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Sorafenib combined with carboplatin, paclitaxel failed to improve OS in advanced melanoma
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The addition of sorafenib to carboplatin and paclitaxel did not improve OS among chemotherapy-naive patients with advanced melanoma, according to results of a randomized, placebo-controlled phase 3 study.
Previous research examined novel immunologic and oncogene-directed therapies for patients with metastatic melanoma. Median survival remained less than 14 months, and long-term survival was less than 20%, according to background information provided by researchers.
The primary objective of the current double blind study was to determine whether the combination of carboplatin, paclitaxel and sorafenib (CPS; Nexavar, Bayer Pharmaceuticals) improved OS compared with carboplatin and paclitaxel in chemotherapy-naive patients with advanced melanoma.
Keith T. Flaherty, MD, director of developmental therapeutics at Massachusetts General Hospital, and colleagues evaluated 823 patients between 2005 and 2008.
The researchers randomly assigned patients to receive CP (n=413) or CPS (n=410). All patients received carboplatin at area under the curve 6 and 225 mg/m² of paclitaxel intravenously once every 21 days. Patients in the CPS arm received 400 mg sorafenib orally, twice per day, on days 2 through 19 of a 21-day cycle. Patients in the CP arm received placebo.
OS served as the primary outcome. Secondary endpoints included PFS, objective tumor response and toxicity.
Median OS among patients in the CP arm was 11.3 months (95% CI, 9.8-12.2) vs. 11.1 months (95% CI, 10.3-12.3) for patients in the CPS arm. The difference was not statistically significant.
Median PFS was 4.9 months among patients in the CPS arm vs. 4.2 months for patients in the CP arm (P=.092). More patients on the CPS arm obtained grade 3 or higher toxicities (84% vs. 74%; P=.027). Adverse effects included increased rash, hand-foot syndrome and thrombocytopenia.
“Sorafenib does not improve OS, PFS or response rate in combination with carboplatin and paclitaxel in chemotherapy-naive patients with metastatic melanoma,” Flaherty and colleagues concluded.
Disclosure: Flaherty serves as a consultant for Onyx Pharmaceuticals. Other researchers involved in the study report funding from and consulting roles with CureTech, Genentech, GlaxoSmithKline and Merck.
Perspective
Back to TopNikhil I. Khushalani, MD
Although it is a negative study, the results provide valuable information. Sorafenib exerts its effects through inhibition of RAF-kinase and VEGF. The newer RAF-kinase inhibitors are more specific and thus more efficacious than sorafenib in melanoma. Sorafenib likely exerts its anti-tumor effects in melanoma via VEGF inhibition rather than RAF-kinase inhibition at the doses that are currently used and tolerable in clinical practice. The added toxicity seen in the sorafenib-containing arm is not surprising and is consistent with the known adverse effect profile of this drug. The control arm in this trial performed better than predicted (OS of 11.3 months compared with the 9 months that was assumed in the statistical design). But the median PFS was similar to that reported in previous trials. One can speculate that subsequent therapy — after progression on carboplatin and paclitaxel — in these patients may have contributed to this.
This study sets the benchmark for combination chemotherapy in advanced melanoma. It suggests that anti-angiogenic therapy should continue to be investigated in melanoma, especially in patients who have an elevated lactate dehydrogenase level (a negative prognostic indicator), as this may be a subset that may benefit. If feasible, it may be of use to examine the NRAS mutational status of the collected tumor tissue on this trial and determine if there was any effect of sorafenib plus chemotherapy in the NRAS-mutant population (this is seen in approximately 20% of melanomas).
This study gives credence that there remains a role for chemotherapy in advanced melanoma despite the availability of newly approved drugs and more in the offing. This is particularly important for patients who may need a rapid tumor response but do not harbor the BRAF V600 mutation and hence are not candidates for BRAF inhibitor therapy such as vemurafenib (Zelboraf, Daiichi-Sankyo). In these patients, immunotherapy may not be a viable option as response to immunotherapy may be delayed for several weeks or even months. It may be reasonable to use chemotherapy as a bridge to immunotherapy here.
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