A randomized phase II study of vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led study.

Abstract

67 Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated, metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts (V/P 60/64) enrolled at 20 sites between 10/09-2/12. Pt characteristics (V/P): median age 58/62; ECOG PS 0: 23 (40%) / 30 (47%); male 39 (65%) / 53 (83%); GEJ 37 (62%) / 39 (61%); diffuse histology 20 (43%) / 14 (30%). Median number of FOLFOX cycles 9.5/11. Most common Gr ≥3 toxicities: (% pts V/P) neutropenia 50.0/31.7 (p=0.07), neuropathy 23.1/14.3 (p=0.33), fatigue 15.4/9.5 (p=0.50), thrombosis 13.5/11.1 (p=0.92), anemia 9.6/9.5 (p=0.99), hypokalemia 9.6/4.8 (p=0.52), nausea 7.7/9.5 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in ITT population 11.5/9.3 mo (95% CI 8.5-14.4/6.7-11.9; p=0.34) and median OS 12.2/13.9 mo (95% CI 10.2-14.3/11.5-16.3; p=0.48). Non-statistically significant trends toward improved PFS with V were noted in female pts, diffuse histology, and PS 1 (p≤ 0.08). RR (%) 33/27 (p=0.64). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06 Clinical trial information: NCT00982592.

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

“…Median overall survival was 12.2 months in the treatment arm compared to 13.9 months in the placebo arm. Unfortunately, this difference was also not found to be statistically significant (p=0.48) [127]. Currently, there is no planned clinical trial studying this agent in gastric cancer.…”

Recent trend in gastric cancer treatment in the USA

“…Two stemness related pathways, Hedgehog and signal transducer and activator of transcription 3 (STAT3) pathway, were assessed in clinical trials so far. Vismodegib, which inhibit Hedgehog signals by binding smoothened (SMO), in combination with FOLFOX was assessed in phase 2, but did not benefit PFS (11.5 months vs. 9.3 months; P = 0.34) [54] . Moreover, BRIGHTER study assessed napabucasin, STAT3 inhibitor, in combination with paclitaxel [55] .…”

Genomic landscape of gastric cancer: molecular classification and potential targets

“…The hedgehog pathway inhibitors, vismodegib, which was approved in 2012 by the FDA for the treatment of locally advanced and metastatic basal cell carcinoma (BCC) (Chang et al, 2014;Sandhiya et al, 2013;Wilkes, 2012), has also been employed in the treatment of advanced gastric and gastroesophageal junction cancer. Patients administered FOLFOX and vismodegib simultaneously, achieved better median overall survival (vismodegib+FOLFOX, 14.9 months compared to FOLFOX, 11.5 months) (NCT00982592) (Cohen et al, 2013). BMS-833923, another SMO inhibitor, has also been combined with cisplatin and capecitabine for the treatment of inoperable metastatic gastric or gastroesophageal cancer patients (NCT00909402).…”