Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali

Transcription

1 Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali Lorenza Rimassa Medical Oncology Unit Humanitas Cancer Center Humanitas Research Hospital Rozzano (Milano)

2 Disclosures Consulting or Advisory Role: Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter Honoraria: AstraZeneca, AbbVie Travel Expenses: ArQule

3 Outline Introduction HCC Immunotherapy Nivolumab Other immune checkpoint inhibitors and combinations Novel immune-based approaches Ongoing phase 3 trials Conclusions

4 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 Cheng AL et al. Lancet Oncol Bruix J et al. Lancet El-Khoueiry AB et al. Lancet Cheng AL et al. ASCO Exelixis press release, Oct 16, 2017

5 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 Zeng Z et al. PLoS One Chen Y et al. Hepatology Morales-Kastresana A et al. Clin Cancer Res 2013

6 Immunotherapy in HCC Durvalumab Atezolizumab Nivolumab Pembrolizumab

7 Immunotherapy: Checkpoint blockade, PDR001, Tremelimumab

8 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

9 Phase 1/2 CheckMate 040 Study design Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

10 Phase 1/2 CheckMate 040 Safety results El-Kohueiry AB et al. Lancet 2017

11 Dose expansion HRQoL outcomes Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

12 Dose expansion Efficacy results El-Kohueiry AB et al. Lancet 2017

13 Dose expansion Percent change in tumor burden El-Kohueiry AB et al, Lancet 2017

14 Dose expansion Best percent change in tumor burden El-Kohueiry AB et al, Lancet 2017

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

16 Dose expansion Change in target lesion Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

17 Phase 1/2 CheckMate 040 Response by PD-L1 expression Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

18 Phase 1/2 CheckMate 040 Overall survival Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

19 Phase 1/2 CheckMate 040 First-line ORR Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

20 Updated Results ORR Crocenzi TS et al. ASCO 2017; abstr 4013

21 Updated Results Overall Survival Crocenzi TS et al. ASCO 2017; abstr 4013

22 Updated Results AEs and AFP N=262; median follow-up months ORR (BICR): 14-20%; median DOR: 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

23 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

24 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

25 EMA: Withdrawal of the application

26 Anti-CTLA-4 and PD-1 combination therapy Abou-Alfa GK. ASCO GI 2017

27 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

28 Anti-CTLA-4 and PD-L1 combination therapy Kelley RK et al. ASCO 2017; abstr. 4073

29 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

30 Phase 1/2 randomized study of durvalumab and tremelimumab Kelley RK et al. ASCO 2017; abstr. 4073

31 Novel immune-based approaches in HCC Lee JH et al. Gastroenterology 2015

32 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

33 Regional therapy as a method to augment the immune response Abou-Alfa GK. ASCO GI 2017

34 TACE plus nivolumab Abou-Alfa GK. ASCO GI 2017; NCT

35 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

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

37 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

38 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

39 Il Tumore del Fegato Prospettive Future nel Trattamento dei Tumori Gastrointestinali Thank you!