Nivolumab Alone, With Ipilimumab Demonstrate Sustained 10-Year Survival Benefit in Advanced Melanoma

Nivolumab (Opdivo) alone or combined with ipilimumab (Yervoy) showed a significant and durable benefit in overall and melanoma-specific survival (MSS) at 10 years vs ipilimumab alone in patients with advanced melanoma, according to the final results from the phase 3 CheckMate 067 trial (NCT01844505) that were presented at the 2024 ESMO Congress¹ and simultaneously published in The New England Journal of Medicine.²

Data showed that with a minimum follow-up of 120 months, the median overall survival (OS) was 71.9 months (95% CI, 38.2-114.4) with nivolumab plus ipilimumab vs 19.9 months (95% CI, 16.8-24.6) with ipilimumab alone (HR, 0.53; 95% CI, 0.44-0.65), and 36.9 months (95% CI, 28.2-58.7) with nivolumab alone vs the 19.9 months with ipilimumab (HR, 0.63; 95% CI, 0.52-0.76). Ten-year OS rates were 43%, 37%, and 19% with nivolumab/ipilimumab, nivolumab monotherapy, and ipilimumab monotherapy, respectively, with a HR of 0.85 between the combination and nivolumab alone (95% CI, 0.69-1.05). The OS benefit was upheld across prespecified subgroups.

“The 10-year CheckMate 067 results for nivolumab plus ipilimumab represent the longest median OS in a phase 3 study of an anti–PD-1 agent for any tumor type,” lead study author James Larkin, MD, professor and consultant medical oncologist at The Royal Marsden Hospital in the United Kingdom, said in an oral presentation during the congress. “These results demonstrate the sustained benefit and impact of dual checkpoint inhibitor therapy on the long-term prognosis of patients with advanced melanoma, highlighting the potential for cure in patients who respond to this type of treatment.”

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of adult and pediatric patients with metastatic melanoma, based on earlier findings from CheckMate 067.3 Nivolumab is also approved for use as a single agent in this patient population.³

In the CheckMate 067 trial, data previously showed that nivolumab combined with ipilimumab, or nivolumab alone, improved OS compared with ipilimumab alone. At 7.5 years, the median OS with nivolumab/ipilimumab was 72 months, 37 months with nivolumab alone, and 20 months with ipilimumab alone.⁴ Additionally, 7.5-year MSS rates were 98%, 97%, and 95% with the combination, single-agent nivolumab, and single-agent ipilimumab, respectively, in patients who were alive and progression free at 3 years.⁵

In the landmark trial, 945 patients with previously untreated, unresectable or metastatic melanoma were randomized 1:1:1 to receive 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses then 3 mg/kg of nivolumab every 2 weeks (n = 314); 3 mg/kg of nivolumab every 2 weeks plus ipilimumab-matched placebo (n = 316); or 3 mg/kg of ipilimumab every 3 weeks for 4 doses plus nivolumab-matched placebo (n = 315) until disease progression or unacceptable toxicity.¹

The coprimary end points were progression-free survival (PFS) and OS with either the combination or nivolumab alone vs ipilimumab; secondary outcome measures were objective response rate, descriptive efficacy assessments, and safety. An exploratory end point was MSS.

Stratification factors included PD-L1 status (<5% vs ≥5%), BRAF mutation status, and AJCC metastasis stage. The final data cutoff date was April 19, 2024, and the final database lock date was May 16, 2024.

Additional results showed that the median MSS was not reached (NR) with nivolumab plus ipilimumab (95% CI, 71.8-NR) and was 49.4 months (95% CI, 35.1-119.4) with single-agent nivolumab vs 21.9 months (95% CI, 18.1-27.4) with single-agent ipilimumab. This led to a HR of 0.48 favoring the combination vs single-agent ipilimumab (95% CI, 0.39-0.59) and a HR of 0.59 of single-agent nivolumab vs ipilimumab (95% CI, 0.49-0.73). In comparing the combination against single-agent nivolumab, the HR was 0.81 (95% CI, 0.64-1.01). The 10-year MSS rates were 52%, 44%, and 23%, respectively.

Larkin noted that the MSS results were consistent by BRAF mutation status and PD-L1 expression level.

In patients who experienced a 3-year or greater PFS from earlier data, the 10-year MSS rates were 96%, 97%, and 88% with the combination, nivolumab alone, and ipilimumab alone, respectively.

“In CheckMate 067, PFS plateaued at 3 years, and these analyses were conducted to determine if being alive and progression free at 3 years may be a surrogate for long-term clinical benefit,” Larkin explained. “Indeed, these data suggest that PFS at 3 years is a strong surrogate marker for long-term survival with 10-year MSS rates of greater than 96% in the nivolumab-containing arms.”

Ten-year MSS rates were also evaluated by depth of response and determined to be a second long-term surrogate marker. In the nivolumab/ipilimumab arm, the best tumor burden reduction was 80% or higher in 87% of patients (n = 102) and was between 50% and 80% in 72% of patients (n = 55); these rates occurred in 88% (n = 85) and 75% (n = 32) of those on nivolumab alone, and 80% (n = 24) and 40% (n = 17) in those on the ipilimumab-only arm, respectively.

Furthermore, 36% of patients on nivolumab plus ipilimumab received subsequent systemic therapy compared with 50% of those on nivolumab alone and 67% of those on ipilimumab alone. Regarding safety, there were no new observed safety signals, and no treatment-related deaths have been reported since the 36-month analysis.

Larkin also noted that the incidence of late-emergent, spontaneously reported treatment-related adverse events (TRAEs), defined as occurring more than 100 days following treatment, was low across all 3 arms. In total, any-grade TRAEs occurred in 96%, 87%, and 86% of patients in the combination, single-agent nivolumab, and single-agent ipilimumab arms, respectively; these were grade 3/4 in 63%, 25%, and 30% of patients, respectively.

Any-grade and grade 3/4 TRAEs that led to treatment discontinuation occurred in 45% and 34% of those on the combination arm, respectively, 16% and 9% in those on nivolumab alone, and 17% and 15% of those on ipilimumab alone, respectively. There were 2 treatment-related deaths on the combination arm compared with 1 each on the monotherapy arms.

The median MSS in patients with grade 3/4 TRAEs was not NR (95% CI, 71.9-NR) with the combination, NR in the nivolumab-alone arm (95% CI, NR-NR), and 30.8 months (95% CI, 22.7-62.8) with ipilimumab alone. The 10-year MSS rates in these patients were 54%, 71%, and 29%, respectively.

“TRAEs did not negatively affect survival as 10-year MSS rates in patients with a grade 3/4 TRAE were higher than in the intent-to-treat population within each treatment arm,” Larkin added.

Disclosures: Dr Larkin cited speaker, consulting, or advisory fees with iOnctura, Apple Tree, Merck, BMS, Eisai, Debiopharm, Incyte, Novartis, touchIME, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Immatics, and TouchEXPERT.

References

1. Larkin J, Sileni VC, Gaudy-Marqueste C, et al. 10-year survival outcomes from the phase 3 CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Presented at: 2024 ESMO Congress; September 12-17, 2024; Barcelona, Spain. Presentation LBA43.
2. Wolchok JD, Chiarion Sileni V, Rutkowski P, et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Eng J Med. Published September 15, 2024. doi:10.1056/NEJMoa2407417
3. Opdivo. Prescribing information. Bristol-Myers Squibb; 2024. Accessed September 15, 2024. https://packageinserts.bms.com/pi/pi_opdivo.pdf
4. Hodi FS, Chiarion-Sileni V, Lewis KD, et al. Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067. J Clin Oncol. 2022;40(suppl 16):9522-9522. doi:10.1200/JCO.2022.40.16_suppl.9522
5. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Durable clinical outcomes in patients (pts) with advanced melanoma and progression-free survival (PFS) ≥3y on nivolumab (NIVO) ± ipilimumab (IPI) or IPI in CheckMate 067. J Clin Oncol. 2023;41(suppl 16):9542. doi:10.1200/JCO.2023.41.16_suppl.9542