Liver and Biliary Tract Cancers Critical Review

Transcription

1 Liver and Biliary Tract Cancers Critical Review Lorenza Rimassa Oncologia Medica e Ematologia Humanitas Cancer Center Humanitas Research Hospital Rozzano (Milano)

2 Critical review Oral presentations Melero I et al. Nivolumab dose escalation and expansion in patients with advanced HCC: The CheckMate 040 study (Abs 226) Edeline J et al. Gemox versus surveillance following surgery of localized BTC: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial (Abs 225) Poster session Bruix J et al. Survival by pattern of tumor progression during prior sorafenib treatment in patients with HCC in the phase 3 RESORCE trial comparing secondline treatment with regorafenib or placebo (Abs 229) Finn RS et al. Outcomes with sorafenib followed by regorafenib or placebo for HCC: Results of the international, randomized phase 3 RESORCE trial (Abs 344) General session: Hepatobiliary Cancers - New Frontiers of Treatment Abou-Alfa GK. The evolving role of immunotherapy in HCC Breakout session: New Drug Development in Hepatobiliary Cancers. O Reilly EM. Selecting high impact targets Lowy AM. Clinical trials desing: Thinking outside the box

3 Hepatobiliary cancers, predominantly hepatocellular carcinoma (HCC), are the 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 Introduction and Challenges

4 Nivolumab dose escalation / expansion in HCC CheckMate 040 Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

5 Nivolumab dose escalation / expansion in HCC CheckMate 040 Safety profile manageable and consistent across patient cohorts, similar to what observed in other tumor types, no new safety signals Objective responses and long-term survival in sorafenib treated and naïve patients Early, stable and durable responses Efficacy irrespective of HCV, HBV or no infection status PD-L1 expression in tumor cells 70% of patients surviving >9 months Patient-reported quality-of-life measures stable until week 25 Melero I et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 226)

6 NCT ; NCT

7 Immunotherapy HCC Immune modulation plays a key role in HCC genesis Checkpoint inhibitors preliminary data confirm responses and suggest a clinical benefit Safety and viral hepatitis benefit and risk from immune checkpoint inhibitors are still under evaluation Checkpoint inhibitors may also be combined with other agents The role in the adjuvant setting and in combination with locoregional therapy in early/intermediate stage is under investigation Predictive biomarkers are critical: PD-L1 expression was not predictive in the current study Several other biomarkers may hold value for enriching the population who may benefit from nivolumab

8 RESORCE: Survival by pattern of tumor progression during prior S Exploratory analysis New extra-hepatic lesions associated with worse survival regardless of treatment Regorafenib provides OS benefit regardless of the prior pattern of progression Pattern of progression may be a prognostic factor and should be considered for future trials Bruix J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 229)

9 RESORCE: Outcomes with sorafenib followed by regorafenib Exploratory analysis Median time from the start of sorafenib to death Regorafenib 26 mos (95% CI ) Placebo 19.2 mos (95% CI ) Similar results in Asian and non-asian populations Regorafenib provides OS benefit regardless of last sorafenib dose (800 mg/day vs <800 mg/day) Regorafenib safety profile similar when analyzed by last sorafenib dose G3 HFSR, fatigue, anorexia slightly higher in the <800 mg/day subgroup In a select group of patients the sequence of sorafenib followed by regorafenib results in longer survival than reported in other studies (comparison with other first-line studies) Finn RS et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 344)

10 Lenvatinib - multikinase inhibitor Eisai Co., Ltd. announced today that a Phase III clinical trial (Study 304) of its in-house discovered and developed anticancer agent lenvatinib mesylate against the comparator sorafenib as a first-line treatment for patients with unresectable HCC has achieved its primary endpoint 954 patients R 1:1 lenvatinib 8 mg or 12 mg daily vs sorafenib Lenvatinib met the statistical criteria for non-inferiority of OS compared to sorafenib Statistically significant and clinically meaningful improvement for PFS, TTP and ORR EISAI press release, 25 Jan 2017

11 MET-HGF, VEGFR2 and biomarkers Second-line randomized Phase III trial of ramucirmab, a moab against VEGFR2, versus placebo in patients with elevated baseline AFP NCT O Reilly EM Gastrointestinal Cancers Symposium

12 Adjuvant therapy in BTCs High risk of failure despite surgery; 5-yr OS 31% in resected IHCCA; median survival 27 months Negative prognostic factors: positive margins, multiple lesions, vascular invasion, nodal involvement SWOG 0809: EHCCA and GBCA (J Clin Oncol 2015) pt>1 or LN+ or resection margins + Gem/cap followed by chemort 79 patients (EHCCA 68%, GBCCA 32%) 2-yr survival 65%; mos 35 mos Meta-analysis (J Clin Oncol 2012) 6712 patients OS improvement compared with surgery alone, p 0.06 CT or CT-RT better than RT alone, p 0.02 Greatest benefit in patients with positive LN (OR=0.49, p 0.004) and R1 disease (OR=0.36, p 0.002)

13 PRODIGE 12 ACCORD 18 phase III trial in resected BTC Edeline J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 225)

14 PRODIGE 12 ACCORD 18 phase III trial in resected BTC Endpoints 2 Co-primary endpoints Relapse-free survival Quality of life Hypothesis Increase median RFS from 18 to 30 mos (HR=0.60) Secondary endpoints OS, DFS, Tolerability/Toxicity, Translational research Conclusions Adjuvant GEMOX is feasible; toxicity as expected and manageable; no detrimental effect in QoL No difference in RFS between the 2 study arms (30.4 vs 22 mos HR=0.83, p 0.31) Negative trial but prespecified RFS reached Edeline J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 225)

15 Study limits: Sample size, heterogeneous population Javle M Gastrointestinal Cancers Symposium

16 Open issues and future perspectives Analysis of predefined subgroups did not uncover any subgroup that might benefit from adjuvant GEMOX with respect to Primary site of disease Nodal status Extent of resection Ongoing BILCAP trial in the United Kingdom 360 patients Primary endpoint: DFS Capecitabine vs surveillance Open issues: Molecular prognostic biomarkers Slow trial accrual Include high incidence countries (Thailand, India, Chile) in clinical trials

17 BTCs are not a single cancer Javle M Gastrointestinal Cancers Symposium

18 Potential molecular targets Javle M Gastrointestinal Cancers Symposium

19 O Reilly EM Gastrointestinal Cancers Symposium

20 O Reilly EM Gastrointestinal Cancers Symposium

21 Immunotherapy BTCs High frequency of tumor-infiltrating lymphocytes and PD-L1 expression suggest that checkpoint inhibition may be effective BTCs included in basket immunotherapy trials targeting a variety of rare tumors with either PD-1 or combination PD-1 and CTLA-4 blockade Potential benefit from assessing the DNA MMR system as a potential predictive biomarker of response to checkpoint inhibitors MSI may produce neoantigens that can be recognized and targeted by T cells in several noncolorectal cancer models, including BTCs Primary sclerosing cholangitis, associated with 30% of cholangiocarcinomas, may be a contraindication to checkpoint blockade

22 O Reilly EM Gastrointestinal Cancers Symposium

23 Conclusions HCC and BTCs Immunotherapy may become a potent weapon in the limited arsenal of HCC therapy if the early success is confirmed Regorafenib exploratory analyses: OS by prior pattern of progression, by last sorafenib dose, sequence of sorafenib followed by regorafenib No role for routine adjuvant therapy in resected BTCs, especially for low risk patients, high risk patients should be offered clinical trials Lowy A Gastrointestinal Cancers Symposium

24 Conclusions HCC and BTCs Development and conduct of clinical trials are challenging due to small sample size (especially for BTCs; subgrouping creates still smaller cohorts) lack of distinction among different subgroups (heterogeneity) enrollment not guided by genomic / biomarker analyses severity of the disease; frequent underlying liver cirrhosis The past decade has been marked by negative phase III studies in HCC, many without strong rational and/or support from phase II data Trial designs using biomarkers, tissue collection and strong signals in early phase trials are needed prior to advance to phase III Better understanding of genetic/molecular drivers and the role of the tumor microenvironment may result in novel putative targets and therapeutics New trial concepts (e.g., adaptive designs, enrichment, umbrella strategies) should be used to detect robust signals and use pt accrual most efficiently Lowy A Gastrointestinal Cancers Symposium

25 Liver and Biliary Tract Cancers Critical Review Thank you!