Novel Combinations Mark Next Step for Melanoma

Immunotherapy has led a transformation for melanoma care but combinations of anti–PD-1 and CTLA-4 agents are toxic and biomarkers are not available to help personalized treatment, calling for further research into less toxic and more effective options.

Caroline Robert, MD, PhD

Immunotherapy has led a transformation for melanoma care but combinations of anti—PD-1 and CTLA-4 agents are toxic and biomarkers are not available to help personalized treatment, calling for further research into less toxic and more effective options, according to a presentation by Caroline Robert, MD, PhD, at the 2017 World Congress of Melanoma.

At this point, the only approved immunotherapy combination remains the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy). However, research into combination approaches is now focusing on triplets of anti—PD-1 therapies and new checkpoints, such as IDO. Additionally, ongoing research continues to search of a biomarker of response for immunotherapy in melanoma.

“Biomarker research needs to continue to develop to provide the best care for patients,” explained Robert, head of the Dermatology Unit at the Institut Gustave Roussy, during her talk at the congress. “Today, there is a lot of interesting data but nothing that we can use for our patients on an individual basis.”

When combined nivolumab and ipilimumab was associated with a 12% reduction in the risk of death versus nivolumab monotherapy for patients with treatment-naïve advanced melanoma, according to results from the phase III CheckMate-067 trial.1 The median overall survival (OS) was not reached with nivolumab/ipilimumab compared with 20 months with ipilimumab alone.

These modest benefits came at the cost of increased adverse events (AEs), Robert noted. Overall, 58.5% of patients experienced treatment-related grade 3/4 AE with the combination compared with 20.8% and 27.7% for nivolumab and ipilimumab alone, respectively.

“There is a slight increase in the progression-free survival and overall survival after longer follow-up,” said Robert. “However, it is difficult to give this combination without knowing who will benefit due to the high rate of grade 3/5 toxicities.”

In the CheckMate 067 study, of the 314 patients treated with ipilimumab and nivolumab, 176 patients discontinued due to AEs at any time. According to Robert, pooled data from CheckMate 067 and CheckMate 069, which also explored the combination, showed that PFS and OS was not significantly different between the patients who discontinued for adverse events during the induction period and those who did not discontinue, leading to the potential to customize treatment.

“Among physicians we have very different ideas of using this combination for patients who do not have a high burden of disease,” said Robert. “We are looking forward to having more indications of when to use this drug combination that gives rise to a higher response rate and longer PFS.”

Some of the ongoing research of new combinations, Robert explained, includes the exploration of the PD-L1 inhibitor atezolizumab (Tecentriq), which is being explored with cobimetinib (Cotellic) and vemurafenib (Zelboraf) in patients with unresectable BRAF-mutant melanoma. Early phase Ib results showed that the overall response rate (ORR) for the triplet combination was 81.6%, with a complete response (CR) of 18.4% after a median follow-up of 10 months. Overall, 41% of patients experienced grade 3/5 AEs.2

PD-1 plus an IDO inhibitor has proved to be a synergistic approach, according to results from the phase I KEYNOTE-037 trial, Robert noted. The PD-1 inhibitor pembrolizumab (Keytruda) in combination with the IDO inhibitor epacadostat demonstrated an ORR of 56% with a CR of 13%. The rate of grade 3/5 AEs was much lower with this combination, at just 20%.3

Additionally, the 2015 approval of T-VEC (talimogene laherparepvec, Imlygic) was an important advance in the treatment landscape for patients with melanoma, Robert noted. This agent was associated with few AEs, representing an ideal candidate for combinations. To this end, the preliminary findings of the phase I MASTERKEY-265 investigating pembrolizumab plus T-VEC showed an ORR of 62% with a CR rate of 33%. The median PFS for this study has not yet been reached.4

The KEYNOTE-034 continues to assess this combination (NCT02263508) along with a phase III expansion cohort of the MASTERKEY-265 trial (NCT02263508).


  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate-067): press conference. In: Proceedings from the 2017 American Association for Cancer Research Annual Meeting; April 2 to 5, 2017; Washington DC. Abstract CT075.
  2. Sullivan RJ, Hamid O, Gonzalez R, et al. Safety and clinical activity of atezolizumab + cobimetinib + vemurafenib in BRAFV600-mutant metastatic melanoma. In: Proceedings from the 2016 Society for Melanoma Research Annual Meeting, November 6-9, 2016, Boston, MA.
  3. Hamid O, Gajewski TF, Frankel AE, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma: Phase 1 and 2 efficacy and safety results from ECHO-202/ KEYNOTE-037. n: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1214O.
  4. Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virotherapy Promotes Intramoral T Cell Infiltration and Improved Anti-PD-1 Immunotherapy. Cell. 2017. doi:

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“This phase I study is attacking more difficult patients who had been treated previously with anti—PD-1 and who have developed resistance,” explained Robert.