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

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

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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

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Pu Published Data with and Appropriate Integr gration

  • n of I
  • f Immune Ch

Checkp kpoi

  • int I

Inhibitor

  • rs

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

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Immunotherapy issues in HCC

  • Checkpoint inhibitors for hepatic-only disease
  • Management of autoimmune toxicity
  • Use in special populations
  • Treatment discontinuation
  • MSI-high disease
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Pu Published Data with and Appropriate Integr gration

  • n of I
  • f Immune Ch

Checkp kpoi

  • int I

Inhibitor

  • rs

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

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Disclosures

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

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

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Dose Dose expansi sion

  • n: treatment related adverse

se events

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

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Wks on Treatment Wks on Treatment

CheckMate 040: Phase I/II of single agent Nivolumab in HCC

Sorafenib Untreated or Intolerant Without Viral Hepatitis Change From Baseline in Target Lesion Tumor Burden (%) 100 75 50 25

  • 25
  • 50
  • 75
  • 100

Sorafenib Progressor Without Viral Hepatitis Change From Baseline in Target Lesion Tumor Burden (%) 100 75 50 25 72 60 48 36 24 12 66 54 42 30 18 6 72 60 48 36 24 12 66 54 42 30 18 6

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  • 75
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HCV Infected 100 75 50 25

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100 75 50 25 72 60 48 36 24 12 66 54 42 30 18 6 72 60 48 36 24 12 66 54 42 30 18 6

  • 25
  • 50
  • 75
  • 100

HBV Infected

El-Khoueiry. Lancet. 2017;389:2492.

ORR (RECIST 1.1): in expansion cohorts, 20%; in post-sorafenib patients, 14.3%

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Ti Time t to r

  • respon
  • nse a

and d duration

  • n of r
  • f respon
  • nse

Crocenzi T et al, J Clin Oncol 35, 2017 (suppl; abstr 4013)

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Su Survival base sed on so sorafenib ex exposure re

Crocenzi T et al, J Clin Oncol 35, 2017 (suppl; abstr 4013)

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OS rate (95% CI), % Complete/partial response n = 22 Stable disease n = 65 Progressive disease n = 59 12 month 100 (100–100) 67 (55–77) 41 (28–53) 18 month 100 (100–100) 45 (33–57) 26 (15–38)

aBest overall response was unable to be determined in 8 patients

CheckMate 040: Overall survival analyzed by best overall response or change in target lesion size

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

n = 146a Probability of survival Months

Complete or partial response (n =22) Stable disease (n = 65) Progressive disease (n = 59)

Median OS (95% CI), mo = 8.9(7.3–13.4) Median OS (95% CI), mo = 16.7(13.8–20.2) Median OS (95% CI), mo = NR (NE–NE)

3 6 9 33 36 39 42 45 48 30 27 12 15 18 21 24

Overall Survival by Best Overall Response (A)

El-Khoueiry A et al, GI Cancers Symposium, 2018

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Zhu AX, et al. Lancet Oncol. 2018 Jul;19(7):940-952.

KEYNOTE-224: Pembrolizumab in advanced HCC

OS, and safety and tolerability

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KEYNOTE-224: Pembrolizumab in advanced HCC

Zhu AX, et al. Lancet Oncol. 2018 Jul;19(7):940-952.

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KEYNOTE-240 Study Design

Key Eligibility Criteria − Pathologically/radiographically confirmed HCC − Progression on/intolerance to sorafenib − Child Pugh class A − BCLC stage B/C − ECOG PS 0-1 − Measurable disease per RECIST v1.1 − Main portal vein invasion was excluded Pembrolizumab 200 mg Q3W + BSC Saline-placebo Q3W + BSC Stratification Factors − Geographic region (Asia w/o Japan vs non-Asia w/Japan) − Macrovascular invasion (Y vs N) − AFP level (≥200 vs <200 ng/mL) Randomized 2:1 N = 413

  • Enrollment May 31, 2016 – November 23, 2017

Finn R et al, ESMO GI 2019

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Data Cutoff: Jan 2, 2019.

Finn R et al, ESMO GI 2019

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Summary of Adverse Events

aAttributed to treatment by the investigator. bOne grade 5 event occurred in 1 patient (death) in the pembrolizumab group. cDeath attributed to malignant neoplasm progression, possibly related to study treatment by investigator. dAny atttribution. eNo grade 5 immune-mediated AEs reported. fBased on sponsor assessment; no HBV/HBC viral flares identified. Data cutoff: Jan 2, 2019.

Adverse Events n (%) Pembrolizumab N=279 Placebo 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-relateda 170 (60.9) 65 (48.5) Grade 3-4b 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-mediatedd 51 (18.3) 11 (8.2) Grade 3-4e 20 (7.2) 1 (0.7) Led to discontinuation 10 (3.6) 0 (0) Immune-mediated hepatic-relatedf 10 (3.6) 0 (0)

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Immune-Mediated Adverse Events and Infusion Reactions

Event of any attribution in order of decreasing frequency for pembrolizumab. No grade 5 immune-mediated events reported. Data cutoff: Jan 2 , 2019 H y p

  • t

h y r

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d i s m H y p e r t h y r

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d i s m P n e u m

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i t i s S e v e r e s k i n r e a c t i

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H e p a t i t i s C

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i t i s I n f u s i

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r e a c t i

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A d r e n a l i n s u f f i c i e n c y H y p

  • p

h y s i t i s M y a s t h e n i a s y n d r

  • m

e M y

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i t i s T h y r

  • i

d i t i s T y p e 1 D i a b e t e s m e l l i t u s 2 4 6 8 F r e q u e n c y ( % ) 1 - 2 3 - 4 1 - 2 3 - 4 P e m b r o l i z u m a b P l a c e b o

Finn R et al, ESMO GI 2019

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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

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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)