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
Outline Introduction HCC Immunotherapy Nivolumab Other immune checkpoint inhibitors and combinations Novel immune-based approaches Ongoing phase 3 trials Conclusions
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
Rationale for immunotherapy in HCC 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) 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, PDR001, Tremelimumab
Phase 2 study of tremelimumab in pts with HCC and HCV 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) 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
Dose expansion HRQoL outcomes Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)
Dose expansion Efficacy results 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 El-Kohueiry AB et al, Lancet 2017
Objective Response Rate 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 Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)
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 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 Sangro B et al. AASLD 2017; abstr 141
Phase 1/2 CheckMate 040 Conclusions 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
FDA: Accelerated approval to nivolumab 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
EMA: Withdrawal of the application
Anti-CTLA-4 and PD-1 combination therapy Abou-Alfa GK. ASCO GI 2017
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 Wainberg ZA et al. ASCO 2017; abstr. 4071
Anti-CTLA-4 and PD-L1 combination therapy Kelley RK et al. ASCO 2017; abstr. 4073
Phase 1/2 randomized study of durvalumab and tremelimumab 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 Kelley RK et al. ASCO 2017; abstr. 4073
Phase 1/2 randomized study of durvalumab and tremelimumab Kelley RK et al. ASCO 2017; abstr. 4073
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
TACE plus nivolumab Abou-Alfa GK. ASCO GI 2017; NCT03143270
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
Conclusions - I 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 - II 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
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