New Immunotherapies for Advanced Melanoma

By Margaret Callahan, MD, PhD,

Over the past two years, extraordinary progress has been made in the development of new, clinically active therapies for advanced melanoma. The landscape changed remarkably with the US Food and Drug Administration’s approval of four new drugs: ipilimumab and vemurafenib (approved in 2011) and dabrafenib and trametinib (approved in 2013).

In addition to the introduction of agents that target specific mutations in the tumor cell (vemurafenib, dabrafenib, and trametinib), there have been advances in the development of agents that stimulate the immune system to fight cancer.

Key Discoveries

Experimental evidence in laboratory animals has long supported the notion that the immune system can recognize and, in some cases, destroy tumor cells. However, translating this preclinical data into a clinically active cancer therapy has been a challenge.

A breakthrough in this area came from experiments performed in the laboratory of James Allison. In the 1990s, Dr. Allison and colleagues were studying some of the molecules that regulate the immune system, specifically a molecule expressed on T cells called CTLA-4 that functions as an “off” switch, or “checkpoint.” (1)

When CTLA-4 is engaged, it functions like a brake on T cell activation, but when CTLA-4 is blocked, the T cells stay in high gear. Dr. Allison made the important leap in proposing that blocking CTLA-4 would allow T cells to fight cancer in a more robust and unrestrained fashion. His  laboratory tested this idea in mice and found that mice that received antibodies that block CTLA-4 were able to effectively fight off tumors in a way that untreated mice could not. (2)

Since this initial research was done, many other laboratories have found that CTLA-4 blockade can treat a diversity of tumor types in mice, from melanoma to sarcoma to ovarian cancer(3)

Based on this work, two drugs to block CTLA-4 in humans were developed and tested in clinical trials: ipilimumab and tremelimumab. Ipilimumab was approved by the FDA in 2011 for the treatment of advanced melanoma after two phase III studies showed that patients who received the drug lived longer than those who did not get the drug (Figure 1). (4), (5)

Jedd Wolchok, senior member of the Melanoma and Sarcoma Service in the Department of Medicine at Memorial Sloan Kettering, was a leader of several of these early studies and the senior author of one of the phase III studies testing the activity of ipilimumab.

Some of the earliest studies of ipilimumab showed clinical activity and suggested some unique properties of the drug. Unlike the targeted inhibitors that typically work very quickly, in days or weeks, responses to ipilimumab often take weeks or months to develop.

However, for those patients who do develop a response, responses tend to last, often several years or more. (6), (7)

Figure 1. -- Ipilimumab improves overall survival for patients with advanced melanoma. Data from a phase III study published in NEJM.<sup>(5)</sup>

CTLA-4 is just one of many nonredundant molecules that regulate T cell activation. In the last decade, basic research has identified molecules that either positively or negatively regulate T cell activation. Many of these appear to have a role to play in fighting tumors (Figure 2). (8)

A second inhibitory receptor, PD-1, has received attention in the past year because of exciting data from phase I clinical trials. As with CTLA-4 blockade, PD-1 blockade can generate a potent antitumor immune response in patients with cancer.

Figure 2. -- T cell activation is regulated by activating and inhibitor receptors. <sup>(8)</sup>

Several drugs that block PD-1 (or its binding partner PD-L1) are being tested in the clinic. Exciting results from phase I studies of three drugs (Nivolumab, BMS; Labrolizumab, Merck; and MPDL3280A, Genetech/Roche) have been published or presented at the American Society for Clinical Oncology (ASCO) Meetings in the past two years, with even higher response rates seen in select cohorts of these studies. (9), (10), (11)

These studies clearly establish that each of these agents has clinical activity, but some caution should be used in considering the response rates for individual agents or making any cross-study comparisons given the small number of patients treated so far. Adding to the enthusiasm for these drugs, some of these PD-1/PD-L1 targeting agents appear to have activity in tumor types other than melanoma, such as lung cancer and kidney cancer(9)

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Next Steps

Despite these successes, there is still much room for improvement. What are the next steps in further developing these immunotherapies for the treatment of melanoma? The field is moving forward in two areas – developing combinations of multiple immunotherapies and developing agents that target new checkpoint molecules.

Memorial Sloan Kettering physicians and research have been a part of both efforts.

Figure 3. -- Clinical activity in patients who received the concurrent regimen of nivolumab and ipilimumab<sup>(12)</sup>

At ASCO in 2013, the results of the first study to test the combination of ipilimumab and nivolumab in patients with advanced melanoma were presented. (12) This study demonstrated that these two agents can be safely combined and also showed that many patients had dramatic reductions in the size of their tumors (Figure 3). Based on the results of these studies, a phase III study in patients with advanced melanoma that progressed despite anti-CTLA-4 therapy has been designed and is now open at our institution and other centers worldwide.

Memorial Sloan Kettering has also been a leader in developing new immunotherapy drugs and phase I studies testing drugs that target GITR, 4-1BB, OX40, and LAG-3, and are open or expected to open over the course of 2013 and 2014.

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