Liver and Biliary Tract Cancers Highlights

Lorenza Rimassa

Oncologia Medica e Ematologia

Humanitas Cancer Center

Humanitas Research Hospital

Rozzano (Milano)

Liver and Biliary Tract Cancers

Highlights

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Hepatocellular Carcinoma (HCC) - Outline and Disclosure

Two General Sessions

• Innovative Approaches to Hepatopancreatobiliary Disease.

Appropriate title: Innovative Approaches to Pancreatic Disease

• Hepatocellular Carcinoma Tumor Board. Finn RS: Medical

Oncologist (Panelist): Video unavailable

Two Oral Presentations

• Abou-Alfa GK (Venook AP) et al: Phase III randomized study of

sorafenib plus doxorubicin versus sorafenib in patients with

advanced HCC: CALGB 80802 (Alliance) (Abstract 192). Slides,

video, and poster unavailable

• Rimassa L et al: Tumor and circulating biomarker analysis from the

randomized controlled phase 2 trial of tivantinib in second-line HCC

(Abstract 197)

Biliary Tract Cancers (BTCs) - Outline

One Breakout Session

• Valle JW: Bile Duct Cancer

One Expert Editorial on GI Cancers Symposium Daily News,

Saturday January 23

• Mody K & Patel T: Precision Medicine for Cholangiocarcinoma

First-line

Child-Pugh A

ECOG PS 0-1

Stratification by

extent of disease (locally

advanced vs metastatic)

Randomization 1:1

(Planned N=480; N=346*)

Sorafenib 400 mg PO BID + Doxorubicin 60 mg/m2 iv q 21 days

(N=173)

Sorafenib 400 mg PO BID

(N=173)

CALGB 80802 (Alliance) - Sorafenib +/- doxorubicin phase III trial

Abou-Alfa GK et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 192)

Background

• Randomized phase 2 study in 96 pts comparing doxorubicin (D) to

doxorubicin plus sorafenib (D+S): OS: 6.5 vs 13.7 mos, p=0.006 (JAMA 2010)

Primary endpoint: OS

Secondary endpoint: PFS

*Study halted after accrual of

346 pts due to futility at planned

interim analysis

Results

• Efficacy for D+S vs S

• OS: 9.3 vs 10.5 mos, HR: 1.06 (95%CI: 0.8-1.4)

• PFS: 3.6 vs 3.2 mos, HR: 0.90 (95%CI: 0.72-1.2)

• Safety for D+S vs S

• Grade 3-4 hematologic adverse events (AEs): 37.8% vs 8.1%

• Non-hematologic AEs and deaths: comparable

Conclusions

• D+S resulted in higher toxicity and did not improve OS or PFS

• The S mOS of about 10 months is consistent with previous reports

CALGB 80802 (Alliance)

Abou-Alfa GK et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 192)

Rimassa L et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 197)

Biomarker analysis from phase 2-3 trials of tivantinib in 2nd line HCC

• MET is the HGF TK receptor, involved in HCC progression and metastasis

• Tivantinib is an oral ATP-independent MET inhibitor active in MET-High pts1-4

• ARQ 197-215, a multi-center, phase 2 RCT of tivantinib in 107 pts, met the

primary aim and the predefined secondary efficacy endpoints in MET-High pts

• Exploratory endpoints included biomarkers correlation with efficacy endpoints

• METIV-HCC is an ongoing phase 3 trial enrolling about 303 MET-High pts

• Circulating MET, HGF, and AFP were centrally tested; median values (AFP:

also 75th percentile) and 10% changes from baseline were set as cut-offs

• Tumor MET was centrally tested (IHC); MET-High: ≥2+ in ≥50% of tumor cells

1Santoro A, Lancet Oncol 2013. 2Scagliotti G, J Clin Oncol 2015.

3Eng C, Int J Cancer 2016 in press. 4Monk P, J Clin Oncol 2015;33 suppl 7, abs 146

ITT Baseline N=102 Median OS Patients Events

Low (<median) 8.9 mos 51 40

High (≥median) 4.6 mos 51 42

HR: 0.42 (95% CI: 0.20-0.91) p=0.02

Baseline median circulating MET concentration: 13.26ng/mL (1.29-49.8ng/mL)

Circulating MET as a Prognostic Factor

HR: 0.61 (95% CI: 0.39-0.94) p=0.03

Placebo Baseline N=34 Median OS Patients Events



Presented by: Lorenza Rimassa, MD

Trend in predictive value for circulating MET-High: tivantinib vs placebo HR: 0.55, p=0.07

(interaction test not significant)

Circulating MET as a Pharmacodynamic Biomarker

ITT: 12.3 mos in 37 pts ≥10%, 6.6 mos in 49 pts <10%, HR: 0.50 (95%CI: 0.30-0.83), p=0.006

Tivantinib N=56 Median OS Patients Events

≥10% 13.3 mos 24 16

<10% 6.3 mos 32 26

HR: 0.46 (95% CI: 0.24-0.86) p=0.01

Placebo N=30 Median OS Patients Events

≥10% 6.2 mos 13 10

<10% 7.9 mos 17 15

HR: 0.64 (95% CI: 0.28-1.49) p=0.3

Patients with best circulating MET reduction from baseline by ≥10% versus <10%

Median best MET change in patients stable at 6 weeks: -37.9% on tivantinib, +18.4% on placebo


Circulating HGF as a Prognostic Factor

Baseline median circulating HGF concentration: 2307 pg/mL (421-58080 pg/mL)

ITT Baseline N=102 Median OS Patients Events



HR: 0.60 (95% CI: 0.39-0.94) p=0.02

ITT Best Change N=86 Median OS Patients Events

≥10% 9.8 mos 39 29

<10% 6.5 mos 47 38

HR: 0.60 (95% CI: 0.36-0.98) p=0.04


Results were overall confirmed when analyzed by treatment arm

Circulating AFP as a Prognostic Factor Baseline median: 186 (1.5-440008) IU/mL. Baseline 75th percentile (Q3): 3507.50 IU/mL

AFP <median vs AFP ≥median HR: 0.75 (95% CI: 0.48-1.15), p=0.18

No difference by best AFP change from baseline observed in 43 patients with AFP ≥20 IU/mL

ITT Baseline by Q3 N=104 Median OS Patients Events

<75th percentile 7.9 mos 78 58

≥75th percentile 3.0 mos 26 25

HR: 0.36 (95% CI: 0.22-0.58) p<0.0001


Baseline Tumor MET Status

1Shi B, J Histochem Cytochem 2013

H-score: percentage of cells staining per the intensity of the stain1

Tum

or

H-S

core


H-Score Median Min Max

MET-High Patients 175 120 300

MET-Low Patients 40 0 125 Correlations: none between tumor MET, circulating MET, HGF; possible between AFP and tumor and circulating MET

MET-High Samples

(rate)

Tested samples (N=77) 37 (48%)

Samples with available biopsy date (N=72)

36 (50%)

Tumor samples taken before sorafenib (N=55)

22 (40%)

Tumor samples taken after sorafenib (N=17)

14 (82%)

Median OS Patients Events

Placebo MET-Low 9.0 mos 13 9

Tivantinib MET-High 7.2 mos 22 17

Tumor MET as a Prognostic and Predictive Factor

Significant interaction test for tivantinib and tumor MET status in terms of OS (p=0.04)

HR: 0.72 (95% CI: 0.30-1.70) p=0.45

Median OS Patients Events

Placebo MET-Low 9.0 mos 13 9

Placebo MET-High 3.8 mos 15 15

HR: 0.34 (95% CI: 0.13-0.86) p=0.02


Tivantinib vs placebo in 40 MET-Low patients: HR: 1.33 (95% CI: 0.58-3.04), p=0.50

MET-High Samples

(rate)

Tested samples (N=1138) 576 (51%)

Samples with available biopsy date (N=925)

527 (57%)

Tumor samples taken before sorafenib (N=438)

173 (39%)

Tumor samples taken after sorafenib (N=487)

354 (73%)

METIV-HCC: Baseline Tumor MET Status* Tu

mo

r H

-Sco

re


*Data are preliminary, from non-cleaned database, from biopsied patients regardless of their enrolment status

H-Score Median Min Max

MET-High Patients 170 120 300

MET-Low Patients 90 0 180

MET-Low to MET-High Conversion

71 patients were MET-Low at biopsy taken before sorafenib and were re-biopsied after sorafenib

50 out of 71 (70%) converted to MET-High at the biopsy taken after sorafenib

Correlations

Between High MET status and treatment with sorafenib, p<0.0001

No correlation between MET status and other factors related to prior therapies


METIV-HCC: Baseline Tumor MET Status*

Before sorafenib After sorafenib

Subject remained MET-Low

Subject became MET-High (median H-Score increase: 114)

Tum

or

H-S

core

Rimassa L et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 197)

Conclusions from the phase 2 trial

• Circulating MET, HGF, and AFP by 75th percentile hold a prognostic value

• Circulating MET is a pharmacodynamic biomarker for tivantinib

• Tumor MET is the only prognostic and predictive biomarker, and is more

frequently “High” after sorafenib

• This analysis supports the use of tivantinib in MET-High pts only

Conclusions from the phase 2 and 3 trials

• Tumor MET results are comparable, strict criteria can make MET IHC more

reliable

• Tumor MET is more frequently “High” after sorafenib as the tumor becomes

more aggressive

• The METIV-HCC trial will validate the role of the analyzed biomarkers

Biomarker analysis from phase 2-3 trials of tivantinib in 2nd line HCC

Presented By Juan Valle at TBD

Bile Duct Cancer

Recent advances in

the understanding

of the genomics of

BTCs offer new

opportunities for

more effective

systemic

therapeutic

approaches that

could improve

outcomes


• Some genomic alterations (e.g., KRAS, TP53, MAPK/mTOR) are associated with a worse prognosis

• Others (e.g., FGFR) correlate with a relatively indolent disease

Limitations of clinical studies

• enrollment not guided by genomic / biomarker analyses

• e.g., CALGB 80802

• lack of distinction among different subgroups (heterogeneity)

• small sample size (especially for BTCs)

Clinical / translational studies may identify genomic changes or

molecular-defined subgroups associated with clinically actionable

factors indicative of drug sensitivity, leading to a truly personalized

therapeutic approach

The use of genomic / biomarker-guided strategy is a meaningful

alternative approach to identify effective therapies

• e.g., MET / tivantinib

Conclusions – HCC and BTCs

Liver and Biliary Tract Cancers

Highlights

Thank you!

Liver and Biliary Tract Cancers Highlights

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