The Growing Genetic Profile of Melanoma

The treatment armamentarium for melanoma has evolved rapidly over the last several years. While the latest generation of agents to gain FDA approval during this time are limited to treating limited types of melanoma, the mere existence of potentially life-prolonging agents is itself a significant development in the score of care. Moreover, a host of experimental agents are currently under investigation and could potentially expand the therapeutic landscape even further. Several recent studies offer a glimpse of what treatment regimens for melanoma might look like in coming years.

Advanced Melanoma Treatments Show Promise

Talimogene laherparepvec. One agent that might be beneficial for patients with advanced melanoma is the recently FDA approved talimogene laherparepvec (Imlygic, Amgen), or T-VEC for short, a herpes simplex virus type 1-derived oncolytic immunotherapy. It is designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. In the phase 3 study, researchers compared T-VEC with GM-CSF in 436 patients with unresected stage IIIB to IV melanoma.¹ Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. Durable response rate (DRR) was significantly higher with T-VEC (16.3 percent) than GM-CSF (2.1 percent), while pverall response rate was also higher in the T-VEC arm (26.4 percent). Additionally, median overall survival was 23.3 months with T-VEC and 18.9 months with GM-CSF.

The authors noted that T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events in the T-VEC group were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in more than two percent of patients of T-VEC–treated patients was cellulitis (2.1 percent). The authors concluded that T-VEC represents a novel therapy for patients with metastatic melanoma. That the FDA recently approved this agent bodes well for its role in the growing treatment paradigm for advanced melanoma.

Pembrolizumab versus Ipilimumab. Another finding with major implications for advanced melanoma treatment is a study published earlier this year in the New England Journal of Medicine.² The article compared two newer agents—pembrolizumab (Keytuda) and ipilimumab (Yervoy). In the Phase 3 study, researchers assigned 834 patients with advanced melanoma to receive pembrolizumab (at a dose of 10mg per kilogram of body weight) every two weeks or every three weeks or four doses of ipilimumab (at 3mg per kilogram) every three weeks. The estimated six-month progression-free-survival rates were 47.3 percent for pembrolizumab every two weeks, 46.4 percent for pembrolizumab every three weeks, and 26.5 percent for ipilimumab. Additionally, the estimated 12-month survival rates were 74.1 percent, 68.4 percent, and 58.2 percent, respectively. The investigators noted that the response rate was improved with pembrolizumab administered every two weeks (33.7 percent) and every three weeks (32.9 percent), as compared with ipilimumab (11.9 percent). Of note, responses were ongoing in 89.4 percent, 96.7 percent, and 87.9 percent of patients, respectively, after a median follow-up of 7.9 months, while efficacy was similar in the two pembrolizumab groups. Regarding safety, the findings indicated that treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3 percent and 10.1 percent) than in the ipilimumab group (19.9 percent).

New Combination for Untreated Melanoma?

Also published in the New England Journal of Medicine earlier this year is a study that looked at a combination approach for untreated melanoma involving ipilimumab and nivolumab (Opdivo).³ In the study, researchers compared nivolumab alone or nivolumab plus ipilimumab with ipilimumab alone in 945 patients with unresectable stage III or IV metastatic melanoma. They found that the median progression-free survival was 11.5 months with nivolumab plus ipilimumab, as compared with 2.9 months with ipilimumab, and 6.9 months with nivolumab. “In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months vs. 5.3 months),” the authors observed. They also noted that treatment-related adverse events of grade 3 or 4 occurred in 16.3 percent of the patients in the nivolumab group, 55 percent of those in the nivolumab-plus-ipilimumab group, and 27.3 percent of those in the ipilimumab group.

While nivolumab alone and nivolumab combined with ipilimumab both resulted in significantly longer progression-free survival than ipilimumab alone, the combination was found particularly effective (more so than nivolumab alone) in patietns with PD-L1-negative tumors, the researchers explained.

Rapid Discovery

Taken together, these studies represent a collective breakthrough in melanoma treatment. All of these newer agents offer increased and sometimes doubling of life expectancy. These studies also seem to suggest that combination regimens will be the future of melanoma care. For example, the viral agent Imlygic could potentially even be used in combination with lymph node removals/SLN procedures.

The continued development of new agents and successful combinations is also a reflection of progressive scientific understanding of the genetic profile of melanoma. After years of discussion and slow discovery, progress is occurring at a rapid pace. In addition, the recent understanding of genetic testing for risk stratification of thin melanomas leading to the identification of stage IB and IIA patients who may be at risk for recurrence (despite negative SLN), may lead to prophylactic use of these new agents to disease free patients to modify future risks. There is no question that the world of melanoma is changing—just as the world of psoriasis has—right before our eyes. n

Jonathan Wolfe, MD is an Associate Professor of Dermatology at the University of Pennsylvania.

1. J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26.

2. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.

3. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31.