TY - JOUR
T1 - Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma
T2 - An analysis of targeted therapy phase 1 trials
AU - Subbiah, Ishwaria M.
AU - Falchook, Gerald S.
AU - Kaseb, Ahmed O.
AU - Hess, Kenneth R.
AU - Tsimberidou, Apostolia M.
AU - Fu, Siqing
AU - Subbiah, Vivek
AU - Hong, David S.
AU - Naing, Aung
AU - Sarina, A. Piha Paul
AU - Akmal, Owais
AU - Janku, Filip
AU - Kurzrock, Razelle
PY - 2015
Y1 - 2015
N2 - 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 progressionfree 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.
AB - 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 progressionfree 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.
KW - Clinical trials
KW - Management
KW - Novel therapeutics
KW - Systemic therapy
KW - Targeted agents
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U2 - 10.18632/oncotarget.4601
DO - 10.18632/oncotarget.4601
M3 - Article
C2 - 26164085
AN - SCOPUS:84944449976
SN - 1949-2553
VL - 6
SP - 28453
EP - 28462
JO - Oncotarget
JF - Oncotarget
IS - 29
ER -