Since 2011, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have approved four immunotherapies, starting with Bristol-Myers Squibb ’s (BMS) CTLA-4 targeting monoclonal antibody (mAb) Yervoy (ipilimumab), followed by Merck & Co.’s PD-1 targeting (mAb) Keytruda (pembrolizumab), Ono Pharmaceutical /BMS’ Opdivo (nivolumab), and Amgen ’s oncolytic viral therapy Imlygic (talimogene laherparepvec).

The addition of these novel therapeutic agents to targeted inhibitors of BRAF and MEK provides renewed hope to improve the treatment outcomes of melanoma patients. However, despite the rapid development of promising targeted therapies and immunotherapies for advanced melanoma, key clinical issues remain unmet.

The principal unmet need in melanoma is the lack of an adequate range of therapeutic options for patients with BRAF wild-type (WT) advanced melanoma. These patients have limited options, especially if they do not respond to or progress after anti-programmed cell death protein 1 (anti-PD-1) therapy. Among BRAF-WT patients, some have NRAS or c-KIT mutations, which contribute to poor prognoses. Efforts to develop NRAS or c-KIT targeting therapies for these patients have been unsuccessful and the current melanoma drug pipeline offers no improvement.

In addition, it remains unclear what the appropriate sequence of immunotherapy and BRAF / MEK inhibition is for the frontline treatment of patients with BRAF V600 mutation-positive melanoma. Acquired resistance, which occurs after approximately twelve months of treatment with BRAF/MEK inhibitor combinations, is both a major problem and a decisive factor shaping the treatment algorithm.

A high unmet need exists for effective neoadjuvant and adjuvant treatments for high risk, resectable melanoma. A significant proportion of these patients suffer disease progression and recurrence, ultimately resulting in poor prognoses. Survival improvements of adjuvant interferon regimens are relatively small by current standards. Moreover, interferon regimens cause significant morbidity and adverse events (AE), with major concerns of various toxicities. Therefore, Adjuvant interferons are no longer a viable first option.

Yervoy is currently considered standard-of-care for high-risk melanoma patients. Ono Pharmaceutical / BMS and Merck & Co. are seeking label expansion for advanced drugs Opdivo and Keytruda into the adjuvant setting. This strategy provides hope for improving the survival of early-stage melanoma, but it also draws concerns regarding drug safety, duration of treatment, and costs.

Predictive markers for checkpoint immunotherapies have to be identified, as there are currently no companion diagnostics for the marketed therapies in the melanoma space. With drug prices for oncology products under the spotlight, payers are becoming increasingly aware of the cost-effectiveness of drugs and are keen to identify what patient segment is going to benefit from treatment. To justify the high price of cancer therapeutics, effective methods to screen for potential drug responders need to be developed.