What are the side effects of relatlimab (combined with nivolumab) in patients ≥12 years old, weighing ≥40 kg, with unresectable or metastatic melanoma?

Side Effects Profile of Relatlimab Combined with Nivolumab

Relatlimab combined with nivolumab demonstrates a favorable safety profile with grade 3-4 treatment-related adverse events occurring in 18.9-23% of patients, significantly lower than nivolumab plus ipilimumab (61-73%), though higher than nivolumab monotherapy (9.7-11.1%). 1

Overall Toxicity Profile

The combination shows moderate toxicity with manageable immune-related adverse events:

• Grade 3-4 treatment-related adverse events (TRAEs): 18.9-21.1% 1, 2
• Any-grade TRAEs leading to discontinuation: 17% 3
• Notably, no grade 3-4 immune-related adverse events (irAEs) were reported in the neoadjuvant setting (n=30 patients) 4

This represents a middle ground between the lower toxicity of nivolumab monotherapy (9.7% grade 3-4 TRAEs) and the substantially higher toxicity of nivolumab plus ipilimumab (61% grade 3-4 TRAEs) 3.

Specific Organ System Toxicities

Endocrine System - Critical Concern

Adrenal insufficiency occurs at unexpectedly high rates (8%) with relatlimab-nivolumab, representing an 8-fold increase compared to nivolumab monotherapy (<1%) 5. This is likely secondary to hypophysitis and represents the most significant safety signal for this combination.

Key clinical features:

• Median onset after 7 doses (range 4-10)
• Presenting symptoms: fatigue, anorexia, nausea, vomiting
• Risk increases with cumulative dosing
• No additional anterior pituitary deficiencies typically develop 5

Cardiac System - Emerging Risk

Relatlimab-nivolumab shows increased cardiac-specific risks compared to other ICI combinations 6:

• Myocarditis (ROR = 2.84 for cardiac disorders)
• Troponin elevation
• Vascular disorders (ROR = 2.04)

This contrasts with nivolumab-ipilimumab, which shows lower cardiac toxicity but higher gastrointestinal, hepatobiliary, and respiratory toxicities 6.

Gastrointestinal, Hepatic, and Respiratory

Lower rates compared to nivolumab-ipilimumab 6:

• Reduced colitis risk (ROR = 1.39 for nivo-ipi vs baseline for nivo-rela)
• Less hepatitis (ROR = 2.32 for nivo-ipi)
• Fewer pneumonitis cases (ROR = 1.18 for nivo-ipi)

Ophthalmologic - Rare but Severe

Complete color vision loss has been reported as a rare but potentially irreversible complication 7:

• Bilateral serous macular detachment
• Persistent "black and white vision" despite treatment
• Likely represents direct photoreceptor or retinal ganglion cell toxicity
• Onset after as few as 2 doses

Temporal Pattern

80% of adverse events occur within 3 months of treatment initiation 6:

• Median time-to-onset: 57 days for relatlimab-nivolumab
• Comparable to nivolumab-ipilimumab (42 days, p=0.66)
• Most intensive monitoring should occur in first 12 weeks

Safety in Special Contexts

Neoadjuvant Setting

Exceptionally favorable profile in the neoadjuvant context 4:

• 0% grade 3-4 irAEs in 30 patients
• 57% pathologic complete response rate
• Supports use in perioperative setting

With Concurrent Local Therapy

Safe combination with stereotactic radiosurgery (SRS) for brain metastases 8:

• No symptomatic radiation necrosis reported
• 75% of patients received concurrent local therapy
• Median CNS-PFS of 5.3 months

Clinical Decision Algorithm

Choose relatlimab-nivolumab when:

1. Patient requires combination immunotherapy efficacy
2. Patient has contraindications to high-dose corticosteroids (needed more often with nivo-ipi)
3. Lower gastrointestinal/hepatic toxicity risk is priority
4. Neoadjuvant setting where minimal toxicity is essential

Avoid or use extreme caution when:

1. Pre-existing cardiac disease (consider nivo-ipi instead)
2. History of pituitary/adrenal disorders
3. Baseline visual impairment where color vision loss would be catastrophic
4. Patient cannot tolerate frequent endocrine monitoring

Monitoring Requirements

Mandatory surveillance:

• Cortisol/ACTH assessment at baseline and with any fatigue, nausea, or hypotension (given 8% adrenal insufficiency risk)
• Cardiac biomarkers (troponin) at baseline and with symptoms
• Ophthalmologic evaluation if any visual changes
• Most intensive monitoring in first 3 months when 80% of events occur

The safety profile remains consistent with longer follow-up (minimum 57.3 months), with no new safety signals emerging over time 9.