Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation (phase 3 study results)
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- full text study results publication following editorial below
Been There, Not Done That - Melanoma in the Age of Molecular Therapy
Marc S. Ernstoff, M.D.
From Dartmouth Medical School and the Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.
N Engl J Med 2011; 364:2547-2548 June 30, 2011
In 1976, the detection of estrogen-receptor expression in melanomas ushered in the era of targeted therapy in melanoma, although we did not use that term back then.1 In 1992, Cocconi et al. found that dacarbazine plus tamoxifen provided a higher response rate and longer survival than dacarbazine, but only in women.2 Subsequently, whether melanoma cells express estrogen receptors was questioned, and the efficacy of tamoxifen could not be confirmed. Since then, the drug has not been used to treat melanoma. However, molecular analysis of tumors has revealed specific growth-promoting pathways in human cancers that have become targets for therapy.
BRAF is a member of the Raf kinase family, which signals from growth factor receptors on the cell surface to the nucleus.3 The most common mutation in BRAF (BRAF V600E) is found in 30 to 60% of melanomas.3 BRAF V600E constitutively activates the MAPK-ERK signal-transduction pathway, which enhances the proliferative and metastatic potential of tumor cells. Sorafenib, the first BRAF-targeted agent that has been studied in metastatic melanoma, has not shown major clinical effects in this disease and is now recognized as a weak BRAF kinase inhibitor.
In a phase 1 study, the use of the selective BRAF V600E kinase inhibitor vemurafenib (PLX4032) was associated with a response rate of 69% in patients with melanoma with tumors that harbored the BRAF V600E mutation.4 In this issue of the Journal, Chapman and colleagues report the results of a phase 3 study, called BRAF Inhibitor in Melanoma 3 (BRIM-3), in which patients with metastatic melanoma with the BRAF V600E mutation were randomly assigned to receive vemurafenib or dacarbazine.5 The treatment response was determined by the investigators. During the trial, an independent data and safety monitoring board determined that survival end points had been met, and patients who were treated with dacarbazine were permitted to cross over to receive vemurafenib. At the time of the reported analysis, the hazard ratio for death in the vemurafenib group was 0.37 (95% confidence interval [CI], 0.26 to 0.55; P<0.001), and the hazard ratio for progression-free survival was 0.26 (95% CI, 0.20 to 0.33; P<0.001). Although the adverse-events profile for vemurafenib was generally mild, dose interruption and modification were required in 38% of patients.
Melanoma, like other cancers, is a collection of heterogeneous tumors that are differentiated by means of molecular markers, and each molecularly defined subgroup will probably have a different treatment algorithm.6 The results of the BRIM-3 study represent a major shift in the way we think about and treat melanoma.
For this preliminary report in the BRIM-3 study, follow-up was short, and the final estimate of survival outcomes is still to be determined. Furthermore, the study used investigator-reported response, not the findings of an independent response-review board, which could bias the rates of response and progression-free survival, though not the rates of overall survival. The latter rates will be influenced by the decision of the data and safety monitoring board to allow patients to cross over to receive vemurafenib. Whether the reportedly low rate of complete response to vemurafenib (0.9%) is the true rate and whether such a response would remain durable after the discontinuation of vemurafenib is not yet known.
To put the BRIM-3 study into perspective, interleukin-2 and ipilimumab have been approved by the Food and Drug Administration as immunotherapies for metastatic melanoma. The 2-week administration of high-dose interleukin-2 produces an objective response in 16% of a highly selected group of patients and complete remission in 6% of patients, with a median duration of complete response of more than 10 years. Four doses of ipilimumab produce a median survival of 10 months (a 4-month advantage over a vaccine control group), a median progression-free survival of 11 weeks, and an objective response rate of 7% (with a rate of complete remission of 0.5%).
There are several potential long-term health consequences of BRAF V600E inhibition, which can cause paradoxical stimulation of MAP-kinase-mediated events in wild-type BRAF cells and has been suggested as a mechanism for susceptibility to nonmelanoma skin cancers in patients receiving vemurafenib.7 Thus, careful surveillance of patients for other cancers is warranted. Although little is known about the use of targeted adjuvant agents in patients undergoing surgery, it is now reasonable to consider testing of adjuvant vemurafenib in patients with high-risk stage II or III melanoma with the BRAF V600E mutation on the basis of the findings in the BRIM-3 study.
Mechanisms of resistance to BRAF V600E kinase inhibitors include upstream and downstream events and activation of alternative pathways that are therapeutic targets.8 Experience with other tumor types has shown that the use of a combination of agents that block multiple pathways has a substantial effect on both efficacy and toxic effects. Thus, the choice of the components of drug combinations must be scientifically based and tested in clinical studies.
The inhibition of BRAF V600E in mutated melanoma cells blocked phosphorylated ERK, up-regulated melanocyte-differentiation antigens with resultant improved recognition by antigen-specific T cells, and did not impair T-cell function, which set the stage for combining immune therapy with BRAF V600E targeted therapy.9 MAPK has been implicated in the control of cell-cycle checkpoints, and MEK inhibition has been shown to enhance the effects of chemotherapy in vitro, providing a platform for combination cytotoxic chemotherapy and BRAF blockade.10 The benefit of vemurafenib does not seem to be adversely affected by previous treatment with other agents.4 Until further information is available, careful consideration of the use of immune therapy before the initiation of vemurafenib may be warranted.
The new understanding of molecular pathways changes the way we classify melanomas and influences therapy. The development of vemurafenib is an example of the translation of these concepts into clinical practice. For patients with metastatic melanoma with the BRAF V600E mutation, the availability of vemurafenib is a major defining moment that will have an important effect on survival and quality of life. Vemurafenib will be part of our therapeutic armamentarium for patients with melanoma and potentially for those with other cancers harboring BRAF V600E mutations, as well as a valuable tool for exploring new approaches to melanoma treatment.
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Paul B. Chapman, M.D., Axel Hauschild, M.D., Caroline Robert, M.D., Ph.D., John B. Haanen, M.D., Paolo Ascierto, M.D., James Larkin, M.D., Reinhard Dummer, M.D., Claus Garbe, M.D., Alessandro Testori, M.D., Michele Maio, M.D., David Hogg, M.D., Paul Lorigan, M.D., Celeste Lebbe, M.D., Thomas Jouary, M.D., Dirk Schadendorf, M.D., Antoni Ribas, M.D., Steven J. O'Day, M.D., Jeffrey A. Sosman, M.D., John M. Kirkwood, M.D., Alexander M.M. Eggermont, M.D., Ph.D., Brigitte Dreno, M.D., Ph.D., Keith Nolop, M.D., Jiang Li, Ph.D., Betty Nelson, M.A., Jeannie Hou, M.D., Richard J. Lee, M.D., Keith T. Flaherty, M.D., and and Grant A. McArthur, M.B., B.S., Ph.D. for the BRIM-3 Study Group
N Engl J Med 2011; 364:2507-2516 June 30, 2011
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.
At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number
Patients and Treatments
A total of 118 patients had died at the time of the interim analysis. The data and safety monitoring board determined that both the overall survival and progression-free survival end points had met the prespecified criteria for statistical significance in favor of vemurafenib. The board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011. Median follow-up for the interim analysis was 3.8 months for patients in the vemurafenib group and 2.3 months for those in the dacarbazine group.
A total of 672 patients were evaluated for overall survival. The hazard ratio for death in the vemurafenib group was 0.37 (95% confidence interval [CI], 0.26 to 0.55; P<0.001) (Figure 1A) The survival benefit in the vemurafenib group was observed in each prespecified subgroup, according to age, sex, ECOG performance status, tumor stage, lactate dehydrogenase level, and geographic region (Figure 1B). At the time of the interim analysis, there were an inadequate number of patients in follow-up beyond 7 months in either study group to provide reliable Kaplan-Meier estimates of the survival curves.17 At 6 months, overall survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. Further follow-up is required.
Progression-free survival could be evaluated in 549 patients. The hazard ratio for tumor progression in the vemurafenib group was 0.26 (95% CI, 0.20 to 0.33; P<0.001) (Figure 2A). The estimated median progression-free survival was 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. Superior progression-free survival with vemurafenib over dacarbazine was observed in all subgroups that were analyzed (Figure 2B).
A total of 439 patients (65%) could be evaluated for tumor response on the basis of having undergone randomization at least 14 weeks before the clinical cutoff date of December 30, 2010. In the vemurafenib group, most patients had a detectable decrease in tumor size (Figure 3A), and 106 of 219 patients (48%; 95% CI, 42 to 55) had a confirmed objective response (including 2 patients with a complete response and 104 with a partial response), with a median time to response of 1.45 months. Ten patients in the vemurafenib group were later found to have BRAF V600K mutations; of these patients, 4 had a partial response (40%). In the dacarbazine group, a minority of patients had a detectable decrease in tumor size (Figure 3B), and only 12 of 220 patients (5%; 95% CI, 3 to 9) met the criteria for a confirmed response (all partial responses), with a median time to response of 2.7 months. The difference in confirmed response rates between the two study groups (48% vs. 5%) was highly significant (P<0.001 by the chi-square test).
A total of 618 patients (92%) underwent at least one assessment as of the clinical cutoff date and were evaluated for toxic effects. Adverse events of grade 2 or more that were reported in more than 5% of the patients in either study group are shown in Table 2Table 2 dverse Events in 618 Patients.); adverse events of any grade that were reported in more than 5% of the patients are shown in Table A in the Supplementary Appendix. The most common adverse events in the vemurafenib group were cutaneous events, arthralgia, and fatigue; photosensitivity skin reactions of grade 2 or 3 were seen in 12% of the patients, with grade 3 reactions characterized by blistering that often could be prevented with sunblock. As expected, the most common severe toxic effects in the dacarbazine group were fatigue, nausea, vomiting, and neutropenia. Adverse events led to dose modification or interruption in 129 of 336 patients (38%) in the vemurafenib group and in 44 of 282 patients (16%) in the dacarbazine group.
In the vemurafenib group, a cutaneous squamous-cell carcinoma, keratoacanthoma, or both developed in 61 patients (18%). All lesions were treated by simple excision. Pathological analyses of skin-biopsy specimens from these patients are currently being performed by an independent dermatology working group.
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.
Supported by Hoffmann-La Roche.