Lorenza Rimassa

Oncologia Medica e Ematologia

Humanitas Cancer Center

Humanitas Research Hospital

Rozzano (Milano)

Liver and Biliary Tract Cancers

Critical Review

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 second-

line 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

• 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

Nivolumab dose escalation / expansion in HCC – CheckMate 040

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

• 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

Nivolumab dose escalation / expansion in HCC – CheckMate 040

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

NCT02576509; NCT02702401

• 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

Immunotherapy – HCC

RESORCE: Survival by pattern of tumor progression during prior S

Bruix J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 229)

• 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

Finn RS et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 344)

RESORCE: Outcomes with sorafenib followed by regorafenib

• Exploratory analysis

• Median time from the start of sorafenib to death

• Regorafenib 26 mos (95% CI 22.6-28.1)

• Placebo 19.2 mos (95% CI 16.3-22.8)

• 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)

• “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

Lenvatinib - multikinase inhibitor

O’Reilly EM. 2017 Gastrointestinal Cancers Symposium

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 NCT02435433

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)

PRODIGE 12 – ACCORD 18 phase III trial in resected BTC

Edeline J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 225)

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

PRODIGE 12 – ACCORD 18 phase III trial in resected BTC

Edeline J et al. J Clin Oncol 35, 2017 (suppl 4S; abstr 225)

Javle M. 2017 Gastrointestinal Cancers Symposium

Study limits: Sample size, heterogeneous population

• 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

Open issues and future perspectives

Javle M. 2017 Gastrointestinal Cancers Symposium

BTCs are not a single cancer

Javle M. 2017 Gastrointestinal Cancers Symposium

Potential molecular targets

O’Reilly EM. 2017 Gastrointestinal Cancers Symposium

O’Reilly EM. 2017 Gastrointestinal Cancers Symposium

• 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

Immunotherapy – BTCs

O’Reilly EM. 2017 Gastrointestinal Cancers Symposium

• 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. 2017 Gastrointestinal Cancers Symposium

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. 2017 Gastrointestinal Cancers Symposium

Conclusions – HCC and BTCs

Liver and Biliary Tract Cancers

Critical Review

Thank you!