280P presented at ESMO 2021.Subgroup analysis of ORR by TC and IC PD-L1 expression (efficacy evaluable analysis set*)Defined cut-offs for PD-L1 tumor cell (TC) or immune cell (IC) expression were used to investigate whether there was an association between PD-L1 expression and tumor responseA trend for higher ORR was observed in patients with higher PD-L1 IC expressionNo association was observed between ORR and PD-L1 TCFurther exploration is required in a larger populationTC PD-L1 expression subgroupsnResponseORR,% (95% CI)IC PD-L1 expression subgroupsnResponseORR,% (95% CI)Total7112Total7112TC < or ≥1%IC < or ≥10% <1%184 <10%212 ≥1%212 ≥10%184TC < or ≥50%IC < or ≥30%

<50%314 <30%

≥50%

≥30%

†

80100

100

Efficacy: Tumor response by PD-L1 expression

Slide27

*AE leading to sitravatinib dose modification includes dose reduction and/or interruption; †AE leading to tislelizumab dose modification includes dose delay and/or interruption; ‡Incidences reported by preferred term for any TEAE or TRAE reported in ≥5% of patients. All AEs are treatment-emergent and graded based on National Cancer Institute–Common Terminology Criteria for Adverse Events (version 5.0).

AE, adverse event; SD, stable disease; TEAE, treatment-emergent AE; TRAE; treatment-related AE.

Zhou Q, et al. Abstract 1280P presented at ESMO 2021.SafetySummary of TEAE and TRAE incidence (safety analysis set)Median duration of exposure was 17.9 weeks (range: 1.3 to 78.1) for sitravatinib and 18.1 weeks (range: 3.0 to 78.1) for tislelizumabMean relative dose intensity was 79.7% (SD: 20.3) for sitravatinib and 93.7% (SD: 11.8) for tislelizumabAll patients had a TEAE and TRAEHypertension was the most commonly reported grade ≥3 TEAE and TRAENo cases of hypertension led to treatment discontinuation73.3% of patients experienced dose modification (including dose reduction and/or interruption) of sitravatinib due to TEAEsTRAEs leading to death were reported in three patients, including one case each of ischemic stroke (considered related to sitravatinib), cardiac failure with pneumonia and respiratory failure (considered related to tislelizumab), and unspecified death (considered related to both drugs)Patients, n (%)All Patients (N=75)TEAEsTRAEsAny AE75 (100.0)75 (100.0) Grade ≥3 AE55 (73.3)38 (50.7)Serious AE41 (54.7)26 (34.7) Grade ≥3 serious AE34 (45.3)14 (18.7)AE leading to death10 (13.3)3 (4)AE leading to sitravatinib discontinuation15 (20.0)13 (17.3)AE leading to tislelizumab discontinuation10 (13.3)9 (12.0)AE leading to sitravatinib dose modification*55 (73.3)54 (72.0)AE leading to tislelizumab dose modification†30 (40.0)28 (37.3)Grade ≥3 AEs reported in ≥5% of patients‡ Hypertension12 (16.0)11 (14.7)

Death4 (5.3)1 (1.3)

Stomatitis

5 (6.7)

Pneumonia

4 (5.3)

2 (2.7)

Slide28

Conclusions

Sitravatinib + tislelizumab had a manageable safety and tolerability

profile consistent with what has previously been reported, in patients with non-squamous or squamous metastatic NSCLC who were either pretreated or naïve to anti-PD-(L)1 treatmentThe combination demonstrated preliminary antitumor activity, both in patients who were naïve to anti-PD-(L)1 treatment and in those with anti-PD(L)1 R/R disease, with an overall ORR of 16.9%, DCR of 84.5% and PFS of 5.5 monthsThese results support further investigation of sitravatinib + tislelizumab in metastatic NSCLC patient populationsDCR, disease control rate; NSCLC, non small cell lung cancer; ORR, objective response rate; PD-(L)1, programmed death protein (ligand)-1; PFS, progression-free survival; R/R, refractory/resistant Zhou Q, et al. Abstract 1280P presented at ESMO 2021.

Slide29

Sitravatinib + tislelizumab

in anti-PD-(L)1 refractory/resistant metastatic NSCLC

Slide30

Ab, antibody; ALK, anaplastic lymphoma kinase; BRAF, v-

raf murine sarcoma viral oncogene homolog B1; DCR, disease control rate; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IV, intravenously; NSCLC, non small cell lung cancer; Nsq, non-squamous; OC, ovarian cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed cell protein-1; PD-L1, programmed death ligand-1; PFS, progression-free survival; PO, orally; QD, once-daily; Q3W, once every three weeks; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; ROS1, c-ros oncogene 1; R/R, refractory/resistant; Sq, squamous.Gao B, et al. Abstract 1284P presented at ESMO 2021.Study design Open-label, multicenter, non-randomized, multi-cohort, Phase 1b trial assessing the safety, tolerability, and antitumor activity of sitravatinib + tislelizumab in various solid tumors: Cohorts reported herein include patients with non-squamous (cohort A) or squamous (cohort F) metastatic NSCLC that is R/R to anti-PD-(L)1 therapyNSCLC cohorts reported here:Cohort A/F: Metastatic Nsq/Sq NSCLC; anti-PD-1/PD-L1 Ab R/ROther cohorts (not reported here):Cohort B: Metastatic Nsq NSCLC; anti-PD-1/PD-L1 Ab-naïveCohort C: Metastatic/advanced RCC; anti-PD-1/PD-L1 Ab R/RCohort D (China only): Metastatic/advanced RCC; without prior systemic therapyCohort E

: Recurrent and platinum-resistant OC; anti-PD-1/PD-L1 Ab-naïveCohort G: Unresectable or metastatic melanoma; anti-PD-1/PD-L1 Ab R/R

Cohort H: Locally advanced or metastatic

NsqNSCLC

; treatment-naïve, positive (≥1%) PD-L1

Cohort I: Locally advanced or metastatic Sq NSCLC; treatment-naïve, positive (≥1%) PD-L1

Key eligibility criteria (all tumor types)

Age ≥18 years

Histologically or cytologically confirmed advanced or metastatic, unresectable solid tumors

ECOG PS 0 or 1

Adequate end organ function

Key eligibility for cohorts A & F:

Radiographic progression on/after anti-PD-(L)1 therapy for metastatic NSCLC

Patients with

EGFR/BRAF

mutations or

ALK/ROS1

rearrangements were ineligible

No other prior immunotherapy

Treatment for all cohorts:

Sitravatinib 120 mg PO QD +

tislelizumab 200 mg IV Q3W

Primary endpoint:

Safety and tolerability*

Secondary endpoints: Investigator-assessed ORR†, DCR†, DoR

† and, PFS*Exploratory analysis:

OS*, retrospective analysis of PD-L1 expression†

Treatment until:

Progressive disease

Unacceptable toxicityDeath

Withdrawal of consentStudy termination by sponsor

Slide31

Treatment with

sitravatinib

+ tislelizumab demonstrated antitumor activity, with an ORR of 13.6%Median duration of response was 6.9 monthsMedian time to response was 2.7 months (range: 1.4 to 5.5 months)Confirmed partial response was reported in 6 patients (13.6%) Disease control was achieved in the majority of patients (86.4%)*Includes two patients who died early with no post-baseline tumor assessment and one patient with an NE tumor response; †DCR = complete response + partial response + stable disease.**Two patients with no post-baseline tumor assessment due to early death were not included in this figure; Tumor responses assessed by investigators per RECIST v1.1.CI, confidence interval; DCR, disease control rate; DoR, duration of response; NE, non-evaluable, ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.Gao B, et al. Abstract 1284P presented at ESMO 2021.Analysis of confirmed disease response per RECIST v1.1 (efficacy evaluable analysis set)Best change in target lesion size from baseline by confirmed best overall response (efficacy evaluable analysis set)

-10

-20

-30

-40

-50

-60

-70

-80

Efficacy: Tumor response

Total (N=71)

ORR, % (95% CI)

13.6 (5.2, 27.4)

Best overall response, n (%)

Complete response

0 (0.0)

Partial response

6 (13.6)

Stable disease

32 (72.7)

Progressive disease

3 (6.8)

Non-evaluable

3 (6.8)

DCR

†

, % (95% CI)

86.4 (72.7, 94.8)

Median DoR, months (95% CI)

6.90 (3.06, NE)

Best

change

target

lesion

size

from

baseline

(%)

PR (n=12)

PD (n=8)

SD (n=48)

NE (

=1)**

Overall

response

Slide32

CI, confidence interval; NSCLC, non small cell lung cancer; OS, overall survival; PD-1, programmed death protein-1; PFS, progression-free survival; R/R, refractory/resistant.

Gao B, et al.

Abstract 1284P

presented

at ESMO 2021.

Efficacy: Survival

PFS (safety analysis set)

OS (safety analysis set)

Median PFS was 5.2 months (95% CI: 4.1, 5.9)

6- and 12- month PFS rates were 33.9% (95% CI: 19.0, 49.4) and 6.4% (95% CI: 0.5, 23.5), respectively

Median OS was 10.1 months (95% CI: 6.1, 18.1)

OS data are not mature (median follow-up duration was 12.4 months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Number

patients

risk

NSCLC PD-1 R/R

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Number

patients

risk

NSCLC PD-1 R/R

Probability

PFS

Probability

Time (

months

)

Time (

months

)

Censored

Slide33

TC PD-L1

expression subgroups

nResponseORR,% (95% CI)IC PD-L1 expression subgroupsnResponseORR,% (95% CI)Total446Total446TC < or ≥1%IC < or ≥10% <1%102 <10%142 ≥1%121 ≥10%81TC < or ≥50%IC < or ≥30% <50%162 <30%182 ≥50%61 ≥30%41 NA†223

NA†223

CI, confidence interval; IC, immune cell; NA, not applicable; ORR, objective response rate; PD-L1, programmed death ligand-1; TC, tumor cell.

Gao B, et al.

Abstract 1284P presented at ESMO 2021.

Efficacy: Tumor response by PD-L1 expression

Subgroup analysis of ORR by TC and IC PD-L1 expression (efficacy evaluable analysis set*)

100

Defined cut-offs for PD-L1 tumor cell or immune cell expression were used to investigate whether there was an association between

PD-L1 expression and tumor response

Based on current results, no association was observed and further exploration is required in a larger population

Slide34

AE, adverse event; SD, stable disease; TEAE, treatment-emergent AE; TRAE; treatment-related AE.

Gao B, et al. Abstract 1284P presented at ESMO 2021.SafetySummary of TEAE and TRAE incidence (safety analysis set)Median duration of exposure was 17.9 weeks (range: 1.3 to 53.9) for sitravatinib and 18 weeks (range: 3.0 to 51.1) for tislelizumabMean relative dose intensity was 77.8% (SD: 21.6) for sitravatinib and 94.3% (SD: 10.4) for tislelizumabAll patients had ≥1 TEAE ≥Grade 3 TEAEs were reported in 68.1% of patientsHypertension was the most reported ≥Grade 3 TEAE (in 9 patients [19.1%]), which was well managed with anti-hypertensivesOne patient had hypertension that led to sitravatinib dose reduction, four patients had hypertension (grouped terms) that led to sitravatinib dose interruption, and one patient had hypertension that led to tislelizumab dose modificationAll patients had ≥1 TRAE≥Grade 3 TRAEs were reported in 19 patients (40.4%)TRAEs leading to death were reported in three patients, including one case each of cardiac failure with pneumonia and respiratory failure (related to tislelizumab), one case of ischemic stroke (related to sitravatinib), and one case of unspecified death (related to sitravatinib + tislelizumab)Patients, n (%)All Patients (N=75)TEAEsTRAEsAny AE47 (100.0)47 (100.0) Grade ≥3 AE32 (68.1)19 (40.0)Serious AE24 (51.1)15 (31.9) Grade ≥3 serious AE21 (44.7)8 (17.0)AE leading to death8 (17.0)3 (6.4)AE leading to treatment discontinuation9 (19.1)9 (19.1)AE leading to sitravatinib dose modification*18 (38.3)17 (36.2)AE leading to tislelizumab dose modification†35 (74.5)34 (72.3)Grade ≥3 AEs reported in ≥5% of patients‡

Hypertension9 (19.1)8 (17.0) Death

4 (8.5)

1 (2.1)

Stomatitis

3 (6.4)

Slide35

Conclusions

Treatment with

sitravatinib + tislelizumab had a manageable safety and tolerability profile in patients with metastatic NSCLC that is R/R to prior anti-PD-(L)1 therapyThe combination demonstrated promising antitumor activity: patients achieved an ORR of 13.6%, DCR of 86.4%, and a median PFS of 5.2 monthsThese findings support sitravatinib in combination with tislelizumab as a potential treatment option for patients with metastatic NSCLC who failed prior anti-PD-(L)1 therapy, and further investigation is warrantedDCR, disease control rate; NSCLC, non small cell lung cancer; ORR, objective response rate; PFS, progression-free survival; R/R, refractory/resistant.Gao B, et al. Abstract 1284P presented at ESMO 2021.

Slide36

Sitravatinib + nivolumab in nonsquamous NSCLC with prior clinical benefit from checkpoint inhibitor therapy

MRTX-500

Slide37

Data as of 1 June 2021aAdditional

cohorts included a CPI-experienced cohort that did not receive prior clinical benefit from CPI therapy (radiographic progression of disease ≤12 weeks after initiation of treatment with CPI) and a CPI-naive cohort in patients that were previously treated with platinum-based chemotherapy.

bObjective response rate based on investigator assessment. Dosing: sitravatinib free base formulation; nivolumab, 240 mg Q2W or 480 mg Q4W. Treatment discontinuation could be due to (but is not limited to) disease progression, global health deterioration, AEs, protocol violation, lost to follow-up, refusal of further treatment, study termination, or death.AE, adverse event; CPI, checkpoint inhibitor; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group (ECOG) performance status; NSCLC, non small cell lung cancer; ORR, objective response rate; PR, partial response; QD, daily; RECIST, Response evaluation criteria in solid tumors; SD, stable disease.Leal T, et al. Abstract 1191O presented at ESMO 2021.Updated efficacy and safety with sitravatinib + nivolumab in the 2L or 3L setting in patients with nonsquamous NSCLC who have experienced clinical benefit on a prior CPI and subsequent disease progression reported herePhase 2, open-label study of sitravatinib + nivolumab in patients with nonsquamous NSCLC with prior clinical benefit from checkpoint inhibitor therapyMRTX-500 Study designSitravatinib 120 mg QD + nivolumabKey eligibility criteria(N=68)Advanced/metastatic nonsquamous NSCLCaNo actionable driver mutationsAnti-PD-1/L1 must be the most recent line of therapy Prior Clinical Benefit (PCB) to CPI: CR, PR or SD > 12 weeks from prior CPI therapyNo uncontrollable brain

metastases

Primary endpoint:

ORR, as defined by RECIST 1.1

Secondary endpoint:

Safety and tolerability, DoR, CBR, PFS, OS, 1-year survival date

Slide38

Duration of

treatment

Duration of treatment with sitravatinib + nivolumab in patients with nonsquamous NSCLC with prior clinical benefit from CPI therapyORR was 18% (12/68), including 2 CRs (3%) and 10 PRs (15%)aDCR was 78% (53/68)Median DoR was 12.8 monthsMedian duration of treatment:Sitravatinib: 4.8 months (range: 0, 40)Nivolumab: 5.2 months (range: 0, 41)Duration of Treatment, monthsDuration of Treatment (n=58)Median follow-up in the PCB cohort was 33.6 months. Data as of 1 June 2021.a10 (14.7%) patients were not evaluable for ORR: 8 patients without post-baseline scan, 1 patient without measurable disease at baseline, and 1 patient for whom all post-baseline scans were NE. The study did not meet the primary endpoint of ORR. CPI, checkpoint inhibitor; CR, complete response; DCR, disease control rate; DoR, duration of response; NE, not evaluable; NSCLC, non small cell lung cancer; ORR, objective response rate; PCB, prior clinical benefit; PD, progressive disease; PR, partial response; SD, stable disease.Leal T, et al. Abstract 1191O presented at ESMO 2021.PR

PD SD

SD PR

SD SD

Progression

First

Response

Treatment

Ongoing

Death

Slide39

PFS

PFS with

sitravatinib + nivolumab in patients with nonsquamous NSCLC with prior clinical benefit from CPI therapyProgression-Free Survival, %Patients at risk:Sitravatinib +Nivolumab6825104321079%31%

45%

Sitravatinib

Nivolumab

(

=68)

Median OS (95% CI)

Events/censored, n (%)

5.7 (4.9, 7.6)

53 (78)/15 (22)

Median follow-up in PCB cohort: 33.6 months. Data as of 1 June 2021.

CI, confidence interval; CPI, checkpoint inhibitor; NSCLC, non small cell lung cancer; OS, overall survival; PBC, prior clinical benefit.

Leal T, et al. Abstract 1191O presented at ESMO 2021.

100

Time,

months

Slide40

56%

32%

45%

OS with

sitravatinib

+ nivolumab in patients with

nonsquamous

NSCLC with prior clinical benefit from CPI therapy

Time,

months

Overall

Survival

, %

Patients

risk

Sitravatinib

Nivolumab

Sitravatinib

Nivolumab

(

=68)

Median OS (95% CI)

Events/

censored

(%)

14.9 (9.3, 21.1)

46 (68)/22 (32)

Median follow-up in PCB cohort: 33.6 months. Data as of 1 June 2021.

CI, confidence interval; CPI, checkpoint inhibitor; NSCLC, non small cell lung cancer; OS, overall survival; PBC, prior clinical benefit.

Leal T, et al. Abstract 1191O presented at ESMO 2021.

100

Slide41

The

most frequent immune-related TRAES included hypothyroidism, diarrhea, ALT increase, AST increase, TSH increase maculopapular rash, and pancreatitisaNo grade 5 events occurred in the CPI-experienced cohortbMost Frequent (≥15%) TRAEs (n=68)2L/3L Sitra + NivoTRAEsAny TRAEsAny grade93%Grade 3-466%Most frequent TRAEs, %DiarrheaFatigue NauseaHypertensionDecreased appetiteWeight decreasedVomitingHypothyroidismDysphoniaALT increaseAST increaseStomatitisPPE syndromeDehydration62%52%44%40%35%31%31%22%19%18%

16%15%15%15%16%4%2%

22%

TRAEs

Incidence of TRAEs

Investigator-assessed AE causality as immune-related.

1 grade 5 TRAE (cardiac arrest) occurred in the CPI-naive patient population. Data as of 1 June 2021.

2L, second line; 3L, third line; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPI, checkpoint inhibitor; PPE, palmar-plantar erythrodysesthesia; TRAE, treatment-related adverse event, TSH, thyroid simulating hormone.Leal T, et al. Abstract 1191O presented at ESMO 2021.

Slide42

2L/3L

Sitra

+ Nivo (n=68)Discontunuation due to TRAEs, %Sitravatinib Nivolumab22219Dose reduction of sitravatinib due to AEsa, %80 mg60 mg40 mg6031227≥1 dose interruption of sitravatinib due to AEsb,c, %81Sitravatinib discontinuation, dose reduction, and dose interruption ratesa Median time from first dose to first dose reduction: 1.4 months. b Dose interruption is defined as any gap in the dosing record that is ≥1 day. c Median time to first dose interruption:1 month. Data as of 1 June 2021.2L, second line; 3L, third line; AE adverse event; TRAE, treatment-related adverse event.Leal T, et al. Abstract 1191O presented at ESMO 2021.

Slide43

MRTX-500 Conclusions

Sitravatinib

is a spectrum-selective TKI targeting TAM (TYRO3, AXL, MERTK) receptors and VEGFR2 that can potentially overcome an immunosuppressive TMESitravatinib + nivolumab demonstrated antitumor activity, encouraging OS, and durable responses in patients with nonsquamous NSCLC with prior clinical benefit from a CPIMedian DoR was 12.8 months; ORR was 18% (12/68)1- and 2-year OS were 56% and 32%, respectivelyNo unexpected safety signals with the combination were observed, and AEs were manageableThese results support the ongoing Phase 3 SAPPHIRE study (NCT03906071), evaluating sitravatinib + nivolumab in patients with nonsquamous NSCLC who received clinical benefit from and subsequently experienced progressive disease on a prior CPIAE, adverse event; CPI, checkpoint inhibitor; DoR, duration of response; NSCLC, non small cell lung cancer; OS, overall survival; ORR, obkective response rate; TKI, tyrosine kinase inhibitor, TME, tumor microenvironemnt. Leal T, et al. Abstract 1191O presented at ESMO 2021.

Slide44

Durvalumab alone or in combination with novel agents in locally advanced, unresectable, Stage III NSCLC

COAST

Slide45

cCRT, concurrent chemoradiation therapy; DCR, disease control rate; DoR, duration of response;

ECOG PS, Eastern Cooperative Oncology Group performance status;

IV, intravenous; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; Q2W, every 2 weeks; Q4W, every 4 weeks; RECIST, Response evaluation criteria in solid tumors; R, ramdomized; SOC, standard of care.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.COAST Study designOpen-label, Phase 2, multi-drug platform study of durvalumab alone or in combination with novel agents in patients with locally advanced, unresectable, Stage III NSCLCThe placebo-controlled Phase 3 PACIFIC study established consolidation durvalumab as SOC for patients with unresectable Stage III NSCLC who have not progressed after cCRTFive-year data from PACIFIC demonstrated robust and sustained OS plus durable PFS benefit with durvalumab in this patient population42.9% remain alive and 33.1% remain alive and progression-free at 5 yearsAdditional immunomodulation through combination therapy is being explored to improve clinical outcomes in this patient populationCOAST [Combination Platform Study in Unresectable Stage III NSCLC; NCT03822351) is a global, open label, randomized, Phase 2 study of durvalumab alone or combined with the anti-CD73 mAb oleclumab or anti-NKG2A mAb monalizumab as consolidation therapy in this settingR 1:1:11-42 days post-cCRTKey eligibility criteriaLocally advanced, unresectable, Stage III NSCLCNo progression after prior cCRTECOG PS 0 or 1N = 189 ramdomizedPrimary endpoint:ORR by investigator assessment (RECIST v1.1)Secondary endpoints:Safety, DoR, DCR, PFS by investigator assessment (RECIST vt.1), OS, PK, immunogenicityStratification by histology (adenocarcinoma and non-adenocarcinoma)

Oleclumab Q2W for cycles 1 and 2, then Q4W starling cycle 3

Arm

Durvalumab

1500mg IV Q4W +

oleclumab

3000mg IV

Control

Durvalumab

1500mg IV

monotherapy

Q4W

Arm

Durvalumab

1500mg IV Q4W +

monalizumab

750mg IV Q2W

Study

treatment

to 12 months

Slide46

Data cutoff: 17 May 2021 (median follow-up of 11.5 months; range, 0.4-23.4)aConfirmed and unconfirmed responses.

95% by Clopper-Pearson exact method; cDCR at 16 weeks = CR+PR+SD for ≥16 weeks.CI, confidence interval; CR, complete response; D, durvalumab; DCR, disease control rate; DoR, duration of response; ITT, intention-to-treat; M, monalizumab; NA, not applicable; NE, not evaluable; NR, not reached; O, oleclumab; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.Interim analysis; ITT populationAntitumor activityD(N=67)D+O(N=60)D+M(N=62)Confirmed ORR (95% CI),b%[n]17.9 (9.6, 29.2)[12]30.0 (18.8, 43.2)[18]35.5 (23.7, 48.7)[22]Confirmed + unconfirmed ORR (95% CI), b%[n]ORR odds ratio (95% CI)a,b25.4 (15.5, 37.5)[17]-38.3 (26.1, 51.8)[23]1.83 (0.80, 4.20)37.1 (25.2, 50.3)[23]1.77 (0.77, 4.11)Objective responses by RECIST,a n (%)CRPRSDPDNE2 (3.0)15 (22.4)27 (40.3)15 (22.4)8 (11.9)1 (1.7)22 (36.7)25 (41.7)7 (11.7)5 (8.3)3 (4.8)20 (32.3)27 (43.5)7 (11.3)4 (6.5)DCR at 16 weeks (95% CI),a,c %[n]58.2 (45.5, 70.2)[39]81.7 (69.6, 90.5)[49]77.4 (65.0, 87.1)[48]Median DoR (95% CI),a monthsRangeNR (2.3, NA)0.0+, 17.5+12.9 (6.7, NA)0.0+, 16.9+NR (9.0, NA)1.9+, 18.4+Antitumor activity by investigator assessment

Slide47

Data cutoff: 17 May 2021 (median follow-up of 11.5 months; range, 0.4-23.4)a

Interim analysis was performed when all patients had a 10-month minimum potential follow-up; Kaplan-Meier estimates for PFS, PFS rate and 95% CIs

bPFS HR and 95% CI estimated by Cox regression model, stratified by histology (adenocarcinoma and non adenocarcinoma)cCompared with the 67 and 64 patients in the D arm enrolled concurrently with patients in the D+O and D+M arms, respectivelyCI, confidence interval; D, durvalumab; HR, hazard ratio; ITT, intention-to-treat; M, monalizumab; mPFS, median progression-free survival; NE, not estimable; NR, not reached; O, oleclumab; PFS, progression-free survival.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.Interim analysis; ITT population

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

from

randomisation

(

months

)

PFS

probability

39.2%

64.8%

72.7%

D+O

D+M

Events/patients,

38/67

22/60

21/62

mPFS

months (95% CI)

6.3

(3.7-11.2)

(10.4-NE)

15.1

(13.6-NE)

(95% CI)

b,c

–

0.44

(0.26-0.75)

0.65

(0.49-0.85)

No. at risk

D+O

D+M

PFS by investigator assessment

Slide48

Durvalumab + Oleclumab vs. Durvalumab alone

D + O

No. Of patients /eventsDNo. Of patients /eventsStratified HR (95% Cl)aOverall22/6038/670.44 (0.26, 0.75)PD-L1 statusTC ≥ 1%TC < 1%Unknown8/231/713/3013/258/1417/280.51 (0.21, 1.26)-0.54 (0.26, 1.12)HistologySquamousNon-squamous7/2415/3616/30

22/370.38 (0.15, 0.92)0.50 (0.26, 0.97)

Disease stage at entry

IIIA

IIIB

IIIC

11/27

9/29

2/4

13/27

21/43

4/6

0.68 (0.31, 1.53)

0.32 (0.14, 0.70)

Prior platinum-based CT

Carboplatin

Cisplatin

13/28

8/2821/4316/230.67 (0.33, 1.36)

0.29 (0.12, 0.69)ECOG0113/339/26

16/3021/360.56 (0.27, 1.18)0.35 (0.16, 0.74)

Durvalumab + Monalizumab vs. Durvalumab alone

D + M

No. Of patients /events

Stratified HR (95% Cl)

Overall

21/62

36/64

0.65 (0.45, 0.85)

PD-L1 status

TC ≥ 1%

TC < 1%

Unknown

4/18

6/12

11/32

13/24

8/14

15/26

0.45 (0.25, 0.80)

0.93 (0.54, 1.60)

0.72 (0.47, 1.08)

Histology

Squamous

Non-squamous

10/27

11/35

15/28

21/36

0.73 (0.49, 1.10)

0.59 (0.41, 0.86)

Disease stage at entry

IIIA

IIIB

IIIC

11/32

8/27

2/3

12/25

20/33

4/6

0.81 (0.54, 1.23)

0.49 (0.32, 0.76)

–

Prior platinum-based CT

Carboplatin

Cisplatin

15/44

6/15

20/41

15/22

0.72 (0.51, 1.01)

0.61 (0.38, 0.99)

ECOG

10/27

11/34

15/28

20/35

0.75 (0.50, 1.13)

0.58 (0.39, 0.84)

Data

cutoff

: 17 May 2021 (median follow-up of 11.5 months; range, 0.4-23.4)

PFS

HR and 95% CI estimated by Cox regression model, stratified by histology (adenocarcinoma and non-adenocarcinoma).

CI, confidence interval; D, durvalumab; HR, hazard ratio; ITT, intention-to-treat; M,

monalizumab

; O,

oleclumab

; PFS, progression-free survival.

Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.

Interim analysis; ITT population

0.0

0.5

1.0

0.5

2.0

D+O

better

D+M

better

0.0

0.5

1.0

0.5

2.0

PFS subgroup analysis by investigator assessment

Slide49

aAll reported deaths within 90 days post-last dose, regardless of relationship to study drug.

In total, 4 deaths were related to study drug, 2 (pneumonitis and radiation pneumonitis) in the D+O arm, and 1 (myocardial infarction) in the D+M arm.AE, adverse event; D, durvalumab; M, monalizumab; O, oleclumab; SAE, serious adverse event; TEAE, treatment-emergent adverse event.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.as-treated populationIncidence, n (%)D (N=66)D+O (N=59)D+M (N=61)Any TEAEs65 (98.5)57 (96.6)61 (100)Grade 3 TEAEs26 (39.4)24 (40.7)17 (27.9)Study drug-related AEs49 (74.2)46 (78.0)50 (82.0)Study drug-related SAEs6 (9.1)7 (11.9)5 (8.2)AEs leading to discontinuation11 (16.7)9 (15.3)9 (14.8)Deathsa,b7 (10.6)4 (6.8)3 (4.9)Safety summary

Slide50

Data cutoff: 17 May 2021 (median follow-up of 11.5 months; range, 0.4-23.4)

In addition, radiation pneumonitis of any grade (grade 3/4) occurred in 3 (1), 7 (0), and 3 (0) patients in the D, D+O and D+M arms, respectivelyD, durvalumab; M, monalizumab; O, oleclumab; TEAE, treatment-emergent adverse event.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.All causality; as-treated populationD (N=66)D+O (N=59)D+M (N=61)All GradesGrade 3/4All GradesGrade 3/4All GradesGrade 3/4

Patients with ≥1 TEAE

65 (98.50

23 (34.8)

57 (96.6)

21 (35.6)

61 (100)

16 (26.2)

Cough

12 (18.2)

18 (30.5)

1 (1.7)

27 (44.1)

Dyspnoea

17 (25.8)

2 (3.0)

15 (25.4)

1 (1.7)

14 (23.0)

1 (1.6) Pruritis7 (10.6)010 (16.9)0

15 (24.6)0 Asthenia10 (15.2)010 (16.9)014 (23.0)0

Hypothyroidism10 (15.2)09 (15.3)0

12 (19.7)0 Diarrhea7 (10.6)1 (1.5)7 (11.9)

012 (19.7)0

Pneumonitisa11 (16.7)011 (18.6)0

10 (16.4)1 (1.6)

Arthralgia11 (16.7)09 (15.3)

010 (16.4)0

Pyrexia6 (9.1)08 (13.6)010 (16.4)

0 Rash

6 (9.1)09 (15.3)08 (13.1)0

Constipation10 (15.2)04 (6.8)

02 (3.3)0

TEAEs occurring in >15% of patients in any arm

Slide51

Data cutoff: 17 May 2021 (median follow-up of 11.5 months; range, 0.4-23.4)

Includes indocytis and pericarditisAESI, adverse event of special interest; D, durvalumab; M, monalizumab; O, oleclumab.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.as-treated populationGrouped term, n (%)D (N=66)D+O (N=59)D+M (N=61)All GradesAll GradesAll GradesAny AESI37 (56.1)36 (61.0)41 (67.2) Pneumonitis12 (18.2)12 (20.3)11 (18.0)

Rash6 (9.1)12 (20.3)14 (23.0)

Hypothyroid events

10 (15.2)

9 (15.3)

12 (19.7)

Diarrhea

7 (10.6)

7 (11.9)

12 (19.7)

Hyperthyroid events

8 (12.1)

6 (10.2)

6 (9.8)

Dermatitis

4 (6.1)

4 (6.8)

2 (3.3)

Hepatic events

3 (4.5)1 (1.7)

0 Other rare/miscellaneousa00

2 (3.3) Renal events0

1 (1.7)0 Infusion related reaction01 (1.7)0 Type I diabetes mellitus

001 (1.6) Colitis1 (1.5)

00 Hypersensitivity/anaphylactic reactions1 (1.5)

00 Myositis

1 (1.5)00

AESIs for durvalumab

Slide52

COAST Conclusions

COAST is the first randomized Phase 2 study to show evidence of improved outcomes with novel IO combinations in the PACIFIC setting

Interim data suggest that oleclumab or monalizumab combined with durvalumab can provide additional clinical benefit for patients with unresectable, Stage III NSCLC who have not progressed following cCRTBoth combinations numerically increased ORR and significantly improved PFS vs durvalumab alonePFS benefit with both combinations was observed across various subgroups, including those based on histology, ECOG PS, prior platinum-based chemotherapy, and PD-L1 statusSafety profiles were consistent across arms, with no new safety signals identified in either combination armThe incidence of AESIs for durvalumab, including pneumonitis, were similar across armsAdditional translational analyses, including blood gene expression, IHC, and ctDNA, are ongoingThese data support further evaluation of these combinations in a registration-intent studyAESI, Adverse event of special interest; cCRT, concurrent chemoradiation therapy; ctDNA, circulating tumor DNA, ECOG PS, Eastern Cooperative Oncology Group performance status; IHC immunohistochemistry; IO, immuno-oncology; NSCLC, non small cell lung cancer; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival.Martinez-Marti A, et al. Abstract LBA42 presented at ESMO 2021.

Slide53

Sugemalimab in unresectable Stage III NSCLC without progression after concurrent or sequential chemoradiotherapy

GEMSTONE-301

Slide54

Both for up to 24 months*

N = 368

Stratification:ECOG PS (0 vs 1)CRT (cCRT vs sCRT)Total RT dose. (<60 Gy vs ≥60 Gy)R 2:1*First dose administered within 1-42 days after cCRT or sCRT (including al least 2 cycles of platinum-based chemotherapy) was completed.BICR, blinded independenl central review: cCRT, concurrent chemcradiotherapy; DoR. duration of response; ECOG PS. Eastern Cooperative Oncology Groupperformance status; Gy, gray (unit); IV, intravenous administration; NSCLC, non small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS. progression-free survival; PK, pharmacokinetics; Q3W, every 3 weeks; RT, radiotherapy; sCRT. sequential chemoradiotherapy; TTDM, lime to death/diatant metaslasis.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.Key eligibility criteriaPatients with unresectable stage III NSCLC who have not progressed following cCRT or sCRT

ECOG PS 0-1No known sensitizing EGFR, ALK, or ROS1 genomic alterations

rimary

endpoint:

PFS by BICR according to RECIST v1.1

Secondary

endpoints:

PFS by investigator according to RECIST v1.1

ORR

DoR

Safety

TTDM

Sugemalimab:

1200mg IV Q3W

Placebo: IV Q3W

Statistical

Considerations

PFS

tested first at a

two-sided alpha of

0.05; if PFS is

significant, then OS would

be tested at

a two-sided alpha of

0.05Interim

and final PFS analysis

were planned when

approximately 194

and

262

PFS

events

occurred,

respectively.

O’Brien-Fleming

method

was

used to

control

the type

error

Interim

and

final

analysis

were

planned

when

approximately

175

and

260

events

occurred,

respectively.

Randomized, double-blind, placebo-controlled, Phase 3 study of

sugemalimab

in patients with unresectable Stage III NSCLC without progression after concurrent or sequential chemoradiotherapy

GEMSTONE-301 Study design

Slide55

Interim PFS analysis (reviewed by

iDMC

) with median follow-up of 14 months; observed 197 PFS events with two-sided alpha of 0.0195.

BICR,

blinded

independent

review

committee

; CI,

confidence

Interval

; HR,

Hazard

ratio;

iDMC

independent data safety monitoring committee;

month

(s); PFS,

progression

-free

survival

Y-L, et al.

Abstract

LBA43

presented

at ESMO 2021.

Patients at Risk

Sugemalimab

255

225

162

130

Placebo

126

115

Sugemalimab (N=255)

Placebo

(N=126)

Median PFS, mo (95% Cl)

9.0 (8.1-14.1)

5.8 (4.2-6.6)

HR (95% Cl)

0.64 (0.48-0.85)

Log-rank P value

0.0026

100

Progression-Free

Survival

(%)

PFS by BICR

Months

45.4%

38.8%

25.6%

23.3%

–––

Sugemalimab

–––

Placebo

Censored

Slide56

*Stratified for all patients, unstratified for the subgroups.#

Staged according to the IASLC classification, version 8.

CRT, chemoradiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; Gy, gray (unit); PFS, progression-free survival.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.SugemalimabNo. patientsPlaceboNo. patientsHazard Ratio (95% CI)*All patients2551260.64 (0.48-0.85)SexMaleFemale23619115110.61 (0.45-0.82)1.40 (0.55-3.57)Age<65 years≥65 years1827394320.75 (0.52-1.06)0.40 (0.23-0.67)Smoking historyNeverFormer or current42213161100.44 (0.20-0.96)0.67 (0.49-0.92)ECOG PS017817738880.47 (0.26-0.86)0.71 (0.51-0.99)CRT typeSequential Concurrent8616941850.59 (0.39-0.91)0.66 (0.44-0.99)

Radiotherapy dose<60 Gy≥60 Gy

212

106

0.55 (0.27-1.12)

0.66 (0.48-0.90)

Cancer stage

before CRT

Stage IIIA

Stage IIIB

Stage IIIC

146

280.74 (0.41-1.34)0.55 (0.38-0.81)0.73 (0.36-1.48)

Pathologic typeSquamous cell carcinomaNonsquamous cell carcinoma17776

86400.57 (0.41-0.80)0.77 (0.42-1.40)

0.1

0.5

Sugemalimab

Better

Placebo

Better

Subgroup analyses of PFS

Stratification

factors

Slide57

CI,

confidence

Interval; CRT, chemoradiotherapy; HR, Hazard ratio; NR, not reached; PFS, progression-free survival.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.Sequential CRT Concurrent CRT Sugemalimab(N=86)Placebo(N=41)Median PFS, mo (95% CI)8.1 (4.0-10.4)4.1 (2.1-6.1)HR (95% CI)*0.59 (0.39-0.91)Sugemalimab(N=169)Placebo(N=85)Median PFS, mo (95% CI)10.5 (8.1-NR)6.4 (4.3-9.9)HR (95% CI)*0.66 (0.44-0.99)

100

Months

Progression-Free

Survival

(%)

37.6%

31.2%

14.6%

11.7%

Sugemalimab

Placebo

Censored

Patients at Risk

Sugemalimab

Placebo

Patients at Risk

Sugemalimab

169

152

111

Placebo

100

Months

Progression-Free

Survival

(%)

Sugemalimab

Placebo

Censored

34.3%

49.7%

43.5%

PFS by CRT Type

Slide58

Preliminary OS analysis

OS data were immature at cutoff date.

CI, confidence Interval; HR, Hazard ratio; mo, month(s); NR, not reached; OS, overall survival.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.

100

50.7%

78.0%

Patients at Risk

Sugemalimab

255

249

221

189

165

149

136

114

Placebo

126

112

Sugemalimab (N=255)

Placebo

(N=126)

events

(%)

32 (12.5)

32 (25.4)

Median OS. Mo (95% Cl)

24.1 (16.5-NR)

HR (95% Cl)

0.44 (0.27-0.73)

–––

Sugemalimab

–––

Placebo

Censored

Overall

Survival

(%)

Months

Slide59

Data cutoff: March 8 2021.Adverse events of special interest were sponsor-assessed immune-related adverse events, which were defined based on a list of preferred categories of terms specified by the sponsor.

AE, adverse evento; TEAE,

treatment-emergent adverse evento; TRAE, treatment-related adverse event.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.Sugemalimab (N=255)Placebo (N=126)TEAEGrade 3-5 TEAE246 (96.5%)62 (24.3%)116 (92.1%)30 (23.0%)TRAEGrade 3-5 TRAE193 (75.7%)26 (10.2%)73 (57.9%)7 (5.6%)Immune-related AEGrade 3-5 immune-related AE109 (42.7%)12 (4.7%)17 (13.5%)1 (0.3%)Infusion-related reaction1 (0.4%)2 (1.6%)TEAE leading to drug permanenlly discontinued29 (11.4%)6 (4.8%)TEAE leading to treatment cycle delay82 (32.2%)31 (24.6%)TEAE leading to death10 (3.9%)3 (2.4%)TEAEs and TRAEs

Slide60

Data cutoff: March 8, 2021.Adverse events of special interest were sponsor-assessed immune-related adverse events, which were defined based on a list of preferred categories of terms specified by the sponsor. *Excluding severe events.

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TEAE, treatment-emergent adverse event.

Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.TEAEs and irAEsTEAEs in ≥10% of PatientsImmune-related AEs

Grade

1-2

≥3

Sugemalimab

Placebo

Slide61

GEMSTONE-301 Summary and conclusions

At this pre-planned interim analysis, a statistically significant and clinically meaningful improvement in PFS was observed with

sugemalimab vs placebo among patients with unresectable stage III NSCLC who had not progressed following cCRT or sCRTBICR assessed mPFS: 9.0 vs 5.8 months, stratified HR = 0.64sCRT subgroup mPFS: 8.1 vs 4.1 months, unstratified HR = 0.59cCRT subgroup mPFS: 10.5 vs 6.4 months, unstratified HR = 0.66OS data were immature, but an encouraging trend for a survival benefit with sugemalimab vs placebo was observed. Follow-up of the patients is ongoingMedian OS: NR vs 24.1 months, stratified HR = 0.44Sugemalimab had a well-tolerated safety profile and no new safety signals were observed, consistent with the safely profile previously reported for sugemalimab monotherapy in NSCLCThe results of the GEMSTONE-301 study suggest that sugemalimab is an effective consolidation therapy for patients with unresectable stage III NSCLC who have not progressed following cCRT or sCRTBICR, blinded independent review committee; cCRT, concurrent chemoradiation therapy; HR, Hazard ratio; mPFS, median progression-free survival; NR, not reached; NSCLC, non small cell lung cancer; OS, overall survival PFS, progression-free survival; sCRT, sequential chemoradiation therapy.Wu Y-L, et al. Abstract LBA43 presented at ESMO 2021.

Slide62

Trastuzumab deruxtecan in HER2-mutated metastatic NSCLC

DESTINY-Lung01

Slide63

aPatients with asymptomatic brain metastases not requiring ongoing steroid or anticonvulsant therapy were allowed to enroll.

HER2 mutation documented solely from a liquid biopsycould not be used for enrolment. cHER2 overexpression without known HER2 mutation was assessed by local assessment of archival tissue and centrally confirmed. dPer RECIST v1.1.CNS, central nervous system; DCR, disease control rate; DOR. duration of response; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; ICR. independent central review; lHC, immunohistochemistry; NSCLC, non small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumours.Li B, et al. Abstract LBA45 presented at ESMO 2021.Cohort 1: HER2-overexpressingc(IHC 3+ or IHC 2+)T-DXd 6.4 mg/kg Q3W N = 49Cohort 2: HER2-mutatedT-DXd 6.4 mg/kg Q3WN = 42Key eligibility criteriaUnresectable/metastatic nonsquarnous NSCLCRelapsed from or is refractory to standard treatmentMeasurable disease by RECIST v1.1Asymptomatic CNS metastases at baselineaECOG PS of O or 1Locally reported HER2 mutation (for Cohort 2)b91 patients with HER2m NSCLC were enrolled and treated with T-DXd

15 patients (16.5%) remain on treatment to date76 patients (83.5%) discontinued, primarily for progressive disease (37.4%) and adverse events (29.7%)

Cohort 1a:

HER2

-overexpressing

(IHC 3+ or IHC 2+)

T-

DXd

5.4 mg/kg Q3W

N = 41

Cohort 2 expansion:

HER2

-mutated

T-

DXd

6.4 mg/kg Q3W

N = 49

Multicenter, international, 2-cohort Phase 2 trial of trastuzumab

deruxtecan

(T-

DXd) in patients with HER2-mutated (HER2m) metastatic NSCLCDESTINY-Lung01 Study design

Primary endpoints:

Confirmed ORR by ICRd

Secondary endpoints:

DORPFS

OSDORSafety

Exploratory

endpointBiomarkers

of response

Slide64

Primary endpoint.

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; PD, progressive disease; PR, partial response.Li B, et al. Abstract LBA45 presented at ESMO 2021.Patients (N=91)Confirmed ORRa, n (%)50 (54.9)95% Cl, 44.2-65.4)Best overall response, n (%)CRPRSDPDNot evaluable1 (1.1)49 (53.8)34 (37.4)3 (3.3)4 (4.4)DCR, n (%)84 (92.3)(95% Cl, 84.8-96.9)Median DoR, months9.3 (95% Cl, 5.7-14.7)Median follow up, months13.1 (range, 0.7-29.1)Confirmed ORR, best overall response, DCR and DoR

Slide65

aBest change in tumor size by ICR for 85 of 91 patients for whom baseline and postbaseline data were available. Baseline is Iasi measurement taken before enrollment.

The Oncomine™ Dx Target Test (Thermo Fisher Scientific) was used to confirm local HER2 mutation status and to determine HER2 amplification status. HER2 protein expression status was determined by immunohistochemistry using a modified PATHWAY anti-HER2 (4B5) (Ventana Medical Systems, Inc.) assay. Shown is best (minimum) percentage change from baseline in the sum of diameters for all target lesions; (-), negative; (+), positive; I, insertion; N no; S, substitution: Y. yes. Blank cells (except for the prior HER2 TKl therapy row) indicate patients whose tumor samples were not evaluable or assessed. The upper dashed horizontal line indicates a 20% increase in tumor size in the patients who had disease progression and the lower dashed line indicates a 30% decrease in tumor size (partial response).HER2, human epidermal growth factor receptor 2, TKI, tyrosine kinase inhibitor.Li B, et al. Abstract LBA45 presented at ESMO 2021.-100-80-60-40-2002040Responses were observed across HER2 mutation subtypes, as well as inPatients

with no detectable HER2 expression or

HER2

gene

amplification

Patients

(N=85)

Best

Percent

Change

from

Baseline

Sum

of DiametersHER2 mutation domain location

HER2

mutation

(exon and subtype)

HER2 protein expression

HER2

gene amplification

Prior HER2 TKI therapy

Best percentage change of tumor size from baseline

Extracellular

domain

Kinase

domain

Slide66

Best percentage change of tumor size from baseline

Given separately or in combination. bPatients had asymptomatic brain metastases not requiring ongoing steroid or anticonvulsant therapy.CI, confidence interval; CNS, central nervous system; ORR, objective response rate.Li B, et al. Abstract LBA45 presented at ESMO 2021.No. Of RespondersConfirmed ORR (95% Cl)ConfirmedORR (95% Cl)All patients50/9154.9 (44.2-65.4)HER2 mutation domainKinase domain49/8557.6 (46.5-68.3)Prior treatment receivedPlatinum-based therapyPlatinum-based therapy and anti-PD-(L) 1 therapya46/8637/5753.5 (42.4-64.3)64.9 (51.1-77.1)Asymptomatic CNS metastasis at baselinebYesNo18/3332/5854.5 (36.4-71.9)55.2 (41.5-68.3)

20%

40%

60%

80%

100%

Slide67

PFS

Median follow-up was 13.1 months (range, 0.7-29.1). PFS assessed by ICR using RECIST v1.1., the median was based on Kaplan-Meier, and 95% CI for median was computed using the Brookmeyer-Crowley method, and dashed lines indicate the 95% CI. Of 91 patients, 41 had progressive disease and 15 had died by the data

cutoff date. Data for 35 patients were censored as indicated by tick marks; patients were censored if they discontinued treatment.CI, confidence interval; PFS, progression-free survival.Li B, et al. Abstract LBA45 presented at ESMO 2021.

20%

40%

60%

80%

100%

Months

Percentage

Patients

Median PFS

8.2

months

(95% CI, 6.0-11.9)

No. At Risk:

Slide68

Median follow-up was 13.1 months (range, 0.7-29.1 months).Dashed lines indicate the 95% CI. Of 91 patients, 47 had died by the data cutoff date. Data for 44 patients were censored as indicated by tick marks; patients were censored if they discontinued treatment.

CI, confidence interval; OS, overall survival.

Li B, et al. Abstract LBA45 presented at ESMO 2021.

20%

40%

60%

80%

100%

Months

Percentage

Patients

Median OS

17.8

months

(95% CI, 13.8-22.1)

No. At Risk:

Slide69

Relationship to study drug was determined by the treating investigator. aPneumonitis (n = 12) and interstitial lung disease (n = 5) were among the drug-related TEAEs associated with discontinuation.

1 patient experienced grade 3 ILD as reported by investigator and died. The reported ILD was subsequently adjudicated as grade 5 by the interstitial lung disease adjudication committee.ILD, interstitial lung disease; TEAE, treatment-emergent adverse event.Li B, et al. Abstract LBA45 presented at ESMO 2021.Median treatment duration was 6.9 months (range, 0.7-26.4 months)The most common drug-related TEAEs associated with treatment discontinuation were investigator-reported pneumonitis (13.2%) and ILD (5.5%)The most common drug-related TEAEs associated with dose reduction were nausea (11.0%) and fatigue (8.8%)N (%)Patients (N=91)Any drug-related TEAE88 (96.7)Drug-related TEAE Grade ≥342 (46.2)Serious drug-related TEAE18 (19.8)Drug-related TEAE associated with discontinuationa23 (25.3)Drug-related TEAE associated with dose reduction31 (34.1)Drug-related TEAE associated with an outcome of deathb2 (2.2)cOverall safety summary

Slide70

Drug-related TEAEs reported by investigator

This category includes the preferred terms fatigue, asthenia, and malaise.bThis category includes the preferred terms neutrophil count decreased and neutropenia.cThis category includes the preferred terms hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.dThis category includes the preferred terms white blood cell count decreased and leukopenia.TEAE, treatment-emergent adverse event.Li B, et al. Abstract LBA45 presented at ESMO 2021.n (%)Patients (N=91)Patients (N=91)n (%)Any gradeAny gradeGrade ≥3Patients with ≥1 drug-related TEAEs88 (96.7)88 (96.7)42 (46.2)Drug-related TEAEs with ≥20% Incidence in all patientsNauseaFatigueaAlopeciaVomitingNeutropeniabAnemiacDiarrheaDecreased appetiteLeukopeniadConstipation66 (72.5)48 (52.7)42 (46.2)36 (39.6932 (35.2)30 (33.0)29 (31.9)27 (29.7921 (23.1)20 (22.0)8 (8.8)6 (6.6)

03 (3.3)17 (18.7)9 (9.9)3 (3.3)04 (4.4)0

Slide71

aDrug-related ILD/pneumonitis was determined by the Independent Adjudication Committee based on the current MedDRA version for the narrow ILD standard MedDRA query (SMQ), selected terms from the broad ILD SMQ: and respiratory failure and acute respiratory failure.

Events of ILD/pneumonitis in the present study were actively managed based on the protocol-defined ILD/pneumonitis management guidelines.ILD, interstitial lung disease.Li B, et al. Abstract LBA45 presented at ESMO 2021.The median time to onset of first reported drug-related ILD/pneumonitis was 141 days (range, 14-462 days), with a median duration of 43 days (95% Cl, 24-94 days)75% of adjudicated drug-related ILD/pneumonitisa cases were of low grade (Grade 1/2)21 of 24 patients with adjudicated drug-related ILD/pneumonitis received >1 dose of glucocorticoids. However, not all glucocorticoid treatment was administered per the ILD/pneumonitis management guidelines15At the time of data cutoff, 54% (13/24) of investigator-reported cases had fully resolvedGrade 1Grade 2Grade 3Grade 4Grade 5Any Graden (%)3 (3.3)15 (16.5)4 (4.4)02 (2.2)24 (26.4)Adjudicated drug-related ILD/pneumonitis

Slide72

DESTINY-Lung01 Conclusions

Trastuzumab deruxtecan (T-

DXd) demonstrated robust and durable anticancer activity in patients with previously-treated HER2m NSCLCEfficacy was consistently observed across subgroups, including in those patients with stable CNS metastasesExploratory analyses demonstrated anticancer activity across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplificationOverall, the safety profile was consistent with previously reported studiesMost adjudicated drug-related ILD/pneumonitis cases were of low gradeILD/pneumonitis remains an important identified risk. Effective early detection and management are critical in preventing high-grade ILD/pneumonitisThe 5.4 mg/kg dose is being explored in future studies to evaluate the optimal dosing regimen in patients with HER2m NSCLC (DESTINY-Lung02; NCT04644237)DESTINY-Lung 01 provides compelling evidence of positive benefit/risk balance with T-DXd in the 2L+ setting and supports its establishment as a potential new treatment standard2L, second line; CNS, central nervous system; ILD, interstitial lung disease; NSCLC, non small cell lung cancer.Li B, et al. Abstract LBA45 presented at ESMO 2021.

Slide73

Gastrointestinal Cancers

Slide74

Nivolumab + chemotherapy or ipilimumab vs chemotherapy as 1L treatment for advanced GC/GEJC/EAC

CheckMate 649

Slide75

1% includes indeterminate tumor cell PD-L1 expression;

bAfter NIVO + chemo arm was added and before new patient enrollment in the NIVO - IPI arm was stopped early (5 June 2018) based on DMC recommendation; patients already enrolled in the NIVO + IPI arm were allowed to remain on study: clncludes patients concurrently randomized to chemo vs NlVO + IPI (October 20l6 – June 2018), and to NIVO + chemo (Apr 2017-Apr 2019); dXELOX; oxaliplatin 130mg/m2 IV (day 1) and capecitabine 100Q mg/m2 orally twice daily (days 1-14); FOLFOX: oxaliplatin 85mg/m2, leucovorin 400mg 400 mg/m2, and FU 400 mg/m2 IV (day 1) and! FU 1200mg/m2 IV daily (days 1-2); eUntil documented disease progression (unless consented to treatment beyond progression for NIVO + chemo or NIVO + IPI), discontinuation due to toxicity, withdrawal of consent, or study end. NIVO is given for a maximum of 2 years; fTime from concurrent randomization of the last patient to data cutoff. 1L, first line; BICR, blinded independent review committee; CPS, combined positive score; EAC, esophageal adenocarcinoma; ECOG PS; Eastern Cooperative Oncology Group performance status; GC, gastric cancer; GEJC, gastroesophageal junction cancer; IPI, ipilimumab; NIVO, nivolumab; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; R, randomization; ROW, rest of world.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.At data cutoff (May 27, 2021), the minimum follow-upf was 24.0 months in the NIVO + chemo arm and 35.7 months in the NIVO + IPI armR1:1:1bN = 2031n = 409n =833cn =789NIVO 360mg +XELOX Q3W orNIVO 240mg +FOLFOX Q2Wd,eXELOX Q3W orFOLFOX Q2Wd,eNIVO (1mg/kg) +IPI (3mg/kg) Q3W x 4then NIVO 240mg Q2We

Key eligibility

criteria

Previously untreated, unresectable, advanced or metastatic GC/GEJC/EAC

No known HER2-positive status

ECOG PS 0-1

Stratification

factors

Tumor cell PD-L1 expression (≥1% vs <1%)

Region (Asia vs United States/Canada vs ROW)

ECOG PS (0 vs 1)

Chemo (XELOX vs FOLFOX)

Dual p

rimary

endpoints:

OS and PFS per BICR (PD-L1 CPS ≥5)

Hierarchically tested secondary

endpoints:

NIVO + chemo vs chemo: OS (PD-L1 CPS ≥1,

all randomized)

NIVO + IPI vs chemo: OS (PD-L1 CPS ≥5, all randomized)

Randomized, open-label, global

Phase

3 study of nivolumab + chemotherapy or ipilimumab vs chemotherapy as

1L treatment for advanced GC/GEJC/EAC

CheckMate 649 Study design

Slide76

Minimum follow up, 24.0 months.

CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; mo, months; NIVO, nivolumab; OS, overall survival.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.OS: NIVO + chemo vs chemoPD-L1 CPS ≥5 All randomizedClinically meaningful improvement in OS with NIVO + chemo vs chemo was maintained with longer follow-upPD-L1 CPS ≥5: 30% reduction in the risk of death and 12% improvement in 24-month OS rateAll randomized: 21% reduction in the risk of death and 9% improvement in 24-month OS rateDirectionally improved HRs relative to the 12-month follow up (PD-L1 CPS ≥5, 0.71 [98.4% Cl, 0.59-0.86]; all randomized; 0.80 [99.3% Cl, 0.68-0.94])No. at riskNIVO + chemo47344038031526322318716114110781614326196

20Chemo

482

424

353

275

215

154

125

NIVO +

chemo(n = 789)

Chemo (n = 792)Median OS,a mo (95% CI)13.8(12.4-14.5)11.6

(10.9-12.5)HR (95% CI)0.79 (0.71-0.88)

NIVO +

chemo

(n = 473)Chemo

(n = 482)Median OS,

a mo (95% CI)14.4(13.1-16.2)11.1

(10.0-12.1)HR (95% CI)0.70 (0.61-0.81)

. at

risk

NIVO +

chemo

789

733

624

508

422

349

287

246

212

156

115

Chemo

792

701

591

475

364

273

215

170

144

103

Slide77

Per BICR assessment; minimum follow up, 24.0 months.

CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; NIVO, nivolumab; PFS, progression-free survival.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.PD-L1 CPS ≥5 All randomizedPFS benefit was maintained with NIVO + chemo vs chemo with longer follow-up in both PD-L1 CPS ≥ 5 and all randomized populationsNo. at riskNIVO + chemo4733852601871421149274584229208310Chemo48233120411682594937

28231613

NIVO +

chemo

(

= 473)

Chemo

(

= 482)

Median

OS,

(95% CI)7.7(7.1-8.6)6.9(6.7-7.2)

HR (95% CI)0.79 (0.70-0.89)

NIVO + chemo

(n = 473)Chemo (n

= 482)Median OS,a mo (95% CI)

8.1(7.0-9.2)6.1(5.6-6.9)HR (95% CI)

0.70 (0.60-0.81)

. at

risk

NIVO +

chemo

473

385

260

187

142

114

Chemo

482

331

204

116

PFS: NIVO +

chemo

Slide78

Randomized

patients who had target lesion measurements at baseline per BICR assessment, MSI-H: NIVO + chemo, n = 20; chemo, n = 18, patients with MSS: NIVO + chemo, n = 535; chemo, n = 533.CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; MSI, microsatellite instability; MSS, microsatellite stable; NIVO, nivolumab; OS, overall survival; ORR, objective response rate.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.Efficacy by MSI status: NIVO + chemo vs chemoMSI-HMSSNIVO + chemo(n = 23)Chemo (n = 21)Median OS, mo (95% CI)38.7(8.4-44.8)12.3(4.1-16.5)Unstratified HR (95% CI)0.38 (0.17-0.84)ORR,a %(95% CI)55(32-77)39(17-64)Longer median OS and higher ORR were observed in all randomized patients with MSI-H and MSS tumors with NIVO + chemo vs chemoThe magnitude of benefit was greater in patients with MSI-H tumors, and patients with MSS tumors had results similar to the all randomized populationNIVO + chemo(n = 696)Chemo (n = 682)Median OS, mo (95% CI)

13.8(12.4-14.5)11.5(10.8-12.5)

Unstratified

HR (95% CI)

0.78 (0.70-0.88)

ORR,

(95% CI)

(55-63)

(42-51)

. at

risk

NIVO +

chemo

121197

6320

Chemo2119

1412117

6653

3000

. at

risk

NIVO +

chemo

696

646

554

452

375

308

251

214

184

137

103

Chemo

682

601

506

405

312

235

188

146

126

Slide79

Minimum follow up, 37.5 months.

CI, confidence interval; CPS, combined positive score; HR, hazard ratio; mo, months; NIVO, nivolumab; OS, overall survival.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.OS: NIVO + IPI vs chemoPD-L1 CPS ≥5 All randomizedNIVO + IPI(n = 409)Chemo (n = 404)Median OS,a mo(95% CI)11.7(9.6-13.5)11.8(11.0-12.7)HR (95% CI)0.91 (0.77-1.07)P valueNot testedNIVO + IPI(n = 234)Chemo (n = 239)Median OS,a mo(95% CI)11.2(9.2-13.4)11.6(10.1-12.7)HR (95% CI)0.89 (0.71-1.10)P value0.2302

The hierarchically tested secondary endpoint of OS with NIVO + IPI vs chemo in patients with PD-L1 CPS ≥5 was not met; OS in all randomized patients was not statistically tested

. at

risk

NIVO + IPI

234

193

156

131

106

Chemo

239

211176143110

74564539

3127221912

7211

. at

risk

NIVO + IPI

409

332

279

235

197

162

132

102

Chemo

404

359

305

255

189

134

Slide80

aMinimum follow up, 35.7 months. CI, confidence interval; CPS, combined positive score; HR, hazard ratio; IPI, ipilimumab; mo, months; NIVO, nivolumab; PFS, progression-free survival.

Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.

PFS: NIVO + IPI vs chemoPD-L1 CPS ≥5 All randomizedNo PFS benefit was observed with NIVO + IPI vs chemo in either the PD-L1 CPS ≥5 or all randomized populationNo. at riskNIVO + IPI2349163473927201613111083210Chemo2391649955392520181715131210

210

. at

risk

NIVO + IPI

409

157

Chemo

404

283182

107714836

31272116

151242

110

NIVO + IPI

(

n = 409)Chemo (n = 404)

Median OS,

(95% CI)

2.8

(2.6-3.6)

7.1

(6.9-8.2)

HR (95% CI)

1.66 (1.40-1.95)

NIVO + IPI

(

= 234

)

Chemo

(

= 239)

Median

OS,

(95% CI)

2.8

(2.6-4.0)

6.3

(5.6-7.1)

HR (95% CI)

1.42 (1.14-1.76)

Slide81

Randomized patients who had target lesion measurements at baseline per ICR assessment;

bNumber of responders. BICR, blinded independent review committee; CI, confidence interval; CPS, combined positive score; CR, complete response; DoR, duration of response; HR, hazard ratio; IPI, ipilimumab; mo, months; NIVO, nivolumab; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.Response and DoR: NIVO + IPI vs chemoPD-L1 CPS ≥5 All randomizedResponse per BICRNIVO + IPI(n = 196)aChemo(n = 183) aORR, % (95% CI)CRPRSDPD27 (20-33)521273247 (40-54)8393510NIVO + IPI(n = 52)bChemo(n = 86) bMedian DoR, mo(95% CI)13.2(8.3-18.3)6.9(5.2-7.6)Response per BICRNIVO + IPI(n = 333)aChemo(n = 299) aORR, % (95% CI)

CRPRSD

23 (18-28)

47 (41-53)

NIVO + IPI

(n = 52)

Chemo

(n = 86)

Median DoR, mo

(95% CI)13.8(9.4-17.7)6.8(5.6-7.2)

Although response rates were lower with NIVO + IPI vs chemo,

DoR was longer in both PD L1 ≥5 and all randomized populations

. at

risk

NIVO + IPI

4636

29231814

9775

4220

0Chemo86

66402118

1310

. at

risk

NIVO + IPI

Chemo

141

117

Slide82

aRandomized patients who had target lesion measurements at baseline per BICR assessment, MSI-H: NIVO + IPI, n = 10; chemo, n = 7, patients with MSS: NIVO + IPI, n = 292;

chemo, n = 257.

CI, confidence interval; HR, hazard ratio; mo, months; MSI, microsatellite instability; MSS, microsatellite stable; NIVO, nivolumab; OS, overall survival; ORR, objective response rate.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.MSI-HMSSNIVO + IPI(n = 11)Chemo (n = 10)Median OS, mo(95% CI)NR(2.7-NR)10.0(2.0-28.2)Unstratified HR(95% CI)0.28 (0.08-0.92)ORR,a %(95% CI)70(35-93)57(18-90)Longer median OS and higher ORR observed in all randomized patients with MSI-H tumors with NIVO + IPI vs chemo, although sample size was smallNo. at risk

NIVO + IPI

Chemo10976

444433211

111110

. at

risk

NIVO + IPI

355

286

240

202

170

137

110

Chemo

344

303

257

216

162

116

NIVO + IPI

(

= 355)

Chemo

(

= 344)

Median OS,

(95% CI)

11.6

(9.4-13.5)

12.0

(11.0-12.9)

Unstratified

(95% CI)

0.96 (0.82-1.12)

ORR,

(95% CI)

(16-25)

(42-54)

Efficacy

MSI

status

: NIVO + IPI

chemo

Slide83

aPatients who received ≥1 dose of study drug; b

Concurrently randomized to NIVO + chemo vs chemo;

cConcurrently randomized to NIVO + IPI vs chemo; dAssessed in all treated patients during treatment and for up to 30 days after the last dose of study treatment; eTRAEs Leading to discontinuation of any drug in the regimen; fTreatment-related deaths were reported regardless of timeframe; gIncluded 4 events of pneumonitis, 2 events of febrile neutropenia or neutropenic fever, and 1 event each of acute cerebral infarction, disseminated intravascular coagulation, Gl bleeding, Gl toxicity, infection, intestinal mucositis, mesenteric thrombosis, pneumonia, septic shock, and stroke; hIncluded 1 event each of asthenia and severe hyporexia, diarrhea, pneumonitis, and pulmonary thromboembolisrn; jIncluded 2 events of cardiac failure and 1 event each of acute hepatic failure, autoimmune hepatitis, general physical health deterioration, herpes simplex reactivation, hypophysitis, immune-mediated enterocolitis, multiple organ dysfunction syndrome, pneumonitis, and upper GI hemorrhage; kIncluded 1 event each of diarrhea, pancytopenia, and pulmonary embolism.ALT, alanine transaminase; AST, aspartate aminotransferase; CPS, combined positive score; IPI, ipilimumab; NIVO, nivolumab; TRAE, treatment related adverse event.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.The most common grade 3-4 TRAEs included:NIVO + chemo: neutropenia (15%), decreased neutrophil count (11%), anemia (6%)NIVO + IPI: increased lipase (7%), increased amylase (4%), increased ALT/AST (4% each)Chemo: neutropenia (11%-13%), decreased neutrophil count (9%-10%), diarrhea (3%-4%)The incidence of TRAEs in patients with PD-L1 CPS ≥5 was consistent with all treated patients across armsAll treated,a n (%)NIVO + chemo (n=782)bChemo (n=767)bNIVO + IPI (n=403)cChemo (n=389)cAny gradeGrade 3-4

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Any TRAEs

739 (95)

471 (60)

682 (89)

344 (45)

323 (80)

155 (38)

356 (92)

180 (46)

Serious TRAEs

175 (22)

133 (17)

94 (12)

77 (10)

122 (30)

93 (23)

54 (14)

45 (12)

TRAEs leading to discontinuation

d,e

300 (38)141 (18)188 (25)70 (9)88 (22)

68 (17)101 (26)37 (10)Treatment-realted deathsf

16 (2)g4 (<1)h

10 (2)f3 (<1)j

TRAEs

Slide84

TRAEs with potential immunologic etiology

Patients who received ≥1 dose of study drug; bAEs were assessed in all treated patients during treatment and for up to 30 days after the last dose of study treatment; cConcurrently randomized to NIVO + chemo vs chemo; dConcurrently randomized to NIVO + IPI vs chemo; eThe most common grade 3-4 events (≥2%) were diarrhea (n=35}. aspartate aminotransferase increased (n = 13), palmar-plantar erythrodysethesia (n = 12) and pneumonitis (n = 12); fThe most common grade 3-4 events (≥2%) were alanine aminotransferase increased (n = 16), aspartate aminotransferase increased (n = 16), diarrhea (n = 11), rash (n = 10), and immune-mediated enterocolitis (n = 9); gTreatment-related select AEs by organ category that have potential immunologic etiology and require frequent monitoring/intervention.AE, adverse event; CPS, combined positive score; IPI, ipilimumab; NIVO, nivolumab; TRAE, treatment-related adverse event.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.TRAEs with potential immunologic etiologyb,g:The majority of events were grade 1 or 2Grade 3-4 events occurred in ≤5% of patients with NIVO + chemo and in ≤12% of patients with NIVO + IPI across organ categoriesThe incidence of events in patients with PD-L1 CPS ≥5 was consistent with all treated patients across all armsAll treated,a,b n (%)NIVO + chemo (n=782)cChemo (n=767)cNIVO + IPI (n=403)dChemo (n=389)dAny gradeGrade 3-4

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Any Grade

Grade 3-4

Endocrine

109 (14)

6 (<1)

3 (<1)

89 (22)

15 (4)

2 (<1)

Gastrointestinal

266 (34)

43 (5)

208 (27)

25 (3)

84 (21)

26 (6)

113 (29)

16 (4)

Hepatic

207 (26)

31 (4)

138 (18)17 (2)104 (26)

47 (12)74 (19)9 (2)Pulmonary41 (5)

14 (2)4 (<1)1 (<1)15 (4)4 (1)1 (<1)

0Renal29 (4)7 (<1)

9 (1)2 (<1)17 (4)6 (1)6 (2)1 (<1)

Skin218 (28)27 (3)108 (14)

8 (1)146 (36)17 (4)

55 (14)

2 (<1)

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CheckMate 649 Conclusions

NIVO + chemo continued to demonstrate improvement in OS, PFS, and objective responses vs chemo in previously untreated patients with advanced GC/GEJC/EAC with an additional 12-month follow-up

Clinically meaningful long-term OS and PFS benefit with sustained separation of the KM curvesHigher ORR and more durable responsesDeepening of response with additional complete responses with longer follow-upNIVO + IPI did not significantly improve OS vs chemo in patients with PD-L1 CPS ≥ 5No new safety signals were identified with NIVO + chemo or NIVO + IPILonger follow-up data for NIVO + chemo further support its use as a new standard 1L treatment in patients with advanced GC/GEJC/EAC1L, first line; EAC, esophageal adenocarcinoma; GC, gastric cancer; GEJC, gastro-esophageal junction cancer; IPI, ipilimumab; KM, Kaplan-Meier; NIVO, nivolumab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.Janjigian Y, et al. Abstract LBA7 presented at ESMO 2021.

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Sintilimab + chemotherapy vs chemotherapy as 1L therapy for advanced or metastatic ESCC: First results

ORIENT-15

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Sintilimab

200 mg for ≥60 kg, 3 mg/kg for body weight <60 kg; TP; paclitaxel 175 mg/m2 plus cisplatin 75 mg/m2; CF: cisplatin 75 mg/m2 plus 5-FU 800 mg/m2 on day 1-5.1L, first line; CF, cisplatin + 5FU; CPS, combined positive score; DCR, disease control rate; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; ESCC, esophageal squamous cell carcinoma; IV, intravenous; OS, overall survival; PFS, progression-free survival; Q3W, every 3 weeks; TP, paclitaxel + cisplatin.Shen L, et al. Abstract LBA52 presented at ESMO 2021.N = 327N = 332Sintilimaba IV Q3W for a maximum of 24 months, plus chemotherapy (TPa or CFa) IV Q3W for a maximum of 6 cyclesKey eligibility criteriaUnrepeatable locally advanced or metastatic ESCC≥18 years ECOG PS 0 or 1At least one measurable lesion per RECIST v1.1Placebo IV Q3W for a maximum of 24 months, plus chemotherapy (TPa or CFa) IV Q3W for a maximum of 6 cyclesStratification factorsPD-L1 (CPS <10% or ≥10%)

ECOG PS (0 or 1)Liver metastasis (yes or no)

Chemo (TP or CF)

The OS in the overall population is evaluated with an a of 0.0125 (one-sided), and OS in the PD-L1 CPS ≥10 subgroup is also evaluated with an

of 0.0125 (one-sided) to strictly control the overall type I error for the hypothesis test of OS in the two populations

This is the interim analysis with data cut-off date on April 9, 2021

Median follow-up for OS was 16.0 months (IQR 12.3-19.4) in the Sinti + Chemo group and 16.9 months (IQR 11.8-20.2) in the Chemo group

Dual primary endpoints:

OS in patients with CPS ≥ 10

OS in all randomized patients

Secondary endpoints:

PFS, ORR, DCR and DoR per Investigator

Multicenter, randomized double-blind, Phase 3 trial to evaluate the efficacy and safety sintilimab + chemotherapy vs chemotherapy as 1L therapy in patients with advanced or metastatic ESCC: First results

ORIENT-15 Study design

1:1

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CI, confidence interval; CPS, combined positive score; HR, hazard ratio;

, month(s); mo, months; OS, overall survival.Shen L, et al. Abstract LBA52 presented at ESMO 2021.OSPD-L1 CPS ≥10All patientsSuperior OS benefit with Sinti + Chemo vs Chemo in patients with PD-L1 CPS ≥10 and all randomized patientsNo. at riskSinti + Chemo18817816714696653314610Chemo193174

15112282

No. at risk

Sinti + Chemo

327

305

283

240

161

105

Chemo

332

300