Omid Hamid, MD
Ipilimumab (Yervoy) and nivolumab (Opdivo) may be getting plenty of buzz; however, the dual immunotherapy regimen is certainly not the only combination making a significant impact in the treatment of patients with advanced melanoma, explains Omid Hamid, MD.
“On the heels of the ipilimumab/nivolumab combination having such a high response rate and while we are still awaiting survival data, we have been looking to find other standard combinations for advanced melanoma,” says Hamid, chief of Translational Research and Immunotherapy, director of Melanoma Therapeutics, The Angeles Clinic. “That is not to say that ipilimumab/nivolumab is not a standard; it is a breakthrough in showing that we can combine these types of agents and have good outcomes. However, it makes a lot of sense to look at these other combinations.”
Numerous combinations with and without immunotherapy backbones are being investigated in phase I and II trials in advanced metastatic melanoma. Several have preliminarily demonstrated high response rates without the high level of toxicities that can sometimes be limiting with ipilimumab/nivolumab, says Hamid.
In an interview with OncLive
, Hamid outlined some of the combinations he is most excited about that are on the horizon in advanced melanoma.
One option with promising combination possibilities in melanoma is IDO1 inhibition. At the 2015 Society for Melanoma Congress, Hamid presented preliminary data on the novel IDO1 inhibitor epacadostat (INCB24360) in combination with the PD-1 antibody pembrolizumab (Keytruda).1
The data were from the melanoma cohort of an ongoing dose-escalation and dose-expansion phase Ib study, in which patients with stage IIIB/IV melanoma, as well as other cancers, received either 25, 50, 100, or 300 mg of epacadostat daily along with pembrolizumab at either 2 mg/kg every 3 weeks or 200 mg twice daily.
Of the 19 evaluable patients with melanoma, the combination demonstrated an overall response rate (ORR) of 53% (n = 10) with 3 complete responses (CRs) and 7 partial responses (PRs). Four patients had stable disease.
In treatment-naïve patients (n = 16), ORR was 56% and the disease control rate was 75%. There was 1 CR in the 25-mg group (n = 2), 2 CRs and 3 PRs in the 50-mg group (n = 12), and 0 CRs and 4 PRs in the 100-mg group (n = 4). No responses were seen in the 300-mg group (n = 1).
The regimen was generally well tolerated, with few patients experienced dose-limiting toxicity (DLT) or grade 3 treatment-related adverse events (AEs), reports Hamid. There were no grade 4 treatment-related AEs or deaths, and a discontinuation rate of 5% for treatment-related AEs.
The recommended dose for the phase II portion of this study is 100 mg of epacadostat, based on the overall efficacy and safety profile demonstrated in the phase Ib study.
Enrollment in the phase II portion of the study has been initiated, and a phase III study in patients with advanced melanoma is planned, with initiation expected in the first half of 2016, according to Hamid.
IDO inhibitors are promising because they take a different approach other than immunotherapy, says Hamid.
“The IDO inhibitor targets the tumor microenvironment; it is a new way of controlling the immune system and getting it revved up,” he says. “It is a great breakthrough in finding ways to reinvigorate the immune system aside from just checkpoint inhibition.”
Another exciting combination on the horizon is talimogene laherparepvec (T-VEC; Imlygic) with ipilimumab, says Hamid.
“It really is a major breakthrough to show that these 2 drugs can come together and have a high response rate with low toxicity,” he adds.
A primary analysis of a phase Ib multicenter trial evaluated the safety and efficacy of T-VEC and ipilimumab in previously untreated, unresected stage IIIB/IV melanoma.2
The study found that of the 17 evaluated patients, ORR was 41%, with 24% of patients experiencing a CR and 18% experiencing a PR. Thirty-five percent of patients had stable disease and median time to response was 2.9 months. Grade 3/4 AEs occurred in 32% of patients and 2 patients had possible immune-related grade 3/4 AEs.
A randomized phase III study investigating this combination is currently ongoing, says Hamid.
Combining targeted therapy with immunotherapy has the potential to harness and enhance the antitumor response following BRAF inhibition, and may lead to durable responses and prolonged survival, says Hamid.
The anti–PD-L1 agent atezolizumab has demonstrated promising response rates in melanoma, bladder cancer, non–small cell lung cancer, and renal cell carcinoma. In 1 study, single-agent atezolizumab had a 33% ORR in patients with advanced melanoma.