Nivolumab/Ipilimumab Misses Coprimary Endpoint in Adjuvant Melanoma Trial

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not show a statistically significant improvement in recurrence-free survival (RFS) compared with single-agent nivolumab as an adjuvant treatment for patients who have had complete surgical removal of stage IIIB/C/D or stage IV melanoma and whose tumors expressed PD-L1 <1%, missing the coprimary endpoint of the phase III CheckMate-915 trial (NCT03068455).¹

The Data Monitoring Committee made a recommendation that the study continue unchanged, according to Bristol-Myers Squibb, the manufacturer of the PD-1 and CTLA-4 inhibitors. The study remains double-blinded and will continue to assess the other coprimary endpoint, which is RFS in the intent-to-treat population.

In the placebo-controlled, double-blind, phase III CheckMate-915 trial, investigators are evaluating nivolumab at 240 mg every 2 weeks in combination with ipilimumab at 1 mg/kg every 6 weeks, versus nivolumab alone at 480 mg every 4 weeks for 1 year, in 1943 patients who have had a complete surgical removal of stage IIIB/C/D or stage IV melanoma.

Patients who were eligible for enrollment had received no prior anti-cancer treatment for melanoma, except surgery for melanoma lesion(s) and/or adjuvant radiation after neurosurgical resection for central nervous system lesions. Those with a history of uveal melanoma, have active or known autoimmune disease, and had received prior treatment with interferon or another antibody or drug targeting T-cell costimulation or checkpoint pathway were excluded from the trial.

The primary endpoint is RFS; secondary endpoints are overall survival (OS) and PD-L1 expression.

Earlier findings with the combination, which were presented at the 2017 World Congress on Melanoma, demonstrated a 3-year sustained relapse-free survival benefit in patients with high-risk, resected IIIC/IV melanoma.² In a single-center, 40-patient study, adjuvant nivolumab combined with ipilimumab led to a 71% relapse-free survival rate at 3 years.

The study, which was conducted at Moffitt Cancer Center, comprised patients with stage IIIC or IV melanoma that was rendered disease free. In cohort A (n = 20), patients received an induction regimen of 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by maintenance nivolumab at 3 mg/kg every 2 weeks for 2 years. In cohort B (n = 20), patients received an induction regimen of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by the same maintenance regimen and schedule as cohort A.

The primary endpoint was treatment tolerability; secondary endpoints were relapse-free survival and OS.

In cohort A, 75% of patients were male and the median age was 50 years (range, 22-78); 45% of patients had stage IIIC disease and 55% of patients had stage IV disease. More than half of patients had an ECOG performance of 0 (55%) and 1 in 45%. Seven (47%) of 15 patients with known BRAF status were BRAF V600 positive. Among all 20 patients, 7 (35%) had prior systemic therapy, but did not include checkpoint inhibition.

In cohort B, 65% of patients were male and the median age was 55 years (range, 29-77). Fifty-five percent of patients had stage IIIC disease and 45% of patients had stage IV disease. ECOG performance status was 0 in 35% of patients and 1 in 65%. Seven of 11 (64%) patients with known BRAF status were BRAF V600 positive. Among all 20 patients, 4 (20%) had prior systemic therapy, which did not include checkpoint inhibitors.

In cohort A, 50% of patients completed their induction regimen, with an average of 3 cycles. Thirty percent of patients completed induction plus 2 years of maintenance, with an average of 34.8 cycles.

In cohort B, 65% of patients completed their induction regimen with an average of 3.6 cycles. Thirty percent of patients completed induction plus 2 years of maintenance, with an average of 36.3 cycles.

At a median follow-up of 2.9 years, the median relapse-free survival had not been reached among all 40 patients. The median follow-up was 3.4 years for cohort A and 2.5 years for cohort B. The 3-year relapse-free survival rates were 70% (95% CI, 45-85) for cohort A and 75% (95% CI, 50-89) for cohort B. The 2-year RFS rates were 80% (95% CI, 55-92) and 75% (95% CI, 50-89), respectively. The median relapse-free survival was not reached for either cohort.

Among the all 20 patients with stage IV disease across both cohorts, the median follow-up was 2.9 years. The 3-year and 2-year relapse-free survival rates were 74% (95% CI, 48-88) and 80% (95% CI, 55-92), respectively. One patient died and the median OS had not been reached.

Regarding safety, elevated AST/ALT, endocrine disorders, and nausea occurred in both cohorts, but were significantly higher in cohort A, which had a lower nivolumab but higher ipilimumab dose schedule.

Ninety percent (n = 18) of patients in cohort A had grade 3/4 treatment-related adverse events (TRAEs), with 11 patients stopping therapy for a TRAE of any grade. Seventy percent (n = 14) of patients in cohort B had grade 3/4 TRAEs, with 9 patients stopping therapy for a TRAE of any grade.

Nivolumab is currently approved by the FDA as a single agent or in combination with ipilimumab for patients with unresectable or metastatic melanoma.

Single-agent nivolumab is also indicated for patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection in the adjuvant setting. Moreover, ipilimumab monotherapy is approved by the FDA for the adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection including total lymphadenectomy, and also for patients with unresectable or metastatic melanoma in adult and pediatric patients.

References

1. Bristol-Myers Squibb Announces Update on CheckMate -915 for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Versus Opdivo Alone in Patients with Resected High-Risk Melanoma and PD-L1 <1%. Bristol-Myers Squibb. Published November 20, 2019. https://bit.ly/2D3mU3n. Accessed November 20, 2019.
2. Eroglu, Z. Mature results of combination nivolumab (NIVO) plus ipilimumab (IPI) as adjuvant therapy in stage IIIC/IV melanoma (MEL). Presented at: 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR09-6.