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. 2015 Sep 29;6(29):28453-62.
doi: 10.18632/oncotarget.4601.

Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials

Ishwaria M Subbiah  1 , Gerald S Falchook  2 , Ahmed O Kaseb  3 , Kenneth R Hess  4 , Apostolia M Tsimberidou  2 , Siqing Fu  2 , Vivek Subbiah  2 , David S Hong  2 , Aung Naing  2 , Sarina A Piha-Paul  2 , Owais Akmal  3 , Filip Janku  2 , Razelle Kurzrock  5
Affiliations

Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials

Ishwaria M Subbiah et al. Oncotarget. .

Abstract

Purpose: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies.

Methods: We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004.

Results: Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013).

Conclusions: In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.

Keywords: clinical trials; management; novel therapeutics; systemic therapy; targeted agents.

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Conflict of interest statement

CONFLICTS OF INTEREST

Razelle Kurzrock (Honoraria and research funding from Roche, Genentech, and AstraZeneca); Filip Janku (Research funding from Novartis). All other authors have no disclosures.

Figures

Figure 1
Figure 1. Waterfall plot showing the best responses to phase I therapy per RECIST
Figure 2
Figure 2. Progression-free survival of patients treated on phase I trials when compared to their first-line, second-line and last systemic antitumor therapy given in advanced setting prior to phase I referral
See this image and copyright information in PMC

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