Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali

Lorenza Rimassa

Medical Oncology Unit

Humanitas Cancer Center

Humanitas Research Hospital

Rozzano (Milano)

Disclosures

Consulting or Advisory Role:

• Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter

Honoraria:

• AstraZeneca, AbbVie

Travel Expenses:

• ArQule

• Introduction

HCC

Immunotherapy

• Nivolumab

• Other immune checkpoint inhibitors and combinations

• Novel immune-based approaches

• Ongoing phase 3 trials

• Conclusions

Outline

Introduction and challenges

• Second leading cause of cancer-related deaths worldwide

• Incidence increasing with minimal improvement in outcomes

• Most of patients diagnosed at an advanced stage with limited therapeutic

options

• Frequent underlying liver cirrhosis / impaired liver function with impact

both on tolerability and activity of new drugs

• Oncogenic drivers not well understood

• Multiple etiologies and subtypes; heterogeneous diseases

• No validated biomarkers

• Sorafenib, regorafenib, and nivolumab (FDA only) are approved

systemic agents for patients with advanced HCC. Lenvatinib has shown

non-inferiority compared to sorafenib. Cabozantinib has shown improved

survival compared to placebo in pretreated patients

Llovet JM et al. N Engl J Med 2008. Cheng AL et al. Lancet Oncol

2009. Bruix J et al. Lancet 2017. El-Khoueiry AB et al. Lancet 2017.

Cheng AL et al. ASCO 2017. Exelixis press release, Oct 16, 2017

• HCC is potentially immunogenic and typically characterized by

inflammation

• Immune modulation plays a key role in HCC genesis

• Chronic HBV and HCV infections are associated with PD-1

upregulation and immune exhaustion

• PD-1 and PD-L1 overexpression associated with poor prognosis

• Checkpoint inhibitors preliminary data suggest a clinical benefit

• Checkpoint inhibitors are well tolerated; independent of liver

function (no metabolism)

Rationale for immunotherapy in HCC

Hato T et al. Hepatology 2014. Zeng Z et al. PLoS One 2011. Chen Y et

al. Hepatology 2015. Morales-Kastresana A et al. Clin Cancer Res 2013

Immunotherapy in HCC

Durvalumab

Atezolizumab Nivolumab

Pembrolizumab

Immunotherapy: Checkpoint blockade

, Tremelimumab

, PDR001

• 21 pts, HCV-related chronic hepatitis, Child-Pugh class A/B, not

amenable to locoregional Tx, pretreated with sorafenib/other systemic Tx

• Tremelimumab 15 mg/kg q 90 days (max 4 cycles)

Phase 2 study of tremelimumab in pts with HCC and HCV

Sangro B et al. J Hepatol 2013

Phase 1/2 CheckMate 040 – Study design

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Phase 1/2 CheckMate 040 – Safety results

El-Kohueiry AB et al. Lancet 2017

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Dose expansion – HRQoL outcomes

Dose expansion – Efficacy results

El-Kohueiry AB et al. Lancet 2017

El-Kohueiry AB et al, Lancet 2017

Dose expansion – Percent change in tumor burden

El-Kohueiry AB et al, Lancet 2017

Dose expansion – Best percent change in tumor burden

Objective Response Rate

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Dose expansion – Change in target lesion

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Phase 1/2 CheckMate 040 – Response by PD-L1 expression

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Phase 1/2 CheckMate 040 – Overall survival

Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

Phase 1/2 CheckMate 040 – First-line ORR

Updated Results – ORR

Crocenzi

TS et al.

ASCO

2017;

abstr

4013

Updated Results – Overall Survival

Crocenzi TS et al. ASCO 2017; abstr 4013

Updated Results – AEs and AFP

Sangro B et al. AASLD 2017; abstr 141

• N=262; median follow-up 14-16 months

• ORR (BICR): 14-20%; median DOR: 16.6-19.4 months

• Baseline AFP levels not associated with response; AFP levels decrease in

reponding patients

• No new safety signals, no drug-related deaths

• Safety profile manageable and consistent across patient cohorts,

similar to what observed in other tumor types, no new safety

signals

• Efficacy irrespective of

HCV, HBV or no infection status

PD-L1 expression on tumor cells

Baseline AFP levels

• Early, stable and durable responses

• 70% of patients surviving >9 months

• Patient-reported quality-of-life measures stable until week 25

Phase 1/2 CheckMate 040 – Conclusions

The recommended dose for

HCC treatment is 240mg q 2

wks

…As a condition of

accelerated approval further

trials will be required to verify

the clinical benefit…

FDA: Accelerated approval to nivolumab

EMA: Withdrawal of the application

Abou-Alfa GK. ASCO GI 2017

Anti-CTLA-4 and PD-1 combination therapy

Wainberg ZA et al. ASCO 2017; abstr. 4071

Phase 1/2 study of durvalumab

• 40 patients in the HCC cohort, dose-expansion part of the study

• Patients had progressed on, were intolerant to, refused sorafenib

• Child-Pugh A

• HBV, HCV, non infected

• Durvalumab 10 mg/Kg Q2W (max 12 months)

• Tolerable and manageable safety profile, promising antitumor

activity and OS

Any-grade treatment-related AEs in 80% of pts; G3-4 AEs in 20%

ORR 10% (no response in HBV positive), median OS 13.2 months

Anti-CTLA-4 and PD-L1 combination therapy

Kelley RK et al. ASCO 2017; abstr. 4073

• Phase 1/2, open-label, randomized multicenter study

• Patients had progressed on, were intolerant to, refused sorafenib

• Child-Pugh A

• HBV, HCV, non infected

• RP2D: Durvalumab 20 mg/Kg Q4W + tremelimumab 1 mg/Kg Q4W for 4

doses, followed by durvalumab 20 mg/Kg Q4W

• Combination well tolerated with no unexpected safety signals

• ORR (confirmed and unconfirmed) 25% (10/40 pts)

• Clinical activity predominantly in uninfected patients but also in HCV and

HBV positive; interpretation limited due to the small subset of pts

• Enrollment to phase 2 and biomarkers analyses ongoing

Phase 1/2 randomized study of durvalumab and tremelimumab

Kelley RK et al. ASCO 2017; abstr. 4073

Kelley RK et al. ASCO 2017; abstr. 4073

Phase 1/2 randomized study of durvalumab and tremelimumab

Novel immune-based approaches in HCC

Lee JH et al. Gastroenterology 2015

Pilot study: Tremelimumab + ablation in advanced HCC

• 32 pts; Child-Pugh A/B; BCLC stage B/C; ECOG PS 0/1; post sorafenib

• Tumor biopsies at the time of the radiologic procedure and compared to

archived samples (immune correlatives)

• ORR and mTTP in non-TACE/RF lesions: 26% and 7.4 mos

• mOS 13.2 mos

Duffy AJ et al. J Hepatol 2017

Regional therapy as a method to augment the immune response

Abou-Alfa GK. ASCO GI 2017

Abou-Alfa GK. ASCO GI 2017; NCT03143270

TACE plus nivolumab

Ongoing Phase 3 Trials in Advanced HCC

First-line

• Nivolumab vs sorafenib

• Durvalumab +/- tremelimumab vs sorafenib

• Atezolizumab + bevacizumab vs sorafenib

• Pexa-Vec followed by sorafenib vs sorafenib

• Sorafenib +/- Y90 microspheres (TheraSphere)

Second-line

• Ramucirumab (2) vs placebo

• Pembrolizumab vs placebo

PHOCUS: First-line Pexa-Vec followed by sorafenib vs sorafenib

• Immunotherapy is a promising option for patients with

advanced HCC

• Preliminary data from clinical trials testing immune checkpoint

inhibitors suggest a clinical benefit

• Checkpoint inhibitors are well tolerated

• Independent of liver function (no metabolism)

• Checkpoint inhibitors may be combined, also with other agents,

and with ablative therapies in the advanced setting

Conclusions - I

• Anti–PD-1/PD-L1 and anti–CTLA-4 are currently being tested in

phase 3 trials in first- and second-line setting

• The role in the adjuvant setting and in combination with

locoregional therapy (ablation; TACE) in early/intermediate stage

is under investigation

• Predictive biomarkers are critical

PD-L1 expression is not predictive in the CheckMate 040 study

Several other biomarkers may hold value for enriching the population who

may benefit from immunotherapy

• Novel immune-based approaches are in (early) clinical evaluation

Conclusions - II

Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali

Thank you!