Melanoma: A 2013 ‘Progress Report’

The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013:

Targeted therapies

Two targeted drugs—Tafinlar (dabrafenib) and Mekinist (trametinib)—for metastatic melanoma were approved by the U.S. Food and Drug Administration (FDA) on May 29, 2013. Both are approved to treat melanomas with mutations in the BRAF gene, including about 50% of the most common type of melanoma: cutaneous melanoma. Dabrafenib, similar to the earlier approved drug vemurafenib (Zelboraf), targets mutant BRAF; trametinib targets MEK (MEK is a protein that is activated by and transmits cancer-causing signals from mutant BRAF). Moreover, a treatment combining dabrafenib with trametinib produced promising results for patients in a phase I/II clinical trial. It is currently in a phase III trial and received FDA priority review status in September.

There was another piece of good news for patients with BRAF-mutant melanoma in 2013. Combining the BRAF inhibitor drug vemurafenib with an investigational drug called PX-866 produced encouraging results in a phase I trial. PX-866 inhibits proteins in the PI3K kinase pathway, a cell signaling process that has been implicated in both the development of melanomas and the development of resistance to treatment with BRAF and MEK inhibitors. Preliminary results from the trial, reported in November, showed that tumors stopped growing or shrank partially or completely in 53% of patients. Seven patients in the trial had previously been treated with either a BRAF or MEK inhibitor, but had failed to respond or developed resistance to those drugs. Three of the seven have now shown some form of response to the combination of vemurafenib and PX-866.

An attractive target in cancer treatment is a group of proteins known as CDKs, which are directly responsible for driving the proliferation of tumor cells. CDKs can be activated by signals from mutant BRAF and NRAS (both found in melanoma). A CDK-inhibitor drug called LEE011 is currently being explored in combination with BRAF inhibitors in two early phase trials for patients with BRAF mutations (NCT01820364, NCT01777776). Another CDK inhibitor called P1446A-05 is also being tested in combination with vemurafenib: NCT01841463.

Melanoma with mutations in the NRAS gene, comprising about 20% of skin cancers, is another area of active clinical research. While there are drugs targeting mutant BRAF, mutant NRAS has not been amenable to be targeted directly with drugs. The combination of a MEK inhibitor (MEK is a shared protein in both the BRAF and NRAS pathways) and CDK inhibitor LEE011 is being explored in a clinical trial for patients with NRAS-mutant melanoma (NCT01781572).

Resistance to targeted therapies

Many patients who undergo targeted therapy treatment with a BRAF or MEK inhibitor, or even a combination thereof, develop resistance to these drugs and their tumors return. Some patients fail to respond at all. A new test developed at the Massachusetts General Hospital Cancer Center in Boston could help doctors predict responses to BRAF inhibitors in melanoma. Using tumor tissue obtained through a standard fine needle biopsy, the test examines a certain protein known as pS6 (or phosphorylated S6). Patients with tumors having diminished phosphorylation of S6 are much more likely to respond to treatment with BRAF and MEK inhibitor drugs.

Intense efforts are underway to determine how melanoma tumors develop resistance to treatment with BRAF and MEK inhibitors. Some tumors initially shrink in response to these drugs, but then acquire new genetic mutations that make them resistant, and they grow back. In one approach to study drug resistance, scientists fully sequence the genomes (DNA) of these tumors before and after treatment to identify new mutations. In 2013, advances in genome sequencing technologies and in the analysis of the vast data that they generate allowed for notable advances in comprehensive analysis of drug resistance. Researchers from Dana-Farber Cancer Institute at Harvard Medical School in Boston, and from the Jonsson Comprehensive Cancer Center of the University of California, Los Angeles, uncovered important new insights and delineated some common patterns of resistance. In particular, they found that new resistance mutations cluster mainly in the genes that are active in the signaling pathways governed by BRAF (the MAPK pathway) and in the aforementioned PI3K pathway. These findings will help researchers design drug combinations to forestall or overcome resistance to BRAF and MEK inhibitors.

Immune therapies

2013 was a great year for validating immune therapies as the most promising approach for the long-term control of melanoma. Immune therapies help activate a patient’s own immune system to recognize cancer cells and kill them. Much was written in 2013 about the success of the ‘immune checkpoint blockade’ strategy, featuring drugs that target the immune system proteins PD-1 and PD-L1 (see promising results for anti–PD-1 drug MK-3475). A previous Cancer Commons feature described advances in investigational immune therapies for melanoma in October. Even in the short time since then, there have been some noteworthy new developments.

Only 15% to 20% of patients with advanced melanoma are expected to survive 5 years, and the average life expectancy for final-stage patients is about 9 months. With the advent of immune checkpoint blockade treatments, this statistic is bound to change. The first approved drug of this kind is ipilimumab (Yervoy), which was approved by the FDA in 2011. Recent analyses showed that even though only a few patients respond to treatment with Yervoy alone, those who do tend to stay disease-free for many years.

Following the approval of ipilimumab, several other new immune checkpoint blockade therapies have shown promise for treating melanoma. In clinical trials that tested the anti–PD1 drug nivolumab as a monotherapy, that is, not combined with any other treatments, patients had an overall survival rate of 80% for at least 1 year, and some showed complete tumor regression or massive shrinkage of tumors. Combining nivolumab with ipilimumab produces even more striking results. In general, responses to immune therapies tend to be more long-lasting than responses to other treatments. In November, the anti–PD-L1 drug MPDL3280A was reported to produce good results in melanoma, inducing tumor shrinkage in about one-third of the patients in a phase I trial.

Individual patients can have vastly different responses to immune therapies. This necessitates scientific efforts to identify the factors that determine which patients’ tumors might shrink when their immune system is activated. One immune therapy with unpredictable results is IL-2, a substance that potently activates the immune system and was approved by the FDA to treat melanoma in 1998. But IL-2 works in only about 15% of patients and sometimes requires hospitalization because of life-threatening side effects. Researchers from the University of Texas MD Anderson Cancer Center in Houston might have just figured out how to predict which patients will respond well to the difficult treatment early on. A paper published in December described a specific set of immune system cells that are scarce in patients who experience tumor shrinkage in response to IL-2, but are found at high levels in nonresponders after just one cycle of treatment.

Perhaps less exciting than immune checkpoint blockade drugs, ‘cancer vaccine’ approaches also started to yield reassuring results in 2013. The cancer vaccine OMS-I100 (ImmunoPulse) directly delivers instructions for making a protein called IL-12 into a patient’s tumor; the patient’s cells then make IL-12, which boosts the immune system to kill cancer cells. ImmunoPulse performed well in a recent phase II trial. Remarkably, more than 60% of patients in the trial experienced shrinkage of other tumors in addition to the one chosen for injection. Another cancer vaccine called T-Vec (talimogene laherparepvec) has shown promising interim results in a clinical trial, with patients having a median overall survival rate of 23.3 months.

A third approach to immune therapy involves adoptive cell transfer, or ACT. In this strategy immune system cells are collected from either the patient’s tumor or the blood supply near the tumor. In the laboratory, these cells are multiplied to produce high numbers of ‘killer’ T cells. Sometimes these cells are modified or ‘trained’ to recognize tumor cells from the same patient. Meanwhile, the patient undergoes ‘lymphodepletion’ to remove immune cells that might inhibit the killer T cells. The killer T cells prepared in the lab are infused back into the patient. This approach, which is not new, sometimes produces outstanding results, but as with other types of immunotherapy, it is difficult to predict who will benefit. Several major clinical cancer centers are working hard to improve the success rate of ACT, one patient at a time.

The emergence of effective targeted therapies for melanoma described in the beginning of this post provided one more hugely promising strategy: combining immune therapy with targeted therapies. The rationale for this is supported by scientific evidence: drugs such as vemurafenib destroy tumor cells and release tumor particles that can be recognized by the immune system, making tumors more susceptible to immune attack. The first trial testing this strategy combined vemurafenib and ipilimumab, but unfortunately it had to be discontinued because of severe life-threatening side effects. Anti–PD-1 drugs might work better than ipilimumab in combination with vemurafenib because anti–PD-1 acts mostly within a tumor, as opposed to throughout the entire body. Several trials have started to look at combining vemurafenib with anti–PD-1 drugs; a trial at the U.S. National Cancer Institute is combining vemurafenib with ACT. The results of these trials might transform melanoma treatment once again.