RESEARCH HIGHLIGHTS Nature Reviews Clinical Oncology advance online publication 16 December 2014; doi:10.1038/nrclinonc.2014.219
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e have reached a golden era in oncology with exciting rapid developments in immunotherapy and targeted therapies that are providing significant survival improvements. Two papers recently published in the New England Journal of Medicine exemplify progress in the oncology field, and highlight new standards of treatment only a couple of years after other first-line therapies were approved in this setting, illustrating the speed at which these therapies have galvanized our treatment armamentarium. The global incidence of melanoma continues to increase, and although patients treated with the monoclonal antibody anti-CTLA-4 targeted agent ipilimumab have demonstrated improvements in both response rate and survival, the median duration of these responses is often less than 1 year. Although the use of combination therapy with BRAF and MEK inhibitors have provided good responses, only 40% of patients who harbour a BRAF V600 mutation benefit from such an approach. Thus, there remains an unmet medical need for improved therapies. Nivolumab, a fully human IgG4 antibody that inhibits the immunecheckpoint by targeting the programmed death 1 (PD‑1) protein had previously shown very promising efficacy and safety results in a phase I study. Now, Caroline Robert and co-authors report the results of a phase III, randomized, doubleblind study that compared nivolumab with the commonly used chemotherapy agent dacarbazine (which remains a first-line therapy in many countries) in patients with previously untreated advancedstage melanoma who lacked BRAFV600 mutations and were thus unlikely to benefit from other targeted therapies. A total of 418 patients were randomly assigned to receive either nivolumab or dacarbazine: the 1‑year overall survival rate was 72.9% for those receiving nivolumab compared with 42.1% in
patients treated with dacarbazine. Median progression-free survival (PFS) was 5.1 months for patients in the nivolumab arm and 2.2 months for patients in the dacarbazine arm. Objective response rates were also substantially greater for nivolumab compared with dacarbazine (40.0% versus 13.9%). These results translate to a 58% decreased risk of death or disease progression with nivolumab compared with dacarbazine. Acquired resistance to BRAF inhibitors often develops owing to paradoxical activation of the MAPK compensatory pathway, and patients can also develop secondary skin tumours. However, combining a BRAF inhibitor with a MEK inhibitor can address the limitations of single-agent therapy. As Robert explains, “the strategy in this second trial is based on targeted therapy that combines antiBRAF and anti-MEK agents. The objective was to delay resistance and to fight the paradoxical activation of the MAPK pathway that is induced by anti-BRAF agents when used as monotherapy, and can lead to epithelial skin tumours.” In the second open-label, randomized, phase III study, 704 patients with metastatic melanoma and a BRAF V600 mutation were randomly assigned to receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib, or the BRAF inhibitor vemurafenib as monotherapy. At the preplanned interim analysis, the study protocol was amended to allow patients in the vemurafenib arm to crossover to the combination therapy arm. At 12 months, the overall survival rate was 72% in patients treated with the combination and 65% in those who received vemurafenib. Median PFS was 11.4 months for the combination therapy arm and 7.3 months for patients treated with vemurafenib. The rate of adverse effects were similar in both groups. The relative reduction in the risk of death was 31%. Skin adverse effects were less frequent with the combination therapy than with vemurafenib monotherapy, as were
NATURE REVIEWS | CLINICAL ONCOLOGY
selvanegra/iStock/Thinkstock
Golden age of melanoma therapy
secondary skin tumours. The clinical findings in this trial correlates with preclinical data showing that addition of a MEK inhibitor can downregulate the BRAF-induced paradoxical activation of the MAPK pathway. Importantly, both studies were stopped before they reached the total number of events as a result of the impressive efficacy outcomes, and both trials demonstrated an overall survival benefit and met their primary end points. Robert provides some context regarding the impressive results of these two trials: “these studies represent new important steps forward not only in the field of melanoma, but also cancer in general. Less than 3 years and 4 years after vemurafenib and ipilimumab, respectively, were the first drugs to demonstrate an overall survival benefit in patients with metastatic melanoma, we now have two treatments that provide significantly better outcomes and will probably also be effective in other cancers.” Lisa Hutchinson Original articles Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. doi:10.1056/NEJMoa1412082 | Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. doi:10.1056/ NEJMoa1412690 Further reading Gibney, G. T. et al. Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma. Nat. Rev. Clin. Oncol. 10, 390–399 (2013)
ADVANCE ONLINE PUBLICATION © 2014 Macmillan Publishers Limited. All rights reserved
SKIN CANCER
W
e have reached a golden era in oncology with exciting rapid developments in immunotherapy and targeted therapies that are providing significant survival improvements. Two papers recently published in the New England Journal of Medicine exemplify progress in the oncology field, and highlight new standards of treatment only a couple of years after other first-line therapies were approved in this setting, illustrating the speed at which these therapies have galvanized our treatment armamentarium. The global incidence of melanoma continues to increase, and although patients treated with the monoclonal antibody anti-CTLA-4 targeted agent ipilimumab have demonstrated improvements in both response rate and survival, the median duration of these responses is often less than 1 year. Although the use of combination therapy with BRAF and MEK inhibitors have provided good responses, only 40% of patients who harbour a BRAF V600 mutation benefit from such an approach. Thus, there remains an unmet medical need for improved therapies. Nivolumab, a fully human IgG4 antibody that inhibits the immunecheckpoint by targeting the programmed death 1 (PD‑1) protein had previously shown very promising efficacy and safety results in a phase I study. Now, Caroline Robert and co-authors report the results of a phase III, randomized, doubleblind study that compared nivolumab with the commonly used chemotherapy agent dacarbazine (which remains a first-line therapy in many countries) in patients with previously untreated advancedstage melanoma who lacked BRAFV600 mutations and were thus unlikely to benefit from other targeted therapies. A total of 418 patients were randomly assigned to receive either nivolumab or dacarbazine: the 1‑year overall survival rate was 72.9% for those receiving nivolumab compared with 42.1% in
patients treated with dacarbazine. Median progression-free survival (PFS) was 5.1 months for patients in the nivolumab arm and 2.2 months for patients in the dacarbazine arm. Objective response rates were also substantially greater for nivolumab compared with dacarbazine (40.0% versus 13.9%). These results translate to a 58% decreased risk of death or disease progression with nivolumab compared with dacarbazine. Acquired resistance to BRAF inhibitors often develops owing to paradoxical activation of the MAPK compensatory pathway, and patients can also develop secondary skin tumours. However, combining a BRAF inhibitor with a MEK inhibitor can address the limitations of single-agent therapy. As Robert explains, “the strategy in this second trial is based on targeted therapy that combines antiBRAF and anti-MEK agents. The objective was to delay resistance and to fight the paradoxical activation of the MAPK pathway that is induced by anti-BRAF agents when used as monotherapy, and can lead to epithelial skin tumours.” In the second open-label, randomized, phase III study, 704 patients with metastatic melanoma and a BRAF V600 mutation were randomly assigned to receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib, or the BRAF inhibitor vemurafenib as monotherapy. At the preplanned interim analysis, the study protocol was amended to allow patients in the vemurafenib arm to crossover to the combination therapy arm. At 12 months, the overall survival rate was 72% in patients treated with the combination and 65% in those who received vemurafenib. Median PFS was 11.4 months for the combination therapy arm and 7.3 months for patients treated with vemurafenib. The rate of adverse effects were similar in both groups. The relative reduction in the risk of death was 31%. Skin adverse effects were less frequent with the combination therapy than with vemurafenib monotherapy, as were
NATURE REVIEWS | CLINICAL ONCOLOGY
selvanegra/iStock/Thinkstock
Golden age of melanoma therapy
secondary skin tumours. The clinical findings in this trial correlates with preclinical data showing that addition of a MEK inhibitor can downregulate the BRAF-induced paradoxical activation of the MAPK pathway. Importantly, both studies were stopped before they reached the total number of events as a result of the impressive efficacy outcomes, and both trials demonstrated an overall survival benefit and met their primary end points. Robert provides some context regarding the impressive results of these two trials: “these studies represent new important steps forward not only in the field of melanoma, but also cancer in general. Less than 3 years and 4 years after vemurafenib and ipilimumab, respectively, were the first drugs to demonstrate an overall survival benefit in patients with metastatic melanoma, we now have two treatments that provide significantly better outcomes and will probably also be effective in other cancers.” Lisa Hutchinson Original articles Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. doi:10.1056/NEJMoa1412082 | Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. doi:10.1056/ NEJMoa1412690 Further reading Gibney, G. T. et al. Paradoxical oncogenesis—the long-term effects of BRAF inhibition in melanoma. Nat. Rev. Clin. Oncol. 10, 390–399 (2013)
ADVANCE ONLINE PUBLICATION © 2014 Macmillan Publishers Limited. All rights reserved
