Ipilimumab Plus Nivolumab-Relatlimab Triplet Yields High MPR in Resectable Melanoma

Potent and durable tumor responses were noted with neoadjuvant ipilimumab (Yervoy) plus nivolumab and relatlimab-rmbw (Opdulag) in patients with macroscopic resectable clinical stage IIIB, IIIC, IIID melanoma, according to results from the phase 2 NeoINR trial (NCT06295159) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Among the 19 patients who underwent surgery with pathologic response assessment, the NeoINR regimen achieved a pathological complete response (pCR) rate of 63.2% (n = 12; 95% CI, 38.4%-83.7%) and a near-pCR rate of 10.5% (n = 2), yielding an major pathological response (MPR) rate of 73.7% (n = 14; 95% CI, 48.8%-90.9%). No patients achieved pathologic partial response, and 5 patients (26.3%) had pathologic nonresponse. Of the 3 patients who did not undergo surgery, 1 experienced a serious adverse event (SAE) precluding surgery, and 2 had a significant radiologic response and elected against surgery.

Preoperative radiologic assessment per RECIST criteria in 21 evaluable patients demonstrated an objective response rate (ORR) of 66.7% (95% CI, 43.0%-85.4%), including 1 complete response (4.8%) and 13 partial responses (61.9%), with 6 patients (28.6%) achieving stable disease.

With a median follow-up of 10.3 months (IQR, 8.2-13.8) from enrollment, the 1-year event-free survival (EFS) rate among the 22 patients who were enrolled and eligible was 95.5% (95% CI, 87%-100%). No progression to unresectability occurred before surgery, and no disease recurrences were observed after surgery. One death was attributable to a grade 5 myocarditis event.

“While limited by follow-up time, neoadjuvant [ipilimumab-nivolumab-relatinib] appears to induce potent and durable antitumor responses early on treatment in a majority of patients, [which] may translate into long term survival benefits considering [data from the phase 1/2 RELATIVITY-48 trial (NCT03459222)]; longer follow-up is ongoing,” Ahmad Tarhini, MD, PhD, tenured senior member in the Moffitt Cancer Center and Research Institute departments of Cutaneous Oncology and Immunology, director of Cutaneous Clinical and Translational Research, leader of the Neoadjuvant and Adjuvant Translational Science Program, and professor of Oncologic Sciences at the University of South Florida Morsani College of Medicine, said during the presentation.

The NeoINR regimen consisted of ipilimumab 1 mg/kg every 8 weeks for 1 cycle plus a fixed-dose combination of nivolumab 480 mg and relatlimab 160 mg every 4 weeks for 2 cycles prior to surgery, which occurs 8 weeks from cycle 1 day 1. The trial planned to enroll approximately 20 patients initially, with 2 additional patients enrolled per protocol, for a total of 22 registered eligible patients. Following surgery, patients who achieved an MPR, defined as pCR or near-pCR, were observed, while those who did not achieve MPR received adjuvant triplet therapy. Secondary end points included EFS, preoperative radiographic response rate, and safety.

Patients had a median age of 65 years; 95% were White and 68% were male. Of note, 100% had an ECOG performance status of 0, 77% had cutaneous disease, and 72% had BRAF V600 wild-type status.

Regarding safety across all 22 patients, common any-grade treatment-related adverse events (TRAEs) included alanine aminotransferase/aspartate aminotransferase (grade 1, 40.9%; grade 2, 13.6%), fatigue (grade 1, 40.9%; grade 2, 13.6%), rash maculo-papular (grade 1, 31.8%; grade 2, 9.1%; grade 3, 9.1%), pruritus (grade 1, 18.2%), and thyroid dysfunction (grade 2, 27.3%; grade 3, 4.5%). Grade 3 TRAEs were observed, including colitis/diarrhea in 9.1%, rash maculo-papular in 9.1%, arthritis in 4.5%, and encephalitis in 4.5%.

One grade 5 myocarditis event occurred in a 75-year-old male patient with an undisclosed history of autoimmune disease, resulting in death approximately 2 weeks after treatment initiation. Due to the grade 2 or higher AEs observed during treatment or patient/physician decision, 36% of patients skipped the second cycle of nivolumab/relatlimab.

The investigators concluded that this neoadjuvant triplet appeared to induce potent and durable antitumor responses in a majority of patients, with early results suggesting potential for long-term survival benefit consistent with the RELATIVITY-048 trial experience with the triplet in the unresectable setting. The regimen may also provide an opportunity to maximize organ preservation in patients with acral melanoma. An expansion cohort of 20 additional patients has been initiated, and comprehensive biomarker analysis, including prognostic and predictive markers, mechanisms of resistance, and predisposition to immune-related AEs, is ongoing.

Reference

Tarhini AA, Eroglu Z, Zager JS, et al. Neoadjuvant ipilimumab-nivolumab-relatlimab combination immunotherapy in macroscopic resectable stage III & IV(M1a) melanoma: NeoINR phase II trial. J Clin Oncol. 2026;44(suppl 16):9501. doi:10.1200/JCO.2026.44.16_suppl.9501