Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma

Abstract

Purpose: The primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapy-naive patients with metastatic melanoma.

Patients and methods: In this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m(2) intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity.

Results: In all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P = .878). Median progression-free survival was 4.9 months for CPS and 4.2 months for CP (P = .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P = .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P = .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference.

Conclusion: Sorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.

Trial registration: ClinicalTrials.gov NCT00110019.

Fig 1.

CONSORT diagram. AJCC, American Joint Committee on Cancer; AUC, area under the [concentration-time] curve; BID, twice per day; CP, carboplatin/paclitaxel; CPS, carboplatin/paclitaxel/sorafenib; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL-2, interleukin-2; IV, intravenously; PO, orally.

Fig 2.

Trial schema. (*) Patients must have a history of melanoma of cutaneous, mucosal, or unknown primary site. Patients must not have ocular melanoma. (†) After four cycles of chemotherapy, the dose of both chemotherapy agents will be reduced by 25% for patients who have not yet had a dose reduction during earlier cycles. (‡) Sorafenib or placebo will be administered twice daily (approximately 12 hours between doses) from day 2 to day 19 of a 21-day cycle. If chemotherapy cannot be administered on schedule for any reason, patients will not be given sorafenib or placebo until day 2 of the next cycle. (§) Patients are eligible to continue sorafenib or placebo until progression after chemotherapy has been discontinued. For patients who are stable or continue to demonstrate partial or complete response, it is recommended that chemotherapy be discontinued after 10 cycles or sooner in the case of unacceptable toxicity. After the cessation of chemotherapy, sorafenib or placebo will be taken twice daily continuously throughout the cycle. AJCC, American Joint Committee on Cancer; AUC, area under the [concentration-time] curve; ECOG, Eastern Cooperative Oncology Group; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL-2, interleukin-2; IV, intravenously; PO, orally.

Fig 3.

(A) Overall survival, determined by using the Kaplan-Meier method for the intention-to-treat population, from time of study registration. (B) Progression-free survival; two patients who were inevaluable for progression-free survival were excluded. CP, carboplatin/paclitaxel; CPS, carboplatin/paclitaxel/sorafenib.

Fig 4.

(A) Overall survival and (B) progression-free survival (PFS) for a subset of patients with increased lactate dehydrogenase at baseline from the time of study registration determined by using the Kaplan-Meier method. CP, carboplatin/paclitaxel; CPS, carboplatin/paclitaxel/sorafenib.