Long-Term CheckMate 238 Data Support Adjuvant Nivolumab Vs Ipilimumab in Resected Melanoma

Adjuvant nivolumab (Opdivo) continued to significantly improve relapse-free survival (RFS) over ipilimumab (Yervoy) in patients with resected stage III or IV melanoma, according to 7-year minimum follow-up efficacy data from the phase 3 CheckMate 238 study (NCT02388906) presented at the 2023 ESMO Congress.¹

In all patients, treatment with nivolumab (n = 453) resulted in a median RFS of 61.1 months (95% CI, 42.9-not reached [NR]) vs 24.2 months (95% CI, 16.6-35.1) with ipilimumab (n = 453; HR, 0.74; 95% CI, 0.62-0.88). The 84-month RFS rates with nivolumab and ipilimumab were 45% and 38%, respectively. Nivolumab demonstrated a RFS benefit over ipilimumab spanning the majority of patient subsets, including those with stage IIIB or IIIC disease, and regardless of BRAF mutational status.

In those with stage IIIB disease, those who received nivolumab (n = 166) experienced a median RFS that was NR (95% CI, 61.1-NR) vs 42.3 months (95% CI, 21.8-NR) with ipilimumab (n = 147; HR, 0.73; 95% CI, 0.53-1.01). The respective 84-month RFS rates were 53% and 46%, respectively. Within the stage IIIC disease subset, those given nivolumab (n = 202) experienced a median RFS of 41.5 months (95% CI, 22.1-62.4) vs 16.8 months (95% CI, 10.8-29.6) with ipilimumab (n = 219; HR, 0.78; 95% CI, 0.60-1.00). The respective 84-month RFS rates were 39% and 34%, respectively.

Within the subset of patients with BRAF-mutated disease, those given nivolumab (n = 187) experienced a median RFS of 68.6 months (95% CI, 35.0-NR) vs 25.5 months (95% CI, 15.9-55.1) with ipilimumab (n = 194; HR, 0.80; 95% CI, 0.61-1.06). The 84-month RFS rates with nivolumab or ipilimumab were 45% and 39%, respectively. In the BRAF wild-type group, the median RGS was 50.2 months (95% CI, 36.3-NR) with nivolumab (n = 197) and 16.6 months (95% CI, 11.6-35.1) with ipilimumab (n = 212; HR, 0.70; 95% CI, 0.54-0.91). The respective 84-month RFS rates were 43% and 35%, respectively.

Moreover, the median distant metastasis-free survival (DMFS) in all randomized patients with stage III disease given nivolumab (n = 370) was NR (95% CI, 70.5-NR) vs 84.0 months (95% CI, 44.9-NR) with ipilimumab (n = 366; HR, 0.82; 95% CI, 0.66-1.01). The respective 84-month DMFS rates were 54% and 50%, respectively. The median time from initial study randomization to second disease progression or death (PFS2) with nivolumab (n = 453) was NR vs NR (95% CI, 68.2-NR) with ipilimumab (HR, 0.76; 95% CI, 0.62-0.93); the 84-month PFS2 rates were 60% and 52%, respectively. In all patients, the median overall survival (OS) was NR in either arm (HR, 0.89; 95% CI, 0.70-1.14); the 84-month OS rates were 71% and 69%, respectively. The median melanoma-specific survival (MSS) was NR in either arm (HR, 0.89; 95% CI, 0.68-1.16); the 84-month MSS rates were 75% and 72%, respectively.

“With the longest follow-up of any adjuvant anti–PD-1 used to treat resected stage III or stage IV melanoma, [of a] minimum [of] 7 years, nivolumab continued to demonstrate significant improvement in RFS vs ipilimumab [at] 10 mg/kg,” Paolo A. Ascierto, MD, of Istituto Nazionale Tumori IRCCS Fondazione Pascale in Naples, Italy, and study authors, wrote in a poster of the data. “…DMFS and PFS2 analyses also favored nivolumab over ipilimumab [at] 10 mg/kg, providing additional evidence to support the treatment benefit.”

In December 2017, the FDA approved nivolumab as adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease based on earlier CheckMate 238 trial data.² The 18-month RFS rates for nivolumab and ipilimumab were 66.4% (95% CI, 61.8%-70.6%) and 52.7% (95% CI, 47.8%-57.4%), respectively, in those with stage IIIB/C or IV melanoma. Five-year follow-up data showed continued superior RFS with nivolumab vs ipilimumab as well as DMFS activity.³ The OS data did not differ significantly between the arms at this time point, which had 75% data maturity.

CheckMate 238 enrolled patients over 15 years of age who had high-risk, completely resected stage IIIB to C or stage IV melanoma by the seventh edition of American Joint Committee on Cancer staging system who had not received prior systemic treatment.¹ They had an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to receive 3 mg/kg of intravenous (IV) nivolumab every 2 weeks plus placebo every 3 weeks for 4 doses then every 12 weeks from week 24 (n = 453) or 10 mg/kg of IV ipilimumab every 3 weeks for 4 doses then every 12 weeks from week 24 and placebo every 2 weeks (n = 453). Patients received up to 1 year maximum of treatment. Randomization was stratified by disease stage (IIIB to C vs IV M1a or M1v vs IV M1c) and PD-L1 status at 5% cutoff.

RFS served as the trial’s primary end point, and key secondary end points included OS and safety. Exploratory end points included DMFS, PFS2, and MSS.

At a data cutoff date of February 24, 2023, about half of patients in the nivolumab and ipilimumab arms experienced recurrence (50% vs 55%). Most recurrences were because of distant (29% vs 33%) and locoregional (18% vs 20%) metastases. Since the 60-month follow-up, a total of 11 new recurrences occurred in the nivolumab arm with 1 death vs 3 new recurrences in the ipilimumab arm with 4 deaths. A total of 13 new deaths since the 5-year update were reported in the nivolumab arm vs 12 new deaths in the ipilimumab arm; 8 and 10, respectively, were because of melanoma.

In the nivolumab and ipilimumab arms, 44% and 50% of those who recurred went on to receive subsequent treatment. Those who received nivolumab were less likely to receive subsequent immunotherapy compared with those who were given ipilimumab, at 26% vs 36%, respectively. In the nivolumab arm, patients went on to receive nivolumab (13%), pembrolizumab (Keytruda; 7%), ipilimumab (16%), ipilimumab plus nivolumab (6%), ipilimumab plus pembrolizumab (<1%), a BRAF inhibitor (16%), a MEK/NRAS inhibitor (14%), other experimental drugs (4%), chemotherapy (10%), radiotherapy (9%), or surgery (22%); in the ipilimumab arm, these respective rates were 18%, 21%, 7%, 6%, 0%, 16%, 17%, 5%, 12%, 10%, and 19%.

“The additional recurrences that occurred after 5 years may indicate a clinical need for follow-up visits and a potential need for imaging assessments extending beyond 5 years,” the study authors concluded.

References

1. Ascierto PA, Del Vecchio M, Merelli B, et al. Adjuvant nivolumab (nivo) vs ipilimumab (ipi) in resected stage III/IV melanoma: 7-y results from CheckMate 238. Ann Oncol. 2023;34(suppl 2):S656. doi:10.1016/j.annonc.2023.09.2223
2. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. FDA. December 20, 2017. Accessed February 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-nivolumab-adjuvant-treatment-melanoma
3. Larkin J, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 5-year efficacy and biomarker results from CheckMate 238. Clin Cancer Res. 2023;29(17):3352-3361. doi:10.1158/1078-0432.CCR-22-3145