New Combinations Explored for Metastatic Melanoma

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mproved outcomes and options for overcoming resistance to targeted therapies are still needed in metastatic melanoma. Researchers are exploring the use of combination therapies to reach these goals.

gp100 peptide vaccine and interleukin-2. The authors of this 2011 randomized phase III trial hypothesized that the effectiveness of melanoma vaccine gp100 could be boosted by adding a cytokine to drive the immune response. In 185 patients with locally advanced stage III or stage IV melanoma, patients receiving gp100 plus interleukin-2 had higher response rates and progression-free survival (PFS) than did patients taking interleukin-2 alone. Combination therapy patients were more than twice as likely to experience a clinical response—the primary endpoint— than were interleukin-2-treated patients (16% vs 6%, P=.03) Patients receiving the combination also had increased average survival (by 7 months) over the single agent—from 11.1 months to 17.8 months. Incidences of sinus tachycardia and supraventricular arrhythmia resulted from the addition of the vaccine, but these were transient and reversible.¹

Ipilimumab plus dacarbazine. In this phase III trial, 502 patients with previously untreated metastatic melanoma were randomized to receive either ipilimumab plus dacarbazine, or dacarbazine plus placebo. Overall survival (OS) was significantly longer in the combination therapy group. After 3 years, 20.8% of ipilimumab-plus-dacarbazine patients were alive, compared with 12.2% of patients receiving dacarbazine plus placebo (P <.001). Adverse events were consistent with other ipilimumab studies, except that rates of elevated liver function values were higher and gastrointestinal events were lower.²

Vemurafenib plus ipilimumab. A phase I/II study of vemurafenib plus ipilimumab in patients with BRAF^V600 mutation-positive metastatic melanoma is currently under way. The rationale for this study is that inhibition of the MAPK pathway in BRAF-driven tumor cells can decrease production of immune- suppressive factors such as IL-10, and enhance expression of antigens that could be recognized by the immune system, making melanoma cells more susceptible to immune attack.³

Dabrafenib plus trametinib. A combination of BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib, has shown promise in patients with advanced melanoma, including fewer serious side effects than the current standard single-agent BRAF-targeted therapy, vemurafenib. Results of a phase I/II study exploring the combination of these two investigational targeted therapies were presented in a press briefing at the 2012 American Society of Clinical Oncology (ASCO) meeting.⁴

A study of 125 melanoma patients who received varying doses of dabrafenib/ trametinib included a subgroup analysis of 77 patients who had not been treated with any BRAF inhibitors, and therefore had no prior resistance to BRAF-targeted therapy. Among the 77 patients who received the combination therapy, the overall response rate (ORR) was 56% (95% CI, 44.1%-67.2%). Six patients achieved a complete response (CR), 38 patients achieved partial response (PR), and 29 patients had stable disease (SD).⁴

The median overall PFS was 7.4 months (95% CI, 5.5-9.2), which was comparable to results with single-agent vemurafenib. The highest PFS was achieved in 24 patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily. (Dabrafenib/trametinib was given at 4 dose levels.) In this group, median PFS was 10.8 months. Fifteen of 24 patients (63%) achieved either CR or PR (95% CI, 40.6%-81.2%). The 150 mg/2 mg dose will be evaluated further in a phase III clinical trial.⁴

The phase III COMBI-d trial will evaluate the combination of the two investigational agents versus dabrafenib alone in stopping or slowing the progression of metastatic melanoma, with a primary endpoint of PFS.

The phase III COMBI-v trial will compare the two investigational agents against the FDA-approved BRAF inhibitor, vemurafenib, in improving OS in patients with metastatic melanoma.⁵

References:

1. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-2127.

2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.

3. Chapman PB. Vemurafenib and ipilimumab to be tried together. Available at: http://www.medscape.com/viewarticle/752983. Accessed May 28, 2012.

4. Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAF-naïve metastatic melanoma. J Clin Oncol 2012;30(suppl; abstr 8510).

5. GlaxoSmithKline. GSK announces start of Phase III programme for combination of dabrafenib (GSK2118436) and trametinib (GSK1120212) in BRAF V600 mutation-positive metastatic cutaneous melanoma. Available at: http://www.gsk.com/media/ pressreleases/2012/2012-pressrelease-1110046.htm. Accessed May 31, 2012.