Results from a phase 3 open-label trial also presented at this meeting found that nivolumab, which is a fully human IgG4 monoclonal antibody, was well tolerated and showed higher response rates than investigator’s choice chemotherapy (ICC; dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin 900 mg plus paclitaxel 175 mg/m2 every 3 weeks) in patients with metastatic melanoma who progressed on or after anti-CTLA-4 therapy or a BRAF inhibitor therapy.3

Jeffrey Weber and colleagues presented interim results on the first 120 nivolumab and 47 ICC patients with follow-up of 6 months or longer. The researchers found that the median time to response was 2.1 months (range: 1.6 to 7.4 months) for the nivolumab arm compared with 3.5 months (range: 2.1 to 6.1 months) for the ICC patients. A reduction of 50% or greater in targeted lesion burden occurred in 82% of the nivolumab responders compared with 60% of ICC responders.

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“The response was faster with immunotherapy,” said lead study investigator Jeffery S. Weber, MD, PhD, of the Moffitt Cancer Center and Research Institute in Tampa, Florida. “It is premature to say there is improved survival in the immunotherapy over the chemotherapy, but it is very promising and I think we will see very impressive increases in survival in the immunotherapy over the chemotherapy at the end of the day. That will take a long time. This was a planned early analysis.”

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Dr. Weber said grade 3 or higher adverse events were observed in 9% of the immunotherapy arm compared with 31% in the chemotherapy arm. Drug-related discontinuation rates were 2.2% in the immunotherapy arm compared with 7.8% in the chemotherapy arm. “The main side effects were the classic immune-related adverse events such as rash and endocrinopathies,” said Dr. Weber in an interview with Cancer Therapy Advisor.

Nikhil Khushalani, MD, who is an associate professor of oncology at Roswell Park Cancer Institute in Buffalo, New York, said the new trial data presented at this meeting affirm that targeting both BRAF and MEK in BRAF-mutant melanoma is clearly the preferred strategy to achieve a prolonged benefit from therapy.

“In a relatively short time since the approval of the vemurafenib in 2011 as the first BRAF inhibitor in melanoma, we have now raised the bar even further. This approach is ideal for a patient who is symptomatic and has a high disease burden. For all others, starting with immunotherapy is still the preferred strategy and the availability of three drugs in this class (interleukin-2, ipilimumab, pembrolizumab) means that therapy for each patient in the present era must now be personalized,” Dr. Khushalani told Cancer Therapy Advisor.

Dr. Khushalani said the next generation of melanoma trials should focus on the appropriate sequencing and/or combination of immunotherapy and targeted agents. Dr. Khushalani also said it is vital that investigators develop ways to overcome the resistance to BRAF and MEK inhibitors that inevitably develops during therapy.


  1. McArthur G, Ascierto P, Larkin J, et al. Phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation–positive patients with unresectable locally advanced or metastatic melanoma. In: Proceedings of the ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA5.
  2. Robert C, Karaszewska B, Schachter J, et al. COMBI-v: A randomised, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. In: Proceedings of the ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA4.
  3. Weber J, Minor D, D’Angelo S, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. In: Proceedings of the ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA3.