SWOG S1616 suggests PFS benefit with ipi-nivo combo in metastatic/unresectable melanoma
The combination of ipilimumab and nivolumab may provide a progression-free survival (PFS) benefit in patients with metastatic or unresectable melanoma who did not respond to anti-PD-1/anti-PD-L1 therapy, according to a small study presented at AACR 2022.
Participants in the SWOG S1616 trial were 91 adults with stage IV or unresectable stage III melanoma who were non-responsive to anti-PD-1/anti-PD-L1 therapy (without exposure to CTLA-4 therapy), had a Zubrod performance status (PS) of ≤2 (65 percent had PS 0), and had no active central nervous system metastases or autoimmune disease. They were randomized 3:1 to receive four cycles of ipilimumab (3 mg/kg) + nivolumab (1 mg/kg) Q3W followed by nivolumab (480 mg) Q4W continued throughout persistent clinical benefit (ipi-nivo arm; n=68; median age 64 years, 67 percent male) or four cycles of ipilimumab (3 mg/kg) Q3W (ipi-only arm; n=23; median age 69 years, 65 percent male).
Tumour assessments were carried out every 12 weeks for 1 year. About two-thirds of patients had been on anti-PD-1 therapy for <6 months. Seventy-eight and 87 percent of patients in the ipi-nivo and ipi-only arms, respectively, had only received anti-PD-1 therapy for metastatic disease, and 84 and 74 percent, respectively, had not received prior adjuvant therapy.
The patients were followed up for a median 25.3 months. During this time, PFS was significantly improved with the ipi-nivo combination compared with ipi only (median 3.0 vs 2.7 months; hazard ratio [HR], 0.63, 90 percent confidence interval [CI], 0.41–0.97; pone-sided=0.037), with 6-month estimated PFS rates of 34 and 13 percent, respectively. [AACR 2022, abstract CT013-S1616]
The PFS results were generally consistent across multiple subgroups except for those with <10 patients, where data was variable, noted study author Dr Ari VanderWalde from The West Cancer Center, Germantown, Tennessee, US. Patients with stage IV disease, no prior receipt of adjuvant therapy, or with <6 months exposure to anti-PD-1 therapy appeared to derive the greatest benefit, he added.
The objective response rate veered in favour of the ipi-nivo vs ipi-only arm (28 percent vs 9 percent; pone-sided=0.05), with complete responses noted in 9 percent vs 0 and partial responses in 18 percent vs 9 percent. The median duration of response was 18.9 months in the ipi-nivo arm and not reached in the ipi-only arm.
After a median 27.3 months, overall survival (OS) did not significantly differ between the ipi-nivo and ipi-only arms (median 21.7 vs 25.7 months; HR, 0.93, 90 percent CI, 0.54–1.60; pone-sided=0.408), though the study was not powered to assess OS. The estimated 12-month OS rates were 63 and 57 percent in the ipi-nivo and ipi-only arms, respectively.
There was no significant difference in post-progression therapy between groups. The most common post-progression therapies were other immunotherapies (19 percent [ipi-nivo] vs 24 percent [ipi only]), targeted therapy (16 percent vs 14 percent), and radiation therapy (12 percent vs 24 percent).
Grade ≥3 adverse events (AEs) occurred in 57 and 35 percent of ipi-nivo and ipi-only recipients, respectively. There was one treatment-related death in each arm, with the cause of death disseminated intravascular coagulation in the ipi-nivo arm and colonic perforation in the ipi-only arm. Early AE-related discontinuations of ipilimumab occurred in 23 and 16 percent of ipi-nivo and ipi-only recipients, respectively. The most common grade ≥3 AE was diarrhoea (13 percent of each arm).
“The toxicities were consistent with the known toxicities of these regimens,” said VanderWalde.
According to VanderWalde, the appropriate sequencing and combination of immune therapy in melanoma remains unknown.
“Treatment with anti-CTLA-4, alone or in combination with continued anti-PD-1, may reverse primary resistance to PD-1/L1 blockade therapy in patients with metastatic melanoma,” he continued.
“With the understanding that ipi-nivo remains very toxic in a high percentage of patients, it is of value to determine which patients truly need combination therapy upfront and which patients can undergo single-agent therapy with combination rescue,” he highlighted.
“Ipi-nivo is an appropriate next-line treatment in patients without response to anti-PD-1 alone,” he concluded.