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Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali

Lorenza Rimassa

Medical Oncology Unit

Humanitas Cancer Center

Humanitas Research Hospital

Rozzano (Milano)

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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

AntiPD-1/PD-L1 and antiCTLA-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!

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