The Growing Arsenal of Immunotherapy Drugs for Melanoma


Large numbers of immune cells (T cells in particular) are frequently found within or adjacent to melanoma tumors, indicating that the tumors attract the attention—if not the action—of the immune system. True to its reputation as one of the most ‘immunogenic‘ cancers, melanoma now has more U.S. Food and Drug Administration (FDA)-approved immunotherapy (immune system-targeting) drugs than any other cancer type. As a consequence, metastatic melanoma is no longer the universally fatal disease it was even just 3 or 4 years ago.

In this post, I outline the current selection of FDA-approved immunotherapy drugs for melanoma (the earlier FDA-approved drugs IL-2 and interferon are not included, because of their inferiority to more recently developed drugs):

Here are the most recent, effective drugs for stage IV (metastatic) or unresectable melanoma listed by their FDA-approved date:

March 2011: Ipilimumab (Yervoy) is an antibody that blocks a protein called CTLA4, which is found on T cells. Yervoy was approved based on the results of a randomized, clinical trial in which patients who received it had an overall survival of 10 months, compared to 6 months for patients who received an experimental cancer vaccine. Eleven percent of the patients showed a partial decrease or disappearance of the signs of their disease (objective response rate, or ORR). However, many in this small group of responding patients continue to be tumor-free years after receiving the prescribed four doses of Yervoy.

September 2014: Pembrolizumab (Keytruda), an antibody that disables the protein PD-1 on T cells, was approved for treatment of melanoma that has not responded to other drugs. In a clinical trial, the ORR was about 24%, and no disease progression for over 8 months was observed in about half of the patients who responded.

December 2014: Nivolumab (Opdivo), also a PD-1 blocker, was approved for treatment of melanoma that has not responded to Yervoy or, if positive for a BRAF gene mutation, to targeted drugs for BRAF. In a pivotal clinical trial, the ORR was 32%.

December 2015: The FDA announced two new approvals for Keytruda. It is now approved for treatment of previously untreated melanoma, regardless of BRAF mutation, as well as for treatment of melanoma that has not responded to Yervoy. In the Keynote-006 and 002 clinical trials, which compared it to Yervoy, Keytruda extended disease-free survival and reduced risk of death by 40%.

November 2015: The FDA extended its approval of Opdivo to allow it to be used as a first-line treatment for melanomas with normal BRAF, based on an observed ORR of 43% in patients who had not received any prior treatment. (The first-line treatment of BRAF-mutant melanoma involves BRAF- and MEK-targeted drugs, an option not available for melanoma with a normal BRAF gene).

September 2015: The FDA approved a combination of Opdivo and Yervoy for melanomas with normal (wild-type) BRAF. In the pivotal Checkmate 069 trial, the ORR for this combination was 60%, of which 79% had responses lasting longer than 6 months. Both drugs are given four times, every 3 weeks, after which Yervoy is dropped, and only Opdivo is continued every 2 weeks.

The combination of Opdivo and Yervoy is associated with significantly more toxicities (side effects) than either drug alone. An effort was made to determine if sequential use of these two drugs could possibly alleviate the side effects, some of which are serious. In a study called Checkmate 064, Opdivo followed by Yervoy achieved an ORR of 41%, while patients who received Yervoy first, followed by Opdivo, had a 20% ORR. The patients received six biweekly cycles of Opdivo, and then four biweekly cycles of Yervoy, or vice versa. Both groups then continued to receive Opdivo. The study suggests that concurrent administration of both drugs is more effective. In addition, the side effects seen with the combination were not much improved if Opdivo and Yervoy were given sequentially.

October 2015: The FDA approved T-VEC (Imlygic) for melanoma that only involves the skin and lymph nodes (no internal tumors). This drug is injected intralesionally, that is, directly into the tumors. In a clinical trial, 16% of patients experienced decrease in tumor size versus 2% in patients who received a control treatment. It is worth mentioning here another intralesional drug, PV-10, which, even though it was as promising as T-VEC in earlier trials, lags behind in development. I predicted the outcome of this competition about 1 year ago, with the win for Amgen (the developer of T-VEC), a very large company with much deeper pockets than Provectus, the company behind PV-10.

Stage III melanoma, a disease that most often recurs as a metastatic one, has also seen the first FDA-approval of an immunotherapy treatment:

October 28, 2015: Yervoy approved for stage III melanoma as an adjuvant treatment after surgery. In a clinical trial, 49% of patients receiving Yervoy recurred over an average period of 26 months versus 62% patients receiving only a placebo. Other trials are currently testing Opdivo and Keytruda in stage III melanoma; the results will be of considerable interest.

Needless to say, numerous trials are exploring combinations of checkpoint inhibitors with other drugs to improve the latter’s efficacy. Keytruda is in 45 trials for melanoma and Opdivo in 30. Hopefully, some of these will have encouraging results soon.