In our study, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of tumor progression in patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation, as compared with dacarbazine. Benefit was seen in all subgroups of patients who were included in the analysis, including patients with stage M1c disease or an elevated lactate dehydrogenase level, both of which are associated with particularly poor prognoses.
Recently, ipilimumab, an anti-CTLA4 antibody, was shown to improve overall survival in patients with metastatic melanoma, as compared with a peptide vaccine, although there was only a modest effect on rates of response and progression-free survival.8
The use of ipilimumab combined with dacarbazine has also been associated with improved rates of survival over dacarbazine alone.9
Overall, 48% of the patients who were treated with vemurafenib met the criteria for a confirmed response, although most patients had some tumor shrinkage. This finding was consistent with the confirmed response rates seen in the phase 1 extension cohort15
and in a recent phase 2 trial involving previously treated patients.16
Furthermore, 4 of 10 patients with the BRAF V600K mutation had a response to vemurafenib, indicating that melanomas with this variant are also sensitive to vemurafenib.
The confirmed response rate in the dacarbazine cohort was 5%, which is slightly lower than that in recent phase 3 trials.4-7
Our study was a randomized trial comparing vemurafenib with dacarbazine in which only patients with BRAF-mutated melanomas were treated. Recent studies have raised the possibility that melanomas with the BRAF V600E mutation are more aggressive18,19
and less sensitive to chemotherapy18,20
than BRAF wild-type melanomas. Also, 48 patients (14%) in the dacarbazine group (29 of whom were available for evaluation in this report) did not receive any treatment, most commonly because the patient withdrew consent (Fig. A in the Supplementary Appendix
). Patients receiving vemurafenib reported relatively few grade 3 or worse adverse events. Other than cutaneous squamous-cell carcinoma and keratoacanthomas, the most common drug-related grade 3 (or worse) toxic effects were rash, arthralgias, photosensitivity, and fatigue. Overall, 38% of the patients receiving vemurafenib required dose modification because of adverse events.
Among patients treated with vemurafenib, 18% were reported to have at least one squamous-cell carcinoma of the skin or keratoacanthoma. These lesions were excised, and none required dose modification of vemurafenib. These rates are slightly lower than those in the phase 1 and 2 trials of vemurafenib,15,16
probably because of shorter follow-up in our study. Cutaneous squamous-cell cancer and keratoacanthomas have also been seen in patients treated with sorafenib,21,22
another compound with inhibitory activity against RAF kinases. No other secondary neoplasia was observed in our patients.
The mechanism of the induction of cutaneous neoplasia is under investigation, but it is speculated to involve the activating effect of vemurafenib on preneoplastic cells in which wild-type BRAF is further primed by upstream pathway activation. Several investigators have shown that vemurafenib and other inhibitors of RAF kinases can potentiate the activity of the MAPK pathway in cells with wild-type BRAF.23-25
This finding might explain the favorable therapeutic index of vemurafenib in patients who have melanoma with the BRAF V600E mutation but also suggests that vemurafenib could accelerate the growth of some tumors with wild-type BRAF.
An important, related ongoing effort by many research groups is to clarify how melanomas become resistant to vemurafenib. Initial studies from several groups have indicated that the MAPK pathway is reactivated in resistant tumors.26-28
Although the precise mechanisms of reactivation are still being investigated, gatekeeper mutations in BRAF, which would prevent vemurafenib from binding BRAF, have not been observed.
Our results show that single-agent vemurafenib improved the rates of response and of both progression-free and overall survival, as compared with dacarbazine, in patients with metastatic melanoma with the BRAF V600E mutation. These findings provide a solid foundation for the development of future combination therapies.