Adding GM-CSF to Ipilimumab Improves OS, Lowers Toxicity in Advanced Melanoma

F. Stephen Hodi, MD

The addition of the GM-CSF agent sargramostim to the CTLA-4 inhibitor ipilimumab (Yervoy) prolonged overall survival (OS) and lowered toxicity for patients with unresectable stage III or IV melanoma, according to results from a phase II study published in the Journal of the American Medical Association.

Treatment with the combination of ipilimumab and sargramostim demonstrated a 1-year OS rate of 68.9% compared with 52.9% with ipilimumab monotherapy. Additionally, grade 3 or higher side effects were substantially lower with the combination. However, a significant improvement in progression-free survival (PFS) was not seen in the study.

"This reveals the possibilities of combining an immune signaling molecule with taking the brakes off at the same time,” first author F. Stephen Hodi, MD, the director of the Melanoma Treatment Center and director of the Center for Immuno-Oncology at the Dana-Farber Cancer Institute, said in a release.

The phase II trial randomized patients with metastatic melanoma in a 1:1 ratio to ipilimumab plus sargramostim (n = 123) or ipilimumab alone (n = 122). Ipilimumab was administered at 10 mg/kg, which was determined prior to the FDA approval of ipilimumab at 3 mg/kg. The primary endpoint of the study was OS.

At a median follow-up of 13.3 months, the median OS for ipilimumab plus sargramostim was 17.5 versus 12.7 months for ipilimumab (HR = 0.64; P = .01). The median PFS was 3.1 months in both arms of the study.

Patients treated with the combination experienced fewer side effects compared with single-agent ipilimumab. The rate of grade 3 or higher adverse events was 45% versus 58%, for the combination and single-agent, respectively (P = .04).

“The assumption at this point is that maybe GM-CSF is regulating the immune system and the organs that protect us all from outside invaders, and that would be the lung and the gut,” Hodi said when he presented the data at the 2013 ASCO Annual Meeting. “And the GM-CSF probably plays a role in that microenvironment that's different than other organs. In this case, it may play a role in keeping the immune system in check.”

In March 2011, the FDA approved ipilimumab as a single-agent for the treatment of unresectable or metastatic melanoma. In the pivotal study, the OS with ipilimumab was 10 months compared with 6.4 months with a gp100 peptide vaccine (HR = 0.66; P = .0026).

Following its approval, ipilimumab continued to be explored as a single-agent and in combination with the PD-1 inhibitor nivolumab in several clinical trials. In the phase I study presented at the 2014 ASCO Annual Meeting, the combination of ipilimumab and nivolumab demonstrated a 2-year OS rate of 79%, regardless of BRAF and PD-L1 status. Additionally, the durable objective response rate with the combination was 43%.

A phase III study looking at ipilimumab monotherapy in the adjuvant setting for patients with melanoma showed a statistically significant improvement in recurrence-free survival (RFS). In this study, ipilimumab was administered at 10 mg/kg. At a median follow-up of 2.7 years, RFS rates were 46.5% with ipilimumab versus 34.8% with placebo. The median RFS was 26.1 versus 17.1 months for ipilimumab and placebo, respectively (HR=0.75, P = .0013).

The ongoing phase III ECOG 1609 trial is comparing two doses of ipilimumab to interferon for patients with stage III/IV melanoma. Patients will receive adjuvant ipilimumab at either 10 mg/kg or 3 mg/kg every 21 days for 4 cycles. This will be followed by a maintenance period, utilizing the same dose administered every 90 days for 4 cycles. This study will help determine the benefits, dose, and optimal duration of treatment for ipilimumab following surgery.