FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: A randomized placebo-controlled multicentric AIO phase II trial.

Abstract

4086 Background: Sunitinib is an receptor tyrosine kinase (RTK) inhibitor of VEGFR1-3, PDGFR-α-β, and other RTK. After we established Sunitinib (Sun) alone associated with limited response rate (RR) and good tolerability in refractory advanced esophagogastric cancer patients (Moehler et al. EUR J Cancer. 2011, 47: 1511), this double-blinded placebo-controlled phase II evaluated safety and efficacy of SUN as add-on in second-line or third-line FOLFIRI (ClinicalTrials.gov NCT01020630). Methods: Patients with failure of any prior docetaxel and/or platinum-based chemotherapy were randomized to receive 6-week cycles including FOLFIRI two weekly and SUN (25 mg) versus (vs) placebo (PLA) daily for 4 consecutive weeks followed by a 2-week rest. Primary endpoint was progression-free survival (PFS). Results: 91 randomized patients (ITT) had similar characteristics in both groups (SUN/PLA 45/46). Both groups had 2.7 treatment cycles. Objective RR was 20/29%, and tumor control rate was 58/56 % for SUN/PLA, respectively. Median PFS was similar for SUN vs. PLA with 3.6 vs. 3.3 months, respectively (HR 1.11; 95%CI 0.70-1.74, P = 0.66). Median overall survival (OS) was longer for SUN vs. PLA with 10.5 vs. 9.0 months, in ITT (HR 0.816; 95%CI 0.50 - 1.34, P = 0.42, one-sided 0.21) and in the per protocol population (HR 0.71; 95%CI 0.41 - 1.24, P = 0.23) respectively. No unexpected higher toxicities, SAE or SUSAR occurred with SUN. For SUN/PLA, all grade AEs (%) possibly related to study drug were nausea 49/47%, fatigue 36/29%, vomiting 27/29%, diarrhoea 36/38%, neutropenia 62/22%, stomatitis 27/20%, and palmar-plantar erythrodysaesthesia 13/3%, and Grade 3+ AEs (%) were neutropenia 56/20%, diarrhoea 2/13%, nausea 7/7%, fatigue 0/9% and pain 0/9%, respectively. Performed quality of life outcomes were mostly in favor of Sunitinib. Conclusions: In our phase II trial, Sunitinib added to FOLFIRI increased hematotoxicity and did not improve response rates or PFS in chemotherapy-resistant GC patients. Since the regimen was safe and patients had a trend to better OS, biomarker analyses will be performed to identify subgroups that benefit from add-on Sunitinib. Clinical trial information: NCT01020630.

Efficacy and safety of angiogenesis inhibitors in advanced gastric cancer: a systematic review and meta-analysis

“…The sample size in the included trials varied from 91 to 774, the median age of the enrolled patients ranged from 52 to 65 years. Of these, two studies [ 25 , 26 ] enrolled patients who were treated with anti-VEGF-based drugs, five studies [ 9 – 11 , 13 , 27 ] enrolled patients who were treated with anti-VEGFR-2 agents, and three trials [ 18 , 23 , 24 ] enrolled patients who were treated with inhibitors of multiple tyrosine kinases (one of the targets is VEGFR-2). Four trials [ 18 , 25 – 27 ] were conducted in the first-line setting and the other six trials [ 9 – 11 , 13 , 23 , 24 ] in the pretreatment setting.…”

“…All included studies [ 9 – 11 , 13 , 18 , 23 – 27 ] reported OS, and nine trials [ 9 – 11 , 13 , 18 , 24 – 27 ] reported PFS. One study [ 23 ] reported time to progression (TTP).…”

A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers

“…Results showed that PFS at 24 weeks was 25% (90% CI: 12–42%), which was not improved from historical control ( Schmitt et al , 2012 ). In addition, a randomised placebo-controlled phase II study of FOLFIRI with or without sunitinib in 91 patients with advanced GE cancers showed that median PFS was similar in the sunitinib vs placebo arm (3.6 vs 3.3 months, respectively, HR 1.11, 95% CI: 0.70–1.74, P =0.66; Moehler et al , 2013 ).…”

Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials

“…Comparison of treatment with the FOLFIRI (irinotecan, leucovorin, and fluorouracil) regimen plus sunitinib versus FOLFIRI alone in patients with advanced chemotherapy-refractory esophagogastric cancer, showed that sunitinib added to FOLFIRI increased hematotoxicity and did not improve ORR or PFS in chemotherapy-resistant patients. 59 …”