Novel Therapy Combinations Are Needed for Melanoma Treatment

Immunotherapy has transformed the treatment of melanoma, bringing new hope to patients with the disease. However, current approved treatments have toxic side effects.

At the 2017 World Congress of Melanoma held in Brisbane, Australia, Caroline Robert, M.D., Ph.D., called for further research into less toxic and more effective treatment options.

One way to mitigate some of the side effects would be through more personalized treatment, but there are currently no genetic biomarkers available to help target individuals’ cancer cells.

Right now, the only approved immunotherapy combination remains the PD-1 inhibitor Opdivo (nivolumab) and the CTLA-4 inhibitor Yervoy (ipilimumab). Research into combination approaches now focuses on using three anti—PD-1 therapies and new checkpoints, such as IDO.

Ongoing research also continues to search for 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 in France. “Today, there is a lot of interesting data, but nothing that we can use for our patients on an individual basis.”

The combination of Opdivo and Yervoy was associated with a 12 percent reduction in the risk of death versus Opdivo alone for patients with treatment-naïve advanced melanoma, according to results from the phase 3 CheckMate-067 trial. The median overall survival (OS) was not reached with the Opdivo/Yervoy combination compared with 20 months with Yervoy alone.

These modest benefits came at the cost of increased side effects, Robert noted. Overall, 58.5 percent of patients experienced treatment-related grade 3/4 side effects with the combination compared with 20.8 percent and 27.7 percent for Opdivo and Yervoy alone, respectively.

“There is a slight increase in the progression-free survival (PFS) and OS 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 study, of the 314 patients treated with Yervoy and Opdivo, 176 patients discontinued due to side effects 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 side effects 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,” she said. “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 Tecentriq (atezolizumab), which is being explored with Cotellic (cobimetinib) and Zelboraf (vemurafenib) in patients with unresectable BRAF-mutant melanoma. Early phase results showed that the overall response rate (ORR) for the triplet combination was 81.6 percent, with a complete response (CR) of 18.4 percent after a median follow-up of 10 months. Overall, 41 percent of patients experienced grade 3/5 side effects.

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

PD-1 plus an IDO inhibitor has proved to be a synergistic approach, according to results from the early phase 1 trial, Robert noted.

Additionally, the 2015 approval of Imlygic (T-VEC or talimogene laherparepvec) was an important advance in the treatment landscape for patients with melanoma, Robert noted.