Frontline Nivolumab/Ipilimumab Combo Delivers Long-Term OS Advantage in Melanoma

Georgina V. Long, BSc, PhD, MBBS

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed a sustained survival benefit compared with nivolumab or ipilimumab alone, according to 5-year follow-up results from the phase III CheckMate-067 trial presented at the 16th International Congress of the Society for Melanoma Research.¹

“The combination therapy continues to have numerically superior survival versus nivolumab alone,” said co-author Georgina V. Long, MBBS, PhD, co-medical director of Melanoma Institute Australia (MIA) and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital. “It gives our patients the highest chance of being alive and treatment free, and demonstrates consistent activity across all patient groups.

Investigators published 5-year outcomes data in October 2019.² At a minimum follow-up of 60 months, the median overall survival (OS) was not reached (95% CI, 38.2—not reached) in the nivolumab/ipilimumab group arm, 36.9 months (95% CI, 28.3-58.7) in the nivolumab group, and 19.9 months (95% CI, 16.9-24.6) in the ipilimumab group (HR for nivolumab/ipilimumab vs ipilimumab, 0.52; HR for nivolumab/ipilimumab vs nivolumab, 0.83). Comparing the single-agent arms head-to-head, the hazard ratio for OS was 0.63 favoring nivolumab over ipilimumab.

A total of 945 patients with previously untreated, unresectable, stage III or IV melanoma, known BRAF V600 mutation status, and an ECOG performance status of 0 or 1 were randomly assigned in a 1:1:1 ratio to 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab for 4 doses followed by 3 mg/kg of nivolumab; 3 mg/kg of nivolumab plus placebo; or 3 mg/kg of ipilimumab plus placebo.

The investigators reported that there was no sustained deterioration of health-related quality of life during or after treatment with either nivolumab-containing regimen.

The minimum follow-up was 60 months from the date the last patient underwent randomization at the July 2, 2019, database lock.

The 5-year OS rate was 52% in the combination arm, 44% in the nivolumab arm, and 26% in the ipilimumab arm.

Patients had better outcomes with nivolumab-containing regimens irrespective of BRAF status. OS was 60% in the combination arm, 46% in the nivolumab arm, and 30% in the nivolumab arm in patients with BRAF-mutant disease. For those with BRAF wild type, OS was 48%, 43%, and 25%, respectively.

Investigators observed a correlation between overall response rate (ORR) and survival. OS was 90% among patients in the combination arm who had complete response (CR) and 65% in those who had partial response (PR). Median OS was not reached among patients who had a CR or PR.

In the nivolumab arm, the 5-year OS rate was 93% in patients who had a CR. The median OS was not reached for patients who had a CR. The median OS was 67 months (95% CI, 60.9-not reached) for those who had a PR, and the 5-year OS rate was 63%.

In the ipilimumab arm, the 5-year OS rate was 83% for patients who had a CR and 56% for those who had a PR. The median OS was not reached in either group.

“One of the best biomarkers of long-term outcome is the on-treatment marker of response,” Long said. “In each of these treatments, there is an obvious trend: CR does a lot better than PR, which does a lot better than stable disease.”

Patients Alive at 5 Years

Long also shared specific data for patients who were alive at 5 years. This group comprised 48% of the combination arm, 41% of the nivolumab arm, and 21% of the ipilimumab arm.

The ORR in the combination arm was 85%, with a CR rate of 38% and a PR rate of 47%. In the nivolumab arm, the ORR rate was 79%, comprising a CR rate of 42% and a PR rate of 37%. Those findings were 51%, 19%, and 31%, respectively, in the ipilimumab arm.

The median duration of response (DOR) was not reached in theses patient subgroups, regardless of treatment.

Among patients alive at 5 years who had BRAF-mutant disease and received nivolumab/ipilimumab (n = 57), 79% were treatment free and/or received no subsequent treatment.

Among patients with BRAF wild-type disease who received the combination (n = 94), 84% were either treatment free and/or received no subsequent treatment.

Long also noted, “Of patients alive at 5 years in all treatment groups, more than half—61% to 65%—had at least 1 poor prognostic factor, and approximately one-quarter—24% to 28%—had 2 or more poor prognostic factors.”

Among patients alive at 5 years who received the combination, 74% had LDH ≤ULN and 26% had LDH>ULN.

“Nivolumab plus ipilimumab demonstrates consistent activity across patient subgroups, including BRAF mutation status, LDH levels, and poor prognostic factors,” Long concluded.

References

1. Long GV, Hodi SF, Chiarion-Sileni V, et al. Characteristics of long-term survivors and subgroup analyses with combination nivolumab plus ipilimumab for advanced melanoma (CheckMate 067). Presented at: 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546. doi: 10.1056/NEJMoa1910836.

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