Pu Published Data with and Appropriate Integr gration on of I of - PowerPoint PPT Presentation

Pu Published Data with and Appropriate Integr gration on of I of Immune Ch Checkp kpoi oint I Inhibitor ors in into the the Car are of Patie tients ts with ith Progressiv ive Me Metastatic HC HCC Anthony El-Khoueiry, MD Associate Professor of Clinical Medicine Medical Director of Clinical Investigations Support Office Phase I Program Director USC Norris Comprehensive Cancer Center Los Angeles, California

Immunotherapy issues in HCC • Checkpoint inhibitors for hepatic-only disease • Management of autoimmune toxicity • Use in special populations • Treatment discontinuation • MSI-high disease

Pu Published Data with and Appropriate Integr gration on of I of Immune Ch Checkp kpoi oint I Inhibitor ors in into the the Car are of Patie tients ts with ith Progressiv ive Me Metastatic HC HCC Anthony El-Khoueiry, MD Associate Professor of Clinical Medicine Medical Director of Clinical Investigations Support Office Phase I Program Director USC Norris Comprehensive Cancer Center Los Angeles, California

Disclosures Agenus Inc, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Exelixis Inc, Genentech, Merck, Roche Advisory Committee Laboratories Inc Contracted Research Astex Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Merck

El-Khoueiry A et al, Lancet, online April 2017

Dose Dose expansi sion on: treatment related adverse se events El-Khoueiry A et al, Lancet, online April 2017

CheckMate 040: Phase I/II of single agent Nivolumab in HCC ORR (RECIST 1.1): in expansion cohorts, 20%; in post-sorafenib patients, 14.3% Sorafenib Untreated or Intolerant HCV Infected 100 100 in Target Lesion Tumor Without Viral Hepatitis Change From Baseline 75 75 50 50 Burden (%) 25 25 0 0 -25 -25 -50 -50 -75 -75 -100 -100 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 Sorafenib Progressor Without Viral Hepatitis HBV Infected 100 100 in Target Lesion Tumor Change From Baseline 75 75 50 50 Burden (%) 25 25 0 0 -25 -25 -50 -50 -75 -75 -100 -100 0 6 12 18 24 30 36 42 48 54 60 66 72 0 6 12 18 24 30 36 42 48 54 60 66 72 Wks on Treatment Wks on Treatment El-Khoueiry. Lancet. 2017;389:2492.

Ti Time t to r o respon onse a and d duration on of r of respon onse Crocenzi T et al, J Clin Oncol 35, 2017 (suppl; abstr 4013)

Su Survival base sed on so sorafenib ex exposure re Crocenzi T et al, J Clin Oncol 35, 2017 (suppl; abstr 4013)

CheckMate 040: Overall survival analyzed by best overall response or change in target lesion size (A) Overall Survival by Best Overall Response 1.0 Median OS (95% CI), mo = NR (NE–NE) 0.9 0.8 Probability of survival 0.7 Complete or partial response (n =22) 0.6 Stable disease (n = 65) Progressive disease (n = 59) 0.5 0.4 0.3 Median OS (95% CI), mo = 16.7(13.8–20.2) 0.2 Median OS (95% CI), mo = 8.9(7.3–13.4) 0.1 0 n = 146 a 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months Complete/partial OS rate (95% response Stable disease Progressive disease CI), % n = 22 n = 65 n = 59 12 month 100 (100–100) 67 (55–77) 41 (28–53) 18 month 100 (100–100) 45 (33–57) 26 (15–38) a Best overall response was unable to be determined in 8 patients El-Khoueiry A et al, GI Cancers Symposium, 2018

KEYNOTE-224: Pembrolizumab in advanced HCC OS, and safety and tolerability Zhu AX, et al. Lancet Oncol. 2018 Jul;19(7):940-952.

KEYNOTE-224: Pembrolizumab in advanced HCC Slide 6 Zhu AX, et al. Lancet Oncol. 2018 Jul;19(7):940-952.

KEYNOTE-240 Study Design Pembrolizumab Key Eligibility Criteria 200 mg Q3W + BSC − Pathologically/radiographically confirmed HCC − Progression on/intolerance to sorafenib − Child Pugh class A Randomized 2:1 N = 413 − BCLC stage B/C − ECOG PS 0-1 − Measurable disease per RECIST v1.1 Saline-placebo − Main portal vein invasion was excluded Q3W + BSC Stratification Factors − Geographic region (Asia w/o Japan vs non-Asia • Enrollment May 31, 2016 – November 23, 2017 w/Japan) − Macrovascular invasion (Y vs N) − AFP level (≥200 vs <200 ng/mL) Finn R et al, ESMO GI 2019

Finn R et al, ESMO GI 2019 Data Cutoff: Jan 2, 2019.

Summary of Adverse Events Pembrolizumab Placebo Adverse Events n (%) N=279 N=134 ≥1 All cause 269 (96.4) 121 (90.3) Grade 3-5 147 (52.7) 62 (46.3) Led to discontinuation 48 (17.2) 12 (9.0) Led to treatment interruption 84 (30.1) 21 (15.7) Led to death 7 (2.5) 4 (3.0) Treatment-related a 170 (60.9) 65 (48.5) Grade 3-4 b 51 (18.3) 10 (7.5) Led to discontinuation 18 (6.5) 1 (0.7) Led to death 1 (0.4) c 0 (0) Immune-mediated d 51 (18.3) 11 (8.2) Grade 3-4 e 20 (7.2) 1 (0.7) 10 (3.6) 0 (0) Led to discontinuation Immune-mediated hepatic-related f 10 (3.6) 0 (0) a Attributed to treatment by the investigator. b One grade 5 event occurred in 1 patient (death) in the pembrolizumab group. c Death attributed to malignant neoplasm progression, possibly related to study treatment by investigator. d Any atttribution. e No grade 5 immune-mediated AEs reported. f Based on sponsor assessment; no HBV/HBC viral flares identified. Data cutoff: Jan 2, 2019.

Immune-Mediated Adverse Events and Infusion Reactions 8 P e m b r o l i z u m a b 1 - 2 3 - 4 P l a c e b o 1 - 2 3 - 4 6 ) F r e q u e n c y ( % 4 2 0 l s s s n a m m n s s s y a s i i i i i i i t o t o t c s s t n t t e n i i i i i i i i i i n t t l t s n t e e s d e d d e a o c c r e y o h i i o i i m b p a d o a C h t o o y c m s r a e e r r e A o i p i r M y f a y y u r r s H o f D h y d h h e u n n u p t t T t n n i M 1 o s y i r o k l i y P n e l H e p s s s i e p p y u e y m f y H r n H T e I v e S Finn R et al, ESMO GI 2019 Event of any attribution in order of decreasing frequency for pembrolizumab. No grade 5 immune-mediated events reported. Data cutoff: Jan 2 , 2019

Nivolumab in Child-Pugh B patients Median DOR 9.9 months (1.4+-9.9) Median OS 7.6 months Kudo M et al, ASCO GI 2019

Summary and Conclusions Single agent anti PD-1 activity in second line and beyond HCC consistent across multiple • phase I/II trials with durable responses – Nivolumab, Pembrolizumab, Camrelizumab Phase 3 KEYNOTE-240 of Pembrolizumab versus Placebo post sorafenib did not reach • statistical significance – However, clinical benefit still noted – Attenuating circumstances: statistical design with co-primary endpoints and cross-over Potential factors that influence clinicians to use anti PD-1 agents post sorafenib or • lenvatinib: – Poor tolerability of TKIs (however only RESORCE trial with regorafenib excluded patients who did not tolerate 400 mg or sorafenib for 20 days) – Available Child-Pugh B data with Nivolumab – Hope for a deep long lasting response (especially in patients who may not make it to third line therapy)