The addition of ipilimumab to nivolumab as an adjuvant treatment failed to improve relapse-free survival in the intent-to-treat and PD-L1 of less than 1% populations compared with nivolumab alone in patients with resected stage IIIB to D/IV melanoma.
The addition of ipilimumab (Yervoy) to nivolumab (Opdivo) as an adjuvant treatment failed to improve relapse-free survival (RFS) in the intent-to-treat (ITT) and PD-L1 of less than 1% populations compared with nivolumab alone in patients with resected stage IIIB to D/IV melanoma, missing the dual primary endpoints of the phase 3 CheckMate-915 trial (NCT03068455) that were presented during the virtual AACR Annual Meeting 2021.1
Findings showed that, in the ITT population, the 2-year RFS rate was 64.6% vs 63.2% with nivolumab alone. The median RFS was not reached (NR) in either arm (HR, 0.92; 97.295 CI, 0.77-1.09; P = .269).
In those who had PD-L1 expression of less than 1%, the 2-year RFS rate was 53.6% vs 52.4% in the doublet and monotherapy arms, respectively. Here, the median RFS was 33.2 months and 25.3 months in each arm, respectively (HR, 0.91; 95% CI, 0.73-1.14).
“The dual primary end points of RFS in the [ITT population] and PD-L1 of less than 1% population were not met,” lead study author Georgina V. Long, BSc, PhD, MBBS, FRACP, FAHMS, co-medical director of the Melanoma Institute Australia (MIA) and chair of melanoma medical oncology and translational research at MIA and Royal North Shore Hospital, The University of Sydney, said during a virtual presentation on the findings.
“Nivolumab combined with ipilimumab vs nivolumab in resected stage IIIB to D and IV melanoma did not improve the RFS or distant metastasis-free survival; these results reaffirm nivolumab as an adjuvant standard of care.”
The rationale for the research was based on several prior studies, one of which was the phase 3 EORTC 18071 trial of adjuvant ipilimumab vs placebo in patients with stage III melanoma who had undergone complete resection.2 Results showed that a 10-mg/kg dose of ipilimumab every 3 weeks elicited an improved 5-year RFS rate vs placebo (65% vs 54%, respectively; HR, 0.72; 95% CI, 0.58-0.88).
The phase 3 CheckMate-238 trial, which examined the role of nivolumab vs ipilimumab in patients who had experienced recurrent melanoma after complete resection of stage IIIB/C or stage IV melanoma, helped to establish nivolumab as a standard of care in this patient population.3 The 3-mg dose of nivolumab every 2 weeks yielded a 4-year RFS rate of 52% vs 41% in patients who received a 10-mg/kg dose of ipilimumab (HR, 0.71; 95% CI, 0.60-0.86).
Early data from phase 3 CheckMate-067 trial (NCT01844505), which examined nivolumab or nivolumab/ipilimumab vs ipilimumab alone in patients with previously untreated advanced melanoma, indicated that patients regardless of PD-L1 expression may experience benefit from the combination.4
In the CheckMate-915 trial, which was conducted at 122 sites across 19 countries, randomized patients with completely resected stage IIIB to D or IV no evidence of disease melanoma to receive either 240 mg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks (n = 920) or 480 mg of nivolumab every 4 weeks (n = 924). Treatment was given for 1 year.
The trial also included an ipilimumab-monotherapy arm, wherein patients received the CTLA-4 inhibitor at 10 mg/kg (n = 99), though this arm was discontinued on July 20, 2017.
Stratification factors were by tumor PD-L1 expression (<1% vs 1% to <5% vs ≥5%), as well as by disease stage (IIIB vs IIIC-D vs IV). Complete lymph node dissection was not required.
The median follow-up was 28 months. Dual primary end points were RFS both in the ITT population and the PD-L1 less than 1% population. Key secondary end points included OS, correlation between PD-L1 and RFS, and outcomes on subsequent therapies. Exploratory end points consisted of distant metastasis-free survival and quality of life (QoL).
The median age was 55 years and the majority of patients (57%) were male. Thirty-eight percent of patients on both arms had a PD-L1 of less than 1% and 31% of patients had a BRAF mutation. Overall, 31% of patients had stage IIIB disease, 52.5% had stage IIIC disease, 3% had stage IIID disease, and 13% had stage IV disease. Fifty-three percent of patients on the nivolumab/ipilimumab arm and 52% of patients on the nivolumab arm had stage IIIC disease.
Notably, patients who received the combination regimen had a median duration of therapy of 7.6 months vs 11.1 months in the nivolumab-alone arm.
“The cumulative dose of nivolumab in the [combination] arm was 3840 mg, which was considerably lower than the cumulative dose in the nivolumab monotherapy [cohort], which was 6240 mg,” Long explained. “If we break down duration by time periods, we can see that nearly one-third of patients in the combination arm received less than 3 months of drug therapy, whereas only 13% in the nivolumab monotherapy arm received less than 3 months of therapy.”
Additional data showed that when examining RFS by stage, patients with stage III disease who were treated with nivolumab/ipilimumab and single-agent nivolumab experienced a 2-year RFS rate of 64.7% and 63.6%, respectively. The median RFS was NR in either arm (HR, 0.94; 95% CI, 0.80-1.11).
In patients with stage IV disease, the 2-year RFS rate in the doublet arm was 63.6% compared with 61.1% in the single-agent arm. Similarly, the median RFS was NR in either arm (HR, 0.88; 95% CI, 0.58-1.32).
Additionally, patients with stage III disease who were treated with the combination had a 2-year dMFS rate of 75.4% with the combination compared with 77.4% with nivolumab alone. The median dMFS was NR in either arm (HR, 1.01; 95% CI, 0.83-1.23).
In those with stage IV disease, the 2-year dMFS rates were 68.4% and 67.9% in the nivolumab/ipilimumab and nivolumab-alone arms, respectively. Similarly, the median dMFS was not reached in this subgroup in either arm (HR, 0.94; 95% CI, 0.70-1.25).
A post hoc analysis of the combination arm evaluated whether duration of therapy impacted RFS by comparing patients who discontinued the regimen after 6 months or less with those who did not discontinue after 6 months or less, according to Long.
“Although we do see a 5% difference in the landmark RFS for the combination in these 2 groups, it is not sufficient to explain the overall negative results of this trial,” Long said.
Use of subsequent therapies was comparable in both arms, she noted, at 32% with the combination and 36% with the monotherapy.
Regarding safety, 94% of patients on nivolumab/ipilimumab experienced all-grade treatment-related adverse effects (TRAEs) and 33% experienced grade 3/4 TRAEs; these rates were 86% and 13% in the nivolumab arm, respectively. Thirty-two percent and 19% of patients in the combination arm experienced any-grade and grade 3/4 TRAEs, respectively, that led to treatment discontinuation compared with 10% and 6% in the monotherapy arm, respectively. No treatment-related deaths occurred in the monotherapy arm vs 4 in the combination arm.
The most common any-grade AEs with nivolumab/ipilimumab were pruritis (33%), rash (24%), fatigue (30%), diarrhea (27%), and hypothyroidism; the most common grade 3/4 AEs were increased lipase (5%), increased alanine amino transferase (3%), diarrhea (2%), hypophysitis (2%), and increased aspartate amino transferase (2%).
In the nivolumab-alone arm, the most common any-grade AEs were fatigue (30%), rash (21%), pruritis (21%), and diarrhea (20%), with common grade 3/4 AEs consisting of increased lipase (2%), rash (1%), and diarrhea (1%).
QoL was comparable between the 2 arms.
“A persistent, stable quality of life [was experienced] by both arms through the duration of the study. There were no improvement or deterioration in [clinically meaningful differences] during the course of the study for both arms. Similar trends were observed for both EQ-5D utility index and EQ-5D visual-analogue scale,” Long concluded.