Pembrolizumab Hope for Treatment-Resistant Advanced Melanoma

Antibody therapy against the programmed-death-receptor-1 may help patients with advanced melanoma progression after ipilimumab and other targeted treatments

medwireNews: The anti-programmed-death-receptor PD-1 Antibody pembrolizumab may be an option for patients with treatment-refractory advanced melanoma, suggest phase Ib trial findings published in The Lancet.

“This is a key finding in view of the lack of effective treatment options for patients whose disease progresses on ipilimumab and BRAF or MEK inhibitors”, say Caroline Robert, from Gustave Roussy and INSERM in Paris, France, and co-authors.

“Results of this study will be invaluable for the future development of pembrolizumab and other monoclonal antibodies that block PD-1 or PD-L1 in different cancers.”

The current study is an extension of the KEYNOTE-001 trial, which showed pembrolizumab to induce a long-lasting objective response in patients with advanced melanoma, including some patients previously treated with the anti-cytotoxic T-lymphocyte-associated-Antigen-4 antibody ipilimumab.

For the open-label study, 137 patients with advanced melanoma progression after ipilimumab were given pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) at 3-week intervals and followed up for a median of 8 months.

The overall response rate for both patient groups was 26%, as measured using Response Evaluation Criteria In Solid Tumours, with a median progression-free survival rate at 24 weeks of 45% and 37% in the 2 mg/kg and 10 mg/kg groups, respectively, the team reports.

Using immune-related response criteria, the overall response rate was 27% in the 2 mg/kg group and 32% in the 10 mg/kg group, with a median 24-week progression-free survival rate of 57% in both treatment arms.

Pembrolizumab was well tolerated at both doses, with grade 2 fatigue, Pruritus and rash the most common effects. Just 12% of patients experienced grade 3 or 4 adverse events; grade 3 fatigue was the only grade 3 or 4 adverse event to occur in more than one patient.

Patients in the extension study were heavily pretreated compared with other pembrolizumab trial participants and this may explain lower response and survival rates than previously reported, the researchers comment.

All patients had been given ipilimumab, 72% of patients had received at least two systemic treatments and all patients with BRAF-mutant melanoma had received a BRAF inhibitor, a MEK inhibitor or both.

Editorialists Shailender Bhatia and John Thompson, from the University of Washington, in Seattle, USA, question whether rapid disease progression after resistance to BRAF or MEK inhibitor treatment may prevent some patients from being able to try other immunotherapies.

“The optimum timing and sequencing of immune and targeted treatments in the BRAF-mutant melanoma population deserve careful study”, they write.

“Perhaps future immunotherapy trials in this population should not mandate previous treatment with BRAF or MEK inhibitors, but should focus instead on the optimum selection criteria to exclude those patients who are less likely to respond to immunotherapy.”


Robert C, Ribas A, Wolchok J, et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. Lancet 2014; Early online publication 15 July. doi:10.1016/S0140-6736(14)60958-2

Bhatia S, Thompson J. Melanoma: immune checkpoint blockade story gets better. Lancet 2014; Early online publication 15 July. doi:10.1016/S0140-6736(14)61140-5

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