Simultaneous treatment with ipilimumab, nivolumab improves outcomes in advanced melanoma

Source: Healio.com/hematology-oncology, April 2015

PHILADELPHIA — Patients with treatment-naive advanced melanoma who underwent simultaneous treatment with ipilimumab and nivolumab demonstrated longer PFS and a higher objective response rate than patients treated with ipilimumab alone, according to phase 2 study results presented at the American Association for Cancer Research Annual Meeting.

“The combination significantly improved overall response rates and PFS rates,”  F. Stephen Hodi, MD, director of the melanoma center at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, said during a press conference. “There was consistency of improvement in response rates and PFS in both wild-type BRAF patients and mutated BRAF patients, and the safety profile was as expected, with no real new safety signals.”

Blockade of the CTLA-4 and PD-1 immune checkpoints via monotherapy has been shown to extend OS in patients with metastatic melanoma.

Preclinical studies in animal models showed the combination of ipilimumab (Yervoy, Bristol-Myers Squibb) — a CTLA-4 antibody — and nivolumab (Opdivo, Bristol-Myers Squibb), a PD-1 pathway inhibitor, was more effective than sequencing of the agents individually. A phase 1 trial demonstrated encouraging antitumor activity for the ipilimumab–nivolumab combination, according to background information provided by researchers.

The current double blind study included 142 patients with treatment-naive advanced melanoma. The majority of patients (n = 109; 76.7%) had BRAF wild-type disease, and about one-quarter of patients (n = 33; 23.2%) harbored BRAF V600 mutations.

Hodi and colleagues randomly assigned 95 patients to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg alone every 2 weeks until disease progression. The other 47 patients received ipilimumab in the same dose schedule but received placebo instead of nivolumab.

Investigator-assessed objective response rate in patients with BRAF wild-type disease served as the primary endpoint. PFS, objective response rate in patients with BRAF V600-positive disease and safety served as secondary endpoints.

“Fifty percent of patients with melanoma have BRAF mutations, so we didn’t know whether those genomic aspects influenced the tumor interaction with the host’s immune system,” Hodi said. “Also, it becomes important in decision-making when we have many drugs available for patients with metastatic melanoma, and certainly knowing, in terms of that patient population, what that [interaction] is to help guide target therapies is important information both for patients and for the development of clinical science.”

Among patients with BRAF wild-type disease, the ipilimumab–nivolumab combination induced a higher rate of objective response (59.7% vs. 10.8%; P < .0001), a higher rate of complete response (16.7% vs. 0%) and longer median PFS (8.9 months vs. 4.7 months; HR = 0.4; 95% CI, 0.22-0.71) than ipilimumab alone. Patients assigned to the combination experienced a median 57% reduction in target lesions, whereas those assigned to ipilimumab alone experienced a median 4% increase in target lesions.

The combination also was associated with higher rates of objective response (43.5% vs. 0%) and longer median PFS (7.4 months vs. 2.7 months; HR = 0.33; 95% CI, 0.1-0.9) among patients with BRAF V600-positive disease.

Patients in both treatment arms experienced comparable rates of any-grade treatment-related adverse events (91.5% vs. 91.3%). However, those assigned to the ipilimumab–nivolumab combination experienced considerably higher rates of grade 3 or grade 4 treatment-related adverse events (51.1% vs. 19.6%), leading to a higher rate of treatment discontinuation in the combination arm. Immune-modulating medications resolved most of the immune-mediated adverse events, researchers wrote.

“Side effects for patients from the combination arm were higher compared with patients treated with ipilimumab alone, and this needs to be interpreted with caution,” Hodi said in a press release. “Following up with patients in the current study over a longer period of time is an important step.” – by Cameron Kelsall

Reference:

Hodi FS, et al. Abstract 4214. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.

Disclosure: The study was funded by Bristol-Myers Squibb. See the full study for the rest of the researchers’ relevant financial disclosures.