Vemurafenib

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

A total of 675 patients were evaluated for OS. Although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the dacarbazine arm.

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

The HRdeath in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor stage, LDH level, and geographical region.

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

The HR for tumor progression was 0.26 (95% CI, 0.20–0.33; P < .001) in the vemurafenib arm. The estimated median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the dacarbazine arm.

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

Twenty patients had non-BRAF V600E pathogenic variants: 19 with BRAF V600K and 1 with BRAF V600D. Four patients with BRAF V600K pathogenic variants had a response to vemurafenib.

Previously untreated patients. The approval of vemurafenib was supported by an international multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for BRAF V600 pathogenic variants and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test.[21] Patients were randomly assigned to receive either vemurafenib (960 mg by mouth twice a day) or dacarbazine (1,000 mg/m2 IV every 3 weeks). Coprimary end points were rates of OS and PFS. At the planned interim analysis, the DMSB determined that both the OS and PFS end points had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib.[21][Levels of evidence A1 and B1]

Adverse events required dose modification or interruption in 38% of patients who received vemurafenib and 16% of those who received dacarbazine. The most common adverse events with vemurafenib were cutaneous events, arthralgia, and fatigue. Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both developed in 18% of patients and were treated by simple excision. The most common adverse events with dacarbazine were fatigue, nausea, vomiting, and neutropenia. For more information, visit Fatigue and Nausea and Vomiting Related to Cancer Treatment.

Previously treated patients. A multicenter phase II trial included 132 patients with BRAF V600E or BRAF V600K pathogenic variants. Patients received vemurafenib (960 mg by mouth twice a day). Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more previous therapies for advanced disease. Median follow-up was 12.9 months.[22][Level of evidence C3]

Previously treated patients. A multicenter phase II trial included 132 patients with BRAF V600E or BRAF V600K pathogenic variants. Patients received vemurafenib (960 mg by mouth twice a day). Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more previous therapies for advanced disease. Median follow-up was 12.9 months.[22][Level of evidence C3]

An independent review committee (IRC) reported a response rate of 53% (95% CI, 44%–62%), with eight patients (6%) achieving a complete response.

Previously treated patients. A multicenter phase II trial included 132 patients with BRAF V600E or BRAF V600K pathogenic variants. Patients received vemurafenib (960 mg by mouth twice a day). Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated LDH level. All patients had received one or more previous therapies for advanced disease. Median follow-up was 12.9 months.[22][Level of evidence C3]

Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiological assessment at 6 weeks. However, some patients did not respond until after receiving therapy for more than 6 months.