The past five years have seen unprecedented progress in the treatment of malignant melanoma, which translated into approval of highly efficacious immunotherapies, targeted small-molecule therapies, and several combination regimens.

One of the most exciting classes of therapies for the treatment of melanoma is immune checkpoint inhibitors. Bristol-Myers Squibb's Yervoy (ipilimumab) was approved for the treatment of unresectable or metastatic melanoma in the US in 2011, and has achieved a 1-year survival rate of 46%. Bristol-Myers Squibb's second immune checkpoint inhibit, Opdivo (nivolumab) was granted accelerated FDA approval in December 2014 for previously-treated melanoma based on interim analysis of tumor response and durability of response in a single-arm Phase III (CheckMate-037) trial. Opdivo followed the approval of Merck & Co.'s immune checkpoint inhibitor, Keytruda (pembrolizumab); Keytruda secured US approval in September 2014 for previously-treated melanoma based on tumor response and durability of response in a Phase Ib trial. Phase III data released at ASCO 2015 revealed that BMS's Opdivo or a combination of Opdivo plus Yervoy results in significantly improved PFS compared with Yervoy alone for advanced melanoma patients.

The approvals of Yervoy, Zelboraf (Roche/Genentech/Chugai's vemurafenib), Tafinlar (Novartis's dabrafenib), Mekinist (Novartis's trametinib), Tafinlar plus Mekinist, Keytruda, and Opdivo for the treatment of melanoma were the result of 14 pivotal trials, which overall recruited over 3,000 patients ? an achievement, which was possible due to the fact that at the time of conducting these studies, clinical trials were one of the accepted  standards of care for unresectable/metastatic malignant melanoma patients. With such a wealth of effective and relatively well tolerated therapeutic options now available, has the standard of care for unresectable/metastatic malignant melanoma changed in 2015, and how will it change in the near term? Could the release of the highly anticipated data from the Phase III (CheckMate-067) trial of Opdivo plus Yervoy at ASCO's plenary session on the 31st of May provide the answer?

CheckMate-067 demonstrated Opdivo plus Yervoy achieved a PFS superiority of 8.6 months over Yervoy monotherapy and of 4.6 months over Opdivo. Similarly, the combination achieved a much higher overall response rate (ORR) of 58% (compared 19% and 44% for Yervoy and Opdivo monotherapies, respectively). However, the impressive efficacy for the combination came at a cost of more frequent grade 3/4 adverse events (55% for the Opdivo plus Yervoy group, 27% for Yervoy monotherapy, and 16% for Opdivo monotherapy) and was associated with a higher number of drug-related treatment discontinuations than the monotherapy comparator arms (36% for Opdivo plus Yervoy, 15% for Yervoy, and 8% for Opdivo). Importantly, no treatment-related deaths were observed in the Opdivo plus Yervoy cohort, while one treatment-related death occurred in each of the monotherapy comparator arms. Perhaps the finding that will have the most significant clinical implications is that of those patients who discontinued treatment with Opdivo plus Yervoy, 68% developed a response, and half of these responses took place after treatment had ended.

As a result of the high incidence of grade 3/4 adverse events, current lack of long-term OS data for this combination, and a wealth of more tolerable therapies, it is difficult to predict whether Opdivo plus Yervoy will become treatment of choice for first-line unresectable/metastatic malignant melanoma. 

So what are some of the other options? Combination regimens are not solely reserved for immunotherapeutic agents, and BRAF/MEK inhibitor combinations have shown remarkable results in BRAF-mutation-positive melanoma patients: Mekinist plus Tafinlar has achieved a median PFS of 11.4 months and Zelboraf plus Roche/Genentech/Exelixis's cobimetinib-treated patients have reached a median PFS of 11.3 months. While these results are impressive, it is clear that the majority of metastatic melanoma patients still currently die of their disease. Several of the melanoma-centered discussions at ASCO 2015 focused on the question, ?How can these outcomes be improved??. One of the major topics was acquired resistance to treatment with BRAF inhibitors, which usually sets in after six months of treatment. To date, more than ten resistance mechanisms have been identified, including NRAS mutations, BRAF amplification and splicing, MEK 1/2 mutations, KRAS mutations as well as alteration in parallel signaling in PI3K/AKT signaling pathway. The difference in the mutation profile of melanoma tumors depending on anatomic site was highlighted; for example, while approximately 60% of tumors without chronic sun damage carry a BRAF mutation, 45% of the tumors with chronic sun damage carry unidentified mutations and less than 20% have BRAF mutations.

While the addition of a MEK inhibitor to a BRAF inhibitor is a widely practiced strategy for delaying BRAF inhibitor treatment-acquired resistance, other methods can be employed. In mouse xenograft models, tumor shrinkage was observed following BRAF inhibitor discontinuation, thereby delaying resistance to Zelboraf. Another study in mice demonstrated that intermittent dosing of a BRAF inhibitor prolongs time to relapse. The mechanism behind this phenomenon was explained; the introduction of a BRAF inhibitor leads to upregulation of BRAF expression, causing the activation of the oncogenic MAPK signaling pathway, yet once treatment with BRAF is discontinued, BRAF expression is downregulated and MAPK signaling subsides. Indeed, this approach was described as favorable in terms of cost containment. Individual cases of patients being repeatedly rescued by the re-introduction of BRAF inhibitors were presented; this treatment strategy could be of particular value to patients who do not respond to treatment with immunotherapies.

Despite the clinical advances seen in BRAF-mutation-positive melanoma, significant unmet need remains in the treatment of BRAF-mutation-negative patients, particularly those who have exhausted their immunotherapy options. Multiple molecular targets have been identified in this subpopulation, however, as Dr. Ryan Sullivan, remarked during the BRAF-wildtype discussion at the 2015 ASCO general meeting, ?Multiple targets often mean no great targets?. Up to 50% of BRAF-mutation-negative patients carry NRAS mutations and 10-15% have NF-1 mutations. The NRAS mutations have been observed to correlate with more favorable immunotherapy responses and MEK inhibitors have been shown to have similar outcomes in NRAS- and BRAF-mutation-positive patients. Array's binimetinib, which specifically targets NRAS-mutation-positive patients, in combination with a BRAF inhibitor, Array's encorafenib, has shown a PFS of 11.3 months, an ORR of 75% and a complete response in 8% of patients in an early-phase trial; a Phase III trial known as COLUMBUS is currently underway and evaluating encorafenib plus binimetinib vs. encorafenib monotherapy vs. vemurafenib monotherapy.

The loss of NF-1 functionality has been demonstrated to be equivalent to NRAS mutation and implies MEK dependence, making NF-1-muation-positive patients good candidates for MEK inhibitor treatment. Alternative targets for BRAF-mutation-negative melanoma include c-KIT (Gleevec [Novartis's imatinib] has demonstrated a response in some c-KIT-mutation-positive patients), and CDK4, which is being evaluated in Phase I/II trials with Ibrance (Pfizer's palbociclib) plus Mekinist or Zelboraf.

As a result of the high mutational load of melanoma tumors, melanoma offers a variety of molecular targets beyond BRAF and MEK. In addition, due to the multitude of effective treatment options, questions regarding best dosing schedules, best sequencing and combination of agents and the setting in which they should be introduced persist, meaning that clinical trials should remain a standard of care for unresectable/metastatic malignant melanoma patients in 2015 and beyond.

Natalia Reoutova, M.A., M.Sc., is a senior business insights analyst on the Oncology team at Decision Resources Group.

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