Randomized Phase II/III Study of Nivolumab plus Ipilimumab plus Sargramostim versus Nivolumab plus Ipilimumab in Patients with Unresectable Stage III or Stage IV Melanoma

By F. Stephen Hodi Jr., MD

The phase 2/3 EA6141 trial is comparing the safety and efficacy of treatment with nivolumab, ipilimumab, and sargramostim to treatment with nivolumab and ipilimumab alone for patients with unresectable stage III or stage IV melanoma.

Combination therapy with the immunotherapy drugs nivolumab and ipilimumab is a commonly used treatment for this patient population. Both drugs are monoclonal antibodies, but they target and block different checkpoints to increase the body’s immune response. Though this combination can be very effective—with response rates of greater than 50% as well as tumor burden reduction rates of greater than 80% in some patients—it is also associated with a significant incidence of high-grade adverse events. Thus, strategies are needed to improve the efficacy and tolerability of combined therapies.

Sargramostim is a human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that is currently used to increase immune cell production after myelosuppressive therapy or bone marrow transplant. This supportive care medication stimulates white blood cell production, including neutrophil, macrophage, and dendritic cell production. GM-CSF is used to decrease the chance of infection and support the immune system.

ECOG-ACRIN trial E1608 revealed that the addition of GM-CSF to ipilimumab improved survival (one-year survival ipilimumab + GM-CSF 68.9% vs. 52.9% for ipilimumab alone) with a p-value of 0.014.¹ Furthermore, the addition of GM-CSF to ipilimumab had a statistically significant impact on decreasing high-grade adverse events, specifically gastrointestinal and pulmonary events. This suggests that adding GM-CSF to combination therapy with nivolumab and ipilimumab may also lead to improvements in survival and treatment tolerability.

The primary objective of EA6141 is to compare the overall survival rates of patients who receive nivolumab/ipilimumab/GM-CSF versus those who receive only nivolumab/ipilimumab. Secondary objectives are to compare progression-free survival and differences in tolerability between the two groups, as well as to evaluate and compare immune-related response rate and response rate.

Study participants will be equally randomized into one of two groups. Group 1 will receive nivolumab/ipilimumab/GM-CSF during induction, followed by maintenance nivolumab/GM-CSF. Group 2 will receive nivolumab/ipilimumab during induction, followed by maintenance nivolumab.

Patients will receive protocol therapy until progressive disease, non-protocol therapy, or up to 2 years, whichever comes first.

To be eligible for this trial, patients must have unresectable stage III or stage IV melanoma and known BRAF mutational status of their tumor; patients with both BRAF mutant and BRAF wild-type melanoma may participate. Patients may have had prior systemic therapy in the adjuvant setting. They may have had anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapy in the adjuvant setting, if at least one year from last dose of treatment has passed prior to beginning protocol therapy. Patients may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the metastatic setting.

The phase 2 portion of this study was completed previously. After a successful planned interim analysis, the study advanced to the phase 3 portion, which is now in the last stages of enrollment. I encourage clinical sites to consider your patients for this important trial.

Learn more about the EA6141 trial at ecog-acrin.org.

Dr. Hodi (Dana-Farber Cancer Institute) is the study chair for this trial. The study co-chair is Ahmad Tarhini, MD, PhD (Moffitt Cancer Center).

^{1Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312:1744–53. doi:10.1001/jama.2014.13943}