ViP Rules Out Advanced Pancreatic Cancer OS Benefit For Vandetanib Plus Gemcitabine

Combining vandetanib and gemcitabine does not boost overall survival in patients with advanced pancreatic cancer

medwireNews: Results from the Vandetanib in Pancreatic Cancer (ViP) trial suggest that adding the multiple tyrosine kinase inhibitor (TKI) to gemcitabine does not improve overall survival (OS) for patients with advanced disease.

The phase II multicentre study of the TKI, which acts against VEGFR2, RET and EGFR, included 142 patients with locally advanced or metastatic pancreatic cancer with an ECOG score of 0–2 and a life expectancy of at least 3 months, explain John Neoptolemos, from the University of Liverpool in the UK, and co-workers.

After a median of 24.9 months, 97% of the 72 patients randomly assigned to receive oral vandetanib 300 mg/day plus weekly gemcitabine 1000 mg/m2 for 7 weeks followed by a 1-week break and 3-weekly cycles thereafter died, as did 87% of the 70 patients given placebo plus gemcitabine.

Median OS did not significantly differ in the combined treatment and placebo groups, at 8.83 versus 8.95 months, the ViP investigators report in The Lancet Oncology. One-year survival rates were 36% and 34%, respectively.

The vandetanib plus gemcitabine and placebo plus gemcitabine groups also had comparable rates of objective radiological response (14 vs 13%) and disease control (51 vs 60%).

Multivariate analysis indicated that OS was significantly predicted by poor ECOG performance status (2 vs 0, hazard ratio [HR]=2.29), undifferentiated carcinoma (vs ductal adenocarcinoma; HR=1.88) and C-reactive protein concentration (>8 vs ≤8 mg/L; HR=1.42). By contrast, tissue analysis indicated that the RET polymorphism and immunohistochemistry for RET expression did not predict OS or other clinical markers.

Grade 3–4 adverse events in the combined and placebo groups included neutropenia (49 vs 31%), thrombocytopenia (28 vs 23%), fatigue (24 vs 21%) and leukopenia (17 vs 19%).

But the researchers observe that grade 2 or more severe rash was reported by 19% of vandetanib-treated patients and 6% of controls, with rash occurring after a median of 131 versus 384 days.

And exploratory post-hoc analysis suggested that grade 2 or worse rash might be linked to longer OS in vandetanib-treated patients, at a median of 11.92 months for affected individuals versus 7.76 months for those without a rash. The test for interaction between rash and OS was significant, the authors note.

“This finding adds to existing evidence for the development of rash as a surrogate biomarker of biological activity in patients receiving EGFR tyrosine kinase inhibitors in pancreatic cancer”, write John Neoptolemos et al.

“[H]owever, in view of the small sample size of patients with grade 2 or worse rash (n=14) this finding should be interpreted with caution.”

Nevertheless, they conclude: “Further research should be directed towards tyrosine kinase inhibitors in pancreatic cancer, identifying biomarkers that could predict the development of a rash to vandetanib and also other tyrosine kinase inhibitors in pancreatic cancer.”

Reference

Middleton G, Plamer DH, Greenhalf W, et al. Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol; Advance online publication 1 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30084-0

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