Adjuvant Nivolumab/Ipilimumab Lengthens DMFS in High-Risk Uveal Melanoma

Adjuvant nivolumab (Opdivo) in combination with ipilimumab (Yervoy) significantly improved 3-year distant metastasis–free survival (DMFS) rates compared with historical controls in patients with high-risk uveal melanoma, according to findings from the phase 2 HCRN MEL17-309 trial (NCT03528408) presented at the 2024 ASCO Annual Meeting.¹

At a median follow-up of 36.8 months, the adjusted 3-year DMFS rate with nivolumab plus ipilimumab was 70.4% (95% CI, 56%-85%) vs 43.4% (95% CI, 30%-56%) with external controls (relative risk, 0.52; 95% CI, 0.31-0.88; 2-sided P = .018). The median DMFS with nivolumab plus ipilimumab was not reached (NR; 95% CI, 44.8 months–NR) vs 32.3 months (95% CI, 29.4-44.8) with controls.

“Metastatic uveal melanoma has a poor prognosis, and the few approved treatment options are restricted to specific populations,” lead study author Suthee Rapisuwon, MD, said in the presentation. Rapisuwon is a medical oncologist, medical geneticist, and hematologist at MedStar Georgetown Cancer Institute at MedStar Washington Hospital Center in Washington, DC.

Nivolumab plus ipilimumab has previously demonstrated limited activity in uveal melanoma metastases. For instance, in the phase 2 GEM-1402 trial (NCT02626962), the combination yielded an overall response rate of 11.5% (95% CI, 2.9%-20.2%), composed of 1 complete response and 5 partial responses.² However, Rapisuwon emphasized that micrometastases may have biological differences from macrometastatic disease.¹

The single-arm HCRN MEL17-309 trial aimed to determine whether administering nivolumab plus ipilimumab in the adjuvant setting could activate immune surveillance and decrease the incidence of distant metastases in patients with uveal melanoma. This investigator-initiated trial enrolled patients with primary, high-risk uveal melanoma. To be considered to have high-risk disease, patients needed to meet at least 1 of the 3 following criteria: a gene expression profile (GEP) class of 2 and a largest basal tumor diameter of at least 12 mm; monosomy 3 and an apical tumor height of at least 8 mm; and a 3-year DMFS of 50% or less per the Liverpool Uveal Melanoma Prognosticator Online (LUMPO) calculator. Patients also needed to have undergone definitive treatment with local therapy within the past 6 months prior to enrollment and have received no prior systemic therapy.

Patients registered on the trial received ipilimumab at 1mg/kg every 6 weeks plus nivolumab at 240 mg every 2 weeks for a total of 48 weeks. This was the same regimen as was investigated in the phase 3 CheckMate915 trial (NCT03068455), Rapisuwon noted. Upon follow-up, survival data were compared with a matched external control in a 2:1 fashion using either contemporaneous databases or historical control data from the Collaborative Ocular Oncology Group Report Number 1 (COOG1), which featured the same DMFS risk profile as the patients enrolled in HCRN MEL17-309.

The primary end point of the trial was 3-year DMFS rate. Secondary end points included median DMFS, median overall survival (OS), 3-year OS rate, and adverse effects (AEs).

In total, 61 patients were assessed for eligibility, 9 of whom were excluded because they did not meet the enrollment criteria (n = 6) or because they declined to participate (n = 3). The remaining 52 patients were assigned to receive adjuvant nivolumab plus ipilimumab, 1 of whom withdrew consent, and 1 of whom was ineligible for treatment due to detected metastasis at registration. Overall, 50 patients were included in the per-protocol population; 27 completed the protocol treatment, 22 discontinued treatment due to AEs, and 1 withdrew consent and discontinued treatment after 4 cycles.

In the per-protocol population, patients had a median age of 61.5 years (range, 36-79), and most patients were male (52%) and White (86%). Patients had a median tumor height of 16.0 mm (range, 2.6-85). Ninety-six percent of patients had a 15-gene GEP class of 2, 4% of patients had monosomy 3 and an apical tumor height of at least 8 mm, and no patients had a 3-year DMFS of 50% or less per the LUMPO calculator. Primary treatments included brachytherapy (70%), proton beam therapy (16%), and enucleation (14%); 6 patients had missing data regarding primary treatment.

In the COOG1 control arm (n = 119), patients had a median age of 67.2 years (range, 39.4-90), and most patients were female (55.46%). All patients had a 15-gene GEP class of 2. Primary treatments included brachytherapy (71%) and enucleation (28%). Baseline characteristics from the contemporaneous control were unavailable at the time of data cutoff, Rapisuwon noted.

Four patients in the per-protocol population developed distant metastases within 6 months of starting treatment. Eight patients developed distant metastases between treatment completion and the landmark 3-year analysis. Most of the 22 patients who discontinued treatment because of treatment-related AEs (TRAEs) remained free of micrometastatic disease at data cutoff.

Among patients in the investigational arm, the most common TRAEs reported in at least 10% of patients included fatigue (any-grade, n = 26; grade ≥3, n = 0), pruritus (23; 1), maculopapular rash (15; 1), nausea (14; 0), hypothyroidism (13; 1), increased aspartate aminotransferase (AST; 10; 1), diarrhea (9; 2), headache (8; 0), increased alanine aminotransferase (ALT; 8; 2), arthralgia (7; 0), increased creatinine (7; 0), hyperthyroidism (7; 0), colitis/proctitis (7; 4), dry skin (6; 0), adrenal insufficiency (6; 2), myalgia (5; 0), anorexia (5; 0), and increased creatinine phosphokinase (5; 0). Overall, 28% of patients had grade 3 or higher TRAEs.

In total, 44% of patients had any-grade TRAEs leading to treatment discontinuation, including myocarditis/increased troponin (6%), pneumonitis (6%), pancreatitis (2%), nephritis (2%), diarrhea (8%), colitis/proctitis (10%), hepatitis/elevated AST/elevated ALT (6%), uveitis (2%), and sensory neuropathy (2%). One patient died from grade 5 treatment-related myocarditis.

“There was a higher-than-expected incidence of TRAEs with this regimen, and there were no new safety signals compared with [those seen in] the cutaneous melanoma cohort [of CheckMate915]. Further investigation of the regimen as an adjuvant treatment for high-risk uveal melanoma is warranted,” Rapisuwon concluded.

Tissue, blood, and correlative biomarker data were collected and are undergoing study.

Disclosures: Dr Rapisuwon reports stock ownership with Cardiff Oncology; receiving honoraria from General Dynamics Information Technology; consulting or advisory roles with Castle Biosciences and Replimune; and receiving institutional research funding from AstraZeneca, Bristol-Myers Squibb, Pfizer, and Seattle Genetics/Astellas.

References

1. Rapisuwon A, Carvajal RD, Ansstas G, et al. Phase II multi-center study of adjuvant nivolumab in combination with ipilimumab in patients with high-risk uveal melanoma (HCRN MEL17-309). J Clin Oncol. 2024;42(suppl 16):9509. doi:10.1200/JCO.2024.42.16_suppl.9509
2. Piulats JM, Espinosa E, de la Cruz Merino L, et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: an open-label, multicenter, phase II trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021;39(6):586-598. doi:10.1200/JCO.20.00550