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
