Nivolumab and ipilimumab combination therapy for melanoma efficacy, safety and clinical integration in metastatic and adjuvant settings

Abstract

Melanoma remains one of the most aggressive cutaneous malignancies, accounting for a disproportionate share of skin cancer-related mortality despite relatively lower incidence. Over the past decade, immune checkpoint inhibitors (ICIs) have revolutionized melanoma management, with dual blockade of programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) representing one of the most impactful therapeutic advances. This narrative review critically examines the clinical integration of nivolumab–ipilimumab (Nivo-Ipi) combination therapy across metastatic, neoadjuvant, and adjuvant melanoma settings, with emphasis on efficacy, safety, and emerging clinical challenges. Evidence from pivotal randomized trials, particularly the 10-year final outcomes of CheckMate 067, demonstrates that Nivo-Ipi confers substantial improvements in overall survival compared with ipilimumab monotherapy, and numerically superior outcomes compared with nivolumab monotherapy—though the trial was not powered to formally establish this latter comparison. Landmark analyses reveal durable survival plateaus extending beyond seven years in approximately 31% of combination-treated patients, redefining expectations for advanced melanoma. However, this enhanced efficacy is accompanied by significantly higher rates of immune-related adverse events (irAEs), necessitating careful patient selection and proactive toxicity management. Emerging data from the NADINA trial establish a compelling neoadjuvant role for the combination, while the adjuvant CheckMate 915 trial failed to demonstrate recurrence-free survival benefit over nivolumab monotherapy. Future progress will depend on biomarker-driven personalization, refined sequencing strategies, and integration of the combination within an increasingly competitive first-line landscape that now includes nivolumab plus relatlimab.

Introduction

Melanoma represents a malignant transformation of melanocytes, the pigment-synthesizing cells residing at the dermal–epidermal junction [1]. While representing a relatively small proportion of all skin cancers, melanoma accounts for a disproportionate burden of skin cancer-related mortality worldwide, driven primarily by the lethality of metastatic disease rather than overall incidence [1].

According to GLOBOCAN 2022 data, melanoma of the skin ranks as the 17th most common cancer globally by incidence, with 331,722 new cases diagnosed worldwide (age-standardized incidence rate: 3.2 per 100,000 population), and 22nd in cancer-related mortality with 58,667 deaths annually [2]. It is important to contextualize these rankings appropriately: the relatively lower mortality rank compared to incidence reflects melanoma’s high curability when detected at an early stage rather than a uniformly favorable prognosis. In the metastatic setting, prior to the immunotherapy era, five-year survival rates were below 10%, establishing metastatic melanoma as one of the most lethal solid tumor diagnoses [1, 2]. Geographic heterogeneity is marked: Europe bears the highest incidence burden (44.1% of global cases), while Asia demonstrates a higher mortality-to-incidence ratio, partly attributable to the greater prevalence of acral lentiginous and mucosal subtypes which carry distinct biology, limited immunogenicity, and historically inferior treatment outcomes [2].

The development of ICIs has fundamentally transformed this landscape. The most extensively characterized checkpoint blockade mechanisms involve inhibition of CTLA-4 and PD-1, both immunosuppressive molecules expressed on T cells and other immune effector cells [3, 4]. The pioneering approval of ipilimumab (anti-CTLA-4) by the US Food and Drug Administration (FDA) in 2011 marked the inaugural validation of checkpoint blockade as a therapeutic strategy in advanced melanoma. The subsequent approval of anti-PD-1 agents, nivolumab and pembrolizumab, demonstrated superior efficacy and tolerability compared with ipilimumab monotherapy, repositioning anti-PD-1 blockade as the backbone of checkpoint immunotherapy [5, 6]. The recognition that CTLA-4 and PD-1 inhibition exert non-redundant, complementary effects on T-cell activation provided the scientific rationale for combining the two approaches, leading to the development of Nivo-Ipi combination therapy [7, 8].

The pivotal CheckMate 067 phase 3 trial established Nivo-Ipi as a frontline therapeutic option in advanced melanoma, demonstrating superior outcomes compared with ipilimumab monotherapy and numerically favourable results versus nivolumab monotherapy—although the latter comparison was not formally powered [9]. This manuscript reviews the efficacy, safety, and clinical integration of Nivo-Ipi in the metastatic, neoadjuvant, and adjuvant settings, incorporating the most recent evidence, including the 10-year final outcomes of CheckMate 067, the NADINA neoadjuvant trial, and the evolving competitive landscape introduced by nivolumab–relatlimab [10].

Methods: This panoptic review was conducted through systematic searches of PubMed/MEDLINE, Embase, and major oncology conference proceedings (ASCO, ESMO, AACR) up to January 2026. Search terms included “nivolumab,” “ipilimumab,” “melanoma,” “immune checkpoint inhibitor,” “combination immunotherapy,” “neoadjuvant,” and “adjuvant,” supplemented by manual reference tracking of key trial publications. Studies were prioritized by evidence hierarchy (randomized controlled trials, then prospective cohorts, then retrospective series), and all major registration trials relevant to Nivo-Ipi in melanoma were included. Real-world evidence was incorporated where it complemented or contextualized trial findings.

Mechanism of action

Ipilimumab

Ipilimumab is a human IgG1 monoclonal antibody targeting CTLA-4, the first immune checkpoint molecule to be clinically validated as a therapeutic target in cancer [11]. CTLA-4 is upregulated on T cells following activation and competes with the co-stimulatory receptor CD28 for binding to B7 molecules (CD80 and CD86) on antigen-presenting cells. The binding of CTLA-4 to B7 delivers a potent inhibitory signal that attenuates T-cell activation, serving as a physiological brake to prevent immune overactivation and autoimmunity [11]. By blocking CTLA-4, ipilimumab sustains T-cell activation, proliferation, and cytokine production, and simultaneously diminishes regulatory T-cell (Treg)-mediated immunosuppression within the tumor microenvironment [11]. Ipilimumab received FDA approval in 2011 for advanced melanoma, marking the first demonstration that immune checkpoint modulation could meaningfully extend survival in this disease [6, 10, 11]. However, with the subsequent approval of anti-PD-1 agents demonstrating superior single-agent activity and tolerability, ipilimumab monotherapy is no longer deployed as the first-line standard in the modern era; its principal clinical value now lies in combination with PD-1 blockade [6].

Nivolumab

Nivolumab is a fully human IgG4 monoclonal antibody targeting PD-1, a critical immune checkpoint expressed on activated T cells [12]. Under physiological conditions, PD-1 interacts with its ligands, PD-L1 and PD-L2, which are frequently upregulated on tumor cells and within the tumor microenvironment. This interaction transmits an inhibitory signal that suppresses T-cell activation, enabling cancer cells to evade immune surveillance. By selectively binding to PD-1, nivolumab interrupts this interaction, restoring T-cell capacity to recognize and eliminate tumor cells [13]. Anti-PD-1 agents, including nivolumab (FDA approved for advanced melanoma in 2014) and pembrolizumab, have demonstrated superior efficacy compared with ipilimumab monotherapy, with more favorable toxicity profiles, and have established themselves as the dominant backbone of checkpoint immunotherapy in melanoma [6, 14].

Scientific basis for combination: Enhanced T-cell activation

The rationale for combining nivolumab and ipilimumab lies in the complementarity of their mechanisms across distinct anatomical compartments of T-cell regulation. Ipilimumab primarily acts in lymphoid tissues, enhancing T-cell priming and proliferation during the initial activation phase [11], while nivolumab restores the effector function of T cells rendered exhausted by PD-1 signaling within the tumor microenvironment [13]. Dual checkpoint blockade leads to increased infiltration of activated cytotoxic T lymphocytes into tumors, enhanced cytokine production, and reduced Treg-mediated immunosuppression—all factors contributing to superior anti-tumor responses compared with either agent alone [7, 8]. The clinical and preclinical data supporting this synergy are well established, though the enhanced immune activation comes at the cost of substantially increased irAEs.

Clinical efficacy: metastatic disease

Combination therapy evidence

CheckMate 067 remains the cornerstone randomized trial establishing the efficacy of Nivo-Ipi in previously untreated, unresectable stage III or IV melanoma. This multinational, randomized, double-blind, phase 3 trial enrolled 945 patients allocated (1:1:1) to nivolumab alone (3 mg/kg every 2 weeks), ipilimumab alone (3 mg/kg every 3 weeks × 4 doses), or the combination (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 doses, followed by nivolumab 3 mg/kg maintenance). The trial was primarily designed to demonstrate superiority of the combination arm and the nivolumab monotherapy arm over ipilimumab and was not formally powered to establish superiority of the combination over nivolumab alone. Comparisons between these two active arms are therefore exploratory in nature and must be interpreted accordingly [9, 10].

The 10-year final outcomes represent the most mature and definitive dataset from this trial [10]. At 10 years, overall survival (OS) rates were approximately 31% for the combination arm, 26% for nivolumab monotherapy, and 15% for ipilimumab monotherapy. A distinctive survival plateau beyond year 7 observed primarily in the combination and nivolumab arms is indicative of durable immune-mediated tumor control rather than ongoing therapeutic effect. Median OS was 72.1 months with Nivo-Ipi, 36.9 months with nivolumab, and 19.9 months with ipilimumab. Objective response rates were 58% (combination), 44% (nivolumab), and 19% (ipilimumab), with median progression-free survival of 11.5, 6.9, and 2.9 months, respectively. Importantly, a significant proportion of responders in the combination arm achieved treatment-free survival, with approximately 71% of complete responders off therapy at 5 years, reflecting deep and durable immune-mediated remissions [10].

The earlier CheckMate 069 phase 2 trial provided initial support for the combination’s synergy, demonstrating an ORR of 61% with Nivo-Ipi versus 11% with ipilimumab alone in BRAF wild-type patients, with a median PFS of 11.7 months [13–15].

Real-world evidence

While the CheckMate 067 dataset provides the definitive efficacy foundation, real-world evidence confirms generalizability. The DAMMED registry analyzed over 1,000 European patients treated with Nivo-Ipi and reported a 2-year OS rate of 63%, consistent with trial findings despite inclusion of patients with comorbidities and poorer performance status typically excluded from randomized trials [16]. US-based real-world cohort studies similarly report prolonged OS in diverse populations, including older adults [16, 17].

Special populations

Patients with brain metastases

Brain metastases historically portended dismal outcomes in melanoma. The CheckMate 204 trial enrolled patients with asymptomatic brain metastases and demonstrated an intracranial ORR of 55% (complete response in 21%), a 6-month PFS of 67%, and a 12-month OS rate of 81.5% [18]. The concordance between intracranial and extracranial responses established that Nivo-Ipi induces systemic immune activation that can cross the blood–brain barrier, repositioning this combination as the preferred frontline approach for eligible patients with brain involvement.

The ABC trial extended this evidence to a broader population, including patients with symptomatic brain metastases [19]. While the combination demonstrated meaningful intracranial activity even in this higher-risk cohort, response rates in symptomatic patients were lower than in asymptomatic patients, underscoring the importance of early intervention before neurological deterioration occurs. These findings support a multidisciplinary approach in which local therapies (stereotactic radiosurgery, surgery) may be combined with systemic Nivo-Ipi, particularly for symptomatic lesions, with the combination continuing to address the broader systemic disease burden.

PD-L1–negative and high tumor burden populations

PD-L1 expression has limited discriminatory value in melanoma treatment selection. CheckMate 067 subgroup analyses demonstrated that patients with PD-L1–negative tumors (< 1%) derived particularly meaningful benefit from Nivo-Ipi relative to nivolumab monotherapy (OS hazard ratio 0.69 for combination vs. nivolumab in PD-L1–negative patients), consistent with the hypothesis that CTLA-4 co-blockade may overcome immunologically cold tumor microenvironments that are less responsive to PD-1 blockade alone [9]. Patients with high tumor burden (elevated LDH, multiple organ metastases) similarly benefited from the upfront intensity of combination therapy, achieving faster and more durable responses.

Neoadjuvant immunotherapy

Rationale for neoadjuvant approach

The neoadjuvant administration of immune checkpoint inhibitors prior to surgical resection of resectable stage III melanoma represents one of the most rapidly evolving areas in melanoma therapeutics. The biological rationale is compelling: intact tumor antigen release in situ may enhance immune priming, tumor-draining lymph nodes provide an active immunological context for T-cell activation, and pathological response at surgery serves as an early surrogate endpoint for long-term outcome, permitting response-adapted adjuvant strategies [20]. This approach contrasts with adjuvant immunotherapy, which operates in a minimal residual disease context with limited antigen stimulus.

Key trials: OPACIN-NEO, PRADO, and NADINA

The OPACIN-NEO trial compared three neoadjuvant dosing schedules of Nivo-Ipi in resectable stage III melanoma, demonstrating that a reduced-dose regimen of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (two cycles before surgery) achieved pathological response rates of 57% with a substantially improved safety profile compared to the standard 3 + 1 dosing (ipilimumab 3 mg/kg plus nivolumab 1 mg/kg), which was associated with prohibitive grade 3–4 toxicity in 90% of patients. This finding established that dose optimization is essential in the neoadjuvant context, where toxicity-related surgical delays represent a clinically significant risk [20].

The PRADO trial, a response-adapted extension of OPACIN-NEO, demonstrated that patients achieving a major pathological response (MPR) after two cycles of neoadjuvant ipilimumab 1 mg/kg plus nivolumab 3 mg/kg could be spared completion lymph node dissection and adjuvant therapy without compromising outcomes, an approach with potential for meaningful reduction in both surgical morbidity and treatment burden [20].

The landmark NADINA phase 3 trial established neoadjuvant nivolumab–ipilimumab followed by response-adapted adjuvant therapy as superior to adjuvant nivolumab alone in resectable stage III melanoma [20, 21]. The 12-month event-free survival (EFS) rate was 83.7% in the neoadjuvant combination arm versus 57.2% in the adjuvant nivolumab arm—a highly significant and clinically meaningful difference. Pathological complete response occurred in 47% of patients receiving neoadjuvant Nivo-Ipi. These results represent a paradigm shift, establishing perioperative immunotherapy as a potential new standard of care for resectable stage III melanoma and underscoring the superior immune priming afforded by neoadjuvant checkpoint blockade compared with postoperative adjuvant therapy [21].

The neoadjuvant principle extends beyond Nivo-Ipi specifically. The SWOG S1801 trial demonstrated that neoadjuvant pembrolizumab followed by adjuvant pembrolizumab was superior to adjuvant pembrolizumab alone in resectable stage III–IV melanoma, with a 2-year event-free survival of 72% versus 49% (HR 0.58; P = 0.004) [22]. This convergent evidence from two independent neoadjuvant trials, one with anti-PD-1 monotherapy and one with dual checkpoint combination establishes the neoadjuvant window as the optimal timing for immune checkpoint inhibition in resectable disease, regardless of the specific agent used. Collectively, these data suggest that neoadjuvant immunotherapy should now be the default perioperative strategy for eligible patients with resectable stage III melanoma, with choice of regimen guided by individual disease burden, performance status, and anticipated toxicity tolerance.

Dosing and toxicity considerations in the neoadjuvant setting

The neoadjuvant ‘Nivo-Ipi’ using the reduced-dose ipilimumab schedule (1 mg/kg + nivolumab 3 mg/kg × 2 cycles) is associated with grade 3–4 irAEs in approximately 30–40% of patients—lower than the ~ 60% observed with standard dosing but still clinically significant [20–22]. The critical practical challenge is irAE-related surgical delay: severe colitis, hepatitis, or endocrinopathy requiring prolonged immunosuppression may postpone planned resection, with implications for staging and resectability. Multidisciplinary coordination between oncology, surgery, and supportive care teams is therefore essential. The development of validated pathological response criteria and standardized irAE management protocols specific to the neoadjuvant context remains an active area of investigation.

Clinical efficacy of adjuvant therapy

Rationale for adjuvant therapy

The goal of adjuvant therapy in resected high-risk melanoma is to eliminate minimal residual microscopic disease, thereby reducing recurrence risk and improving long-term survival. In high-risk stage III and resected stage IV melanoma, residual tumor cells may escape immune surveillance despite complete macroscopic resection. The immunological rationale for postoperative checkpoint blockade rests on the ability of anti-PD-1 and anti-CTLA-4 agents to sustain T-cell activation and prevent the reestablishment of immunosuppressive tumor microenvironments at potential sites of micrometastatic disease [22].

Evidence for monotherapy: Checkmate 238 (nivolumab)

The CheckMate 238 trial established nivolumab monotherapy as superior to ipilimumab (at the 10 mg/kg adjuvant dose) in resected stage IIIB–C or IV melanoma. In this randomized, double-blind, phase 3 trial (n = 906), nivolumab demonstrated a significantly better recurrence-free survival (RFS), with a median RFS of 11.0 months versus 5.5 months for ipilimumab (HR 0.65; P < 0.001), and 12-month RFS rates of 70.5% versus 60.8%. At five-year follow-up, RFS rates were 50% versus 39%, with a substantially more favorable safety profile (grade 3–4 adverse events: 14.4% versus 45.9%) [22, 23]. These data resulted in FDA approval of nivolumab for adjuvant treatment of high-risk melanoma in 2017, establishing anti-PD-1 monotherapy as the reference standard.

Evidence for combination: Checkmate 915

CheckMate 915 directly addressed whether adding ipilimumab to adjuvant nivolumab confers additional benefit over nivolumab alone. In this randomized, phase 3 trial in patients with resected stage IIIB–D or IV melanoma, the combination arm (nivolumab 240 mg + ipilimumab 1 mg/kg) failed to demonstrate a statistically significant improvement in RFS compared with nivolumab monotherapy (HR 0.92; 95% CI 0.77–1.09; P = 0.269), with 24-month RFS rates of 64.6% versus 63.2% [24, 25]. Furthermore, grade 3–4 treatment-related adverse events were significantly more frequent in the combination arm (32.6%) than in the nivolumab-alone arm (12.8%), leading to greater treatment discontinuation and reduced cumulative drug exposure, which may have contributed to the neutral efficacy outcome.

Several explanations have been proposed for the negative result. The enrolled population (resected stage IIIB–D), while high-risk, may have had sufficient immune priming from anti-PD-1 alone in the adjuvant context, where low tumor antigen burden limits the additive contribution of CTLA-4 co-blockade. The relatively lower ipilimumab dose (1 mg/kg) may have been insufficient to achieve meaningful CTLA-4 inhibition in this setting. Additionally, immune activation sufficient for durable tumor surveillance may reach a ceiling effect with anti-PD-1 alone in surgically rendered disease, beyond which further stimulation does not add clinical benefit.

It is essential to note that the subgroup analyses from CheckMate 915, including apparent signals in specific subgroups such as ulcerated primaries or elevated LDH, are exploratory and were not the primary endpoints of the trial. The majority of subgroup analyses were consistent with the overall null result, and isolated apparent benefits (including the counterintuitive greater benefit from monotherapy in BRAF-mutant tumors) most plausibly reflect chance findings given the multiple comparisons performed. These exploratory signals should not be used to justify routine combination adjuvant use.

The IMMUNED trial: a signal in higher-risk disease

The IMMUNED trial provides the most clinically plausible signal for adjuvant Nivo-Ipi in a specifically selected high-risk population [26]. IMMUNED enrolled patients with resected stage IV melanoma and high-risk resected stage IIIC disease, randomizing them to nivolumab–ipilimumab versus nivolumab alone versus ipilimumab alone. The combination demonstrated a statistically significant improvement in 2-year RFS compared with ipilimumab alone (68% vs. 40%), with a numerically but non-significantly higher 2-year RFS than nivolumab monotherapy (68% vs. 56%). While these data do not establish the combination as a new adjuvant standard, they suggest that in patients with resected stage IV disease—carrying substantially higher relapse risk than stage III—the combination may warrant consideration, particularly where PD-L1–negative disease or other high-risk features are present. Prospective validation remains needed.

Safety profile

Combination-specific toxicities: comparison with monotherapy

Nivo-Ipi is associated with a substantially higher irAE burden than either agent alone. In CheckMate 067, grade 3–4 treatment-related adverse events occurred in approximately 59% of patients in the combination arm, compared with 21% in the nivolumab arm and 28% in the ipilimumab monotherapy arm. This significantly higher toxicity translated to treatment discontinuation in 39% of combination-treated patients, compared with 10% and 14% for the monotherapy arms [9, 18].

Qualitatively, the combination produces a broader and more severe irAE profile than monotherapy. Gastrointestinal irAEs [colitis and diarrhea] are more frequent and more severe with the combination, reflecting the critical role of CTLA-4 in intestinal immune homeostasis; grade 3–4 diarrhea/colitis occurs in approximately 15–17% of combination-treated patients, versus 2% with nivolumab monotherapy. Hepatitis, including grade 3–4 ALT/AST elevation, occurs in approximately 18% of combination patients versus 4% with nivolumab alone. Endocrine irAEs, particularly hypophysitis (6–8% with combination versus < 1% with nivolumab), thyroiditis, and adrenal insufficiency, are substantially more frequent with dual blockade. The onset of dermatologic irAEs[rash and pruritus] tends to occur earlier with the combination than with monotherapy, often within the first two cycles.

Vitiligo, which may develop during or after therapy, is associated with improved anti-tumor immune response and should not trigger treatment interruption in isolation. Maculopapular rashes, lichenoid reactions, and psoriasiform eruptions are the most commonly encountered dermatologic presentations.

CheckMate 511 directly addressed the dose-dependent toxicity of Nivo-Ipi by randomizing patients to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). N3I1 demonstrated a significantly lower incidence of grade 3–4 irAEs (34% versus 48%) with no statistically significant difference in ORR (45.3% versus 51.4%) or PFS [27]. Accordingly, N3I1 has become the preferred dosing schedule for first-line metastatic disease, given its superior tolerability while maintaining meaningful efficacy.

It is important to distinguish common from rare irAEs. Diarrhea/colitis, rash, pruritus, hepatitis, and thyroid dysfunction are common, collectively affecting 30–60% of combination-treated patients. Conversely, myocarditis and new-onset type 1 diabetes mellitus are rare but potentially life-threatening irAEs, occurring in fewer than 1–2% of patients. Despite their low incidence, myocarditis carries a high mortality risk if not recognized early, and early troponin surveillance should be considered in high-risk patients (Table 1).

Table 1.

Approximate grade 3–4 irAE frequency comparison between Nivo-Ipi and nivolumab monotherapy, based on CheckMate 067 aggregate data. Gr: grade; GI: gastrointestinal; Mono: monotherapy

irAE category	Nivo-Ipi (Gr 3–4%)	Nivolumab Mono (Gr 3–4%)	Frequency classification
GI (colitis/diarrhea)	15–17%	2–3%	Common
Hepatitis (ALT/AST)	~ 18%	~ 4%	Common
Hypophysitis	6–8%	< 1%	Uncommon (combination)
Thyroid dysfunction	~ 22%	~ 8%	Common
Dermatologic (rash/pruritus)	~ 3–4%	~ 1–2%	Common (any grade)
Myocarditis	< 1%	< 0.5%	Rare, high mortality
Type 1 Diabetes	< 2%	< 1%	Rare, typically permanent

Management algorithms

Dermatologic irAEs

Management is graded by severity per ASCO and NCCN guidelines. Grade 1 reactions (macules/papules covering < 10% body surface area) may be managed with symptomatic treatment and continuation of immunotherapy; persistent reactions require topical steroids and close monitoring. Grade 2 reactions necessitate holding ipilimumab, initiating topical or systemic corticosteroids (prednisone 0.5–1 mg/kg/day), and considering dermatology consultation. For grade 3–4 reactions, including severe cutaneous manifestations such as Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), permanent discontinuation is mandatory, with high-dose systemic steroids (1–2 mg/kg/day) and urgent dermatology review [28]. For steroid-refractory or severe dermatologic presentations, a composite study provides a comprehensive management framework, recommending the utilization of systemic immunomodulators like infliximab or mycophenolate mofetil for persistent or life-threatening cutaneous reactions that fail to respond to high-dose corticosteroids [29].

Gastrointestinal irAEs

Gastrointestinal irAEs, particularly colitis are among the most common and clinically significant toxicities with Nivo-Ipi. Grade 1 diarrhea is managed conservatively with antidiarrheal agents and close monitoring. Grade 2 diarrhea requires withholding immunotherapy and initiating corticosteroids (prednisone 0.5–1 mg/kg/day) if persistent; endoscopic evaluation should be considered [29–31]. Grade 3–4 colitis necessitates permanent discontinuation of ipilimumab (or nivolumab Grade 4) and initiation of high-dose corticosteroids (1–2 mg/kg/day IV methylprednisolone) [28, 30]. For steroid-refractory cases—defined as failure to respond within 2–3 days of high-dose corticosteroids—infliximab (5 mg/kg IV, anti-TNF-α) is the preferred second-line agent, with repeat dosing at 2 weeks if initial response is incomplete. Vedolizumab (anti-integrin, gut-selective) is an alternative immunosuppressant preferred in patients in whom systemic immunosuppression is contraindicated or infliximab is not well tolerated; emerging data support its efficacy in steroid- and infliximab-refractory ICI colitis [29, 30]. An important clinical consideration is the impact of corticosteroid use on oncological outcomes. A study demonstrated that high-dose corticosteroid use for irAE management was associated with reduced overall survival in patients receiving anti-PD-1 therapy, likely reflecting both the severity of the underlying irAE and the potential immunosuppressive dampening of the anti-tumor immune response [29, 32]. This finding reinforces the clinical imperative to use the minimum effective corticosteroid dose and duration, and to promptly escalate to steroid-sparing immunosuppressants (infliximab, vedolizumab) in steroid-refractory cases rather than increasing corticosteroid intensity indefinitely. The general principle of using corticosteroids judiciously across all irAE types, initiating promptly for significant toxicity but tapering rapidly once clinical control is achieved, should guide management decisions at every grade.

Endocrine irAEs

Endocrine irAEs require organ-specific management. Thyroid dysfunction (hypothyroidism, thyroiditis) is managed with hormone replacement for symptomatic cases, with immunotherapy continuation where feasible. Hypophysitis, more common with ipilimumab than with anti-PD-1 alone, presents with headache, fatigue, and anterior pituitary hormone deficiencies; high-dose corticosteroids are used for acute management (1–2 mg/kg/day), with long-term hormone replacement for persistent deficiencies. For suspected adrenal crisis, both ICIs should be immediately held, sepsis excluded, and stress-dose intravenous corticosteroids with mineralocorticoid activity administered urgently [28].

Special populations

Elderly patients exhibit a heightened susceptibility to pneumonitis as an irAE, likely reflecting age-related changes in immune regulation and greater baseline pulmonary comorbidity [33]. Heightened respiratory symptom surveillance is warranted in this group, with prompt corticosteroid initiation at the first sign of immune-mediated pulmonary toxicity. Performance status and comorbidity should guide upfront combination versus monotherapy selection in elderly patients, recognizing that the toxicity burden of Nivo-Ipi may be disproportionately harmful in those with limited physiological reserve [34].

In the adjuvant setting, the threshold for tolerating and managing irAEs differs from the metastatic context. As the treatment goal is recurrence prevention in a curative-intent setting, there is a lower tolerance for chronic irAEs that impair quality of life; earlier discontinuation of combination therapy is appropriate in the adjuvant setting when irAEs are not rapidly controlled [35]. Patients with pre-existing autoimmune conditions present a unique challenge: while not universally excluded from treatment, they carry higher rates of irAE flares and require particularly close monitoring and proactive management planning.

Therapeutic integration

First-line positioning and the nivolumab–relatlimab contender

Nivo-Ipi has been firmly established as a first-line option for metastatic melanoma, particularly in patients with PD-L1–negative tumors, high tumor burden, or brain metastases. However, the therapeutic visage has evolved significantly with the approval of nivolumab plus relatlimab (RELATIVITY-047 trial), which combines PD-1 and LAG-3 inhibition and offers an alternative dual-checkpoint blockade approach with a markedly more favorable toxicity profile [36].

In RELATIVITY-047, nivolumab–relatlimab demonstrated superior PFS over nivolumab alone (median PFS 10.1 vs. 4.6 months; HR 0.75) with grade 3–4 irAEs occurring in only 18.9% of patients, substantially lower than the ~ 59% observed with Nivo-Ipi [36]. An indirect treatment comparison analysis suggested that while nivolumab–relatlimab and Nivo-Ipi may have comparable OS outcomes at the population level, the combination’s different mechanisms and toxicity profiles necessitate individualized patient selection [37]. Patients with high tumor burden, PD-L1–negative disease, or those deemed able to tolerate the ipilimumab-related toxicity profile may still derive the greatest benefit from Nivo-Ipi, while nivolumab–relatlimab may be preferred in patients with baseline autoimmune risk, borderline performance status, or where treatment tolerability is a primary concern [38]. Direct head-to-head comparative trials are currently lacking, and this represents a critical evidence gap for the field.

Adjuvant decision-making

Anti-PD-1 monotherapy (nivolumab or pembrolizumab) remains the standard adjuvant approach for resected high-risk stage III and IV melanoma, supported by robust RFS benefit and favorable tolerability [39]. The combination of Nivo-Ipi does not have a standard adjuvant role based on current evidence. Adjuvant decision-making should focus on selecting between anti-PD-1 monotherapy, BRAF/MEK inhibitors in BRAF-mutant disease, and, in specific highest-risk cases (resected stage IV), careful case-by-case consideration of Nivo-Ipi based on IMMUNED data pending further prospective validation [26].

Sequencing with targeted therapy

In patients with BRAF-mutant metastatic melanoma, sequencing of immunotherapy and BRAF/MEK inhibitors is clinically critical. The DREAMseq trial demonstrated that initiating treatment with Nivo-Ipi followed by dabrafenib–trametinib upon progression yielded a 2-year OS of 72%, compared with 52% for the reverse sequence [31]. These data support an immunotherapy-first strategy in patients with adequate performance status and non-rapidly progressing disease. In patients with life-threatening visceral crisis or rapid progression requiring immediate response, BRAF-targeted therapy may be appropriate as initial treatment, given its more rapid tumor response kinetics [40].

Anti-PD-1 refractory population

The efficacy of Nivo-Ipi in patients previously treated with and refractory to anti-PD-1 therapy is substantially limited compared with the treatment-naïve setting. While earlier retrospective series suggested ORRs of 10–20% following anti-PD-1 failure [41], two additional studies have reported objective response rates of approximately 30% in this setting, indicating potentially greater salvage activity than initially described [42, 43]. These more encouraging response rates should nonetheless be interpreted with caution: responses are typically less durable than those observed in PD-1 inhibitor-naive patients, and patient selection across studies is heterogeneous. The biological rationale for residual activity rests on the hypothesis that CTLA-4 co-blockade may rescue a subset of T cells rendered anergic by prior PD-1 exposure; however, prior immune exhaustion may limit the depth of recoverable effector function. The evidence base in this context remains largely retrospective, and prospective trials are needed to definitively characterize the role of Nivo-Ipi after anti-PD-1 progression [44].

Unresolved issues

Biomarker limitations

Despite the clinical success of Nivo-Ipi, robust biomarkers to guide patient selection remain elusive. PD-L1 expression, while predictive of differential anti-PD-1 monotherapy benefit in some solid tumors, has shown inconsistent utility in melanoma. CheckMate 067 subgroup analyses demonstrated that patients with PD-L1–negative tumors derived substantial benefit from the combination relative to nivolumab monotherapy, limiting PD-L1’s discriminatory value for combination versus monotherapy selection [9, 10].

Tumor mutational burden (TMB), initially proposed as a surrogate of neoantigen load and immunogenicity, has failed to achieve routine clinical applicability in melanoma due to several compounding limitations: the absence of standardized cutoff definitions across assay platforms, variable predictive performance across melanoma subtypes (with acral and mucosal melanomas typically exhibiting lower TMB regardless of response), and the lack of prospectively validated TMB thresholds specifically for dual checkpoint blockade. While high-TMB melanomas tend to be more immunogenic, this association does not reliably translate to differential Nivo-Ipi benefit in clinical practice [3, 4].

Emerging biomarker candidates include interferon-γ gene expression signatures (reflecting T-cell-inflamed tumor microenvironments), circulating tumor DNA (ctDNA) as an early response and minimal residual disease marker, tumor-infiltrating lymphocyte (TIL) density, and gut microbiome composition. The latter has attracted particular interest given preclinical and observational data suggesting that specific commensal bacterial genera influence checkpoint inhibitor responsiveness through modulation of systemic T-cell function. However, all these candidates remain exploratory and have not been prospectively validated for clinical decision-making in the Nivo-Ipi setting [3].

Adjuvant knowledge gaps

In the adjuvant setting, major uncertainties persist regarding optimal duration and intensity of immunotherapy. Current practice largely extrapolates fixed treatment durations (typically one year) from clinical trial protocols rather than from biological evidence of duration-dependent benefit. CheckMate 915 failed to demonstrate incremental RFS benefit with combination therapy, while IMMUNED provides a preliminary signal in a higher-risk population [39]. Whether response-adaptive approaches analogous to those being evaluated in the neoadjuvant PRADO model could be applied in the adjuvant context to de-escalate or escalate therapy based on early ctDNA dynamics or immune biomarkers represents an important future research direction [39, 40].

Cost-effectiveness

The financial burden of Nivo-Ipi is substantial. Annual treatment costs are variably high, excluding toxicity-related hospitalization and management expenditures [45]. Cost-effectiveness analyses suggest that in the metastatic setting, where a meaningful proportion of patients achieve durable long-term survival, the combination may be economically justifiable within health systems with high thresholds for cost per quality-adjusted life year. However, in the adjuvant setting where the CheckMate 915 trial demonstrated no RFS benefit over the less expensive nivolumab monotherapy, the cost-effectiveness of Nivo-Ipi is not established and likely unfavorable [24]. In resource-limited settings globally, the high acquisition cost represents a major barrier to equitable access, necessitating biosimilar development and health technology assessment to guide sustainable formulary decisions [46].

Conclusion

The nivolumab–ipilimumab (Nivo-Ipi) combination has demonstrated transformative efficacy in advanced melanoma, establishing durable survival in a substantial subset of metastatic patients that was inconceivable in the pre-immunotherapy era. The 10-year final outcomes of CheckMate 067 document OS rates of approximately 31% at a decade—a survival plateau that reflects enduring immune-mediated tumor control. These results, contextualized by the important caveat that CheckMate 067 was not designed to formally establish superiority over nivolumab monotherapy, position Nivo-Ipi as a frontline option for selected patients with metastatic disease, particularly those with PD-L1–negative tumors, high tumor burden, or brain metastases.

The emergence of neoadjuvant immunotherapy, most compellingly demonstrated in the NADINA trial, represents a paradigm shift for resectable stage III melanoma, where perioperative Nivo-Ipi with response-adapted adjuvant strategies substantially outperforms adjuvant nivolumab alone. In the adjuvant setting for resected disease without neoadjuvant treatment, the CheckMate 915 trial conclusively demonstrated no RFS benefit of Nivo-Ipi over nivolumab monotherapy, despite substantially increased toxicity, confirming anti-PD-1 monotherapy as the postoperative standard. The IMMUNED data provide a possible exception in resected stage IV disease, warranting prospective confirmation.

The safety profile of Nivo-Ipi requires careful navigation. Grade 3–4 irAEs affect approximately 59% of combination-treated metastatic patients, demanding proactive monitoring, prompt recognition, and evidence-based immunosuppressive management, including infliximab or vedolizumab for steroid-refractory gastrointestinal toxicity. The evolving first-line landscape—with nivolumab–relatlimab offering comparable or potentially similar efficacy with substantially reduced toxicity—necessitates individualized treatment selection rather than reflexive combination use.

Future progress in optimizing the role of Nivo-Ipi will depend on validated predictive biomarkers, response-adaptive treatment strategies, equitable access solutions, and integration of this powerful regimen within a multidisciplinary, precision-medicine framework for melanoma care.

Abbreviations

ASCO

American Society of Clinical Oncology

BRAF

B-Raf Proto-Oncogene

CTLA

4-Cytotoxic T-Lymphocyte-Associated Protein 4

ctDNA

Circulating Tumor DNA

EFS

Event–Free Survival

FDA

US Food and Drug Administration

GI

Gastrointestinal

HR

Hazard Ratio

ICI

Immune Checkpoint Inhibitor

irAE

Immune-related adverse eventelated Adverse Event

LAG

3-Lymphocyte-Activation Gene 3

LDH

Lactate Dehydrogenase

MPR

Major Pathological Response

NCCN

National Comprehensive Cancer Network

Nivo

Ipi–Nivolumab and Ipilimumab (introduced at first use)

N1I3

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg

N3I1

Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg

ORR

Objective Response Rate

OS

Overall Survival

PD

1-Programmed Death Receptor 1

PD

L1-Programmed Death-Ligand 1

PFS

Progression-free survival

RFS

Recurrence-free survival

SJS/TEN

Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis

TIL

Tumor–infiltrating lymphocyte

TMB

Tumor mutational burden

Treg

Regulatory T cell

Author contributions

R.A.: Conceptualization, Writing—original draft, Writing—review & editing. P.A.: Supervision, Validation.P.A., S.B., E.E., M.O.O., A.B.A., E.K.S., A.O.A., S.I., Y.M.O., A.O., Y.N., C.A., S.O.: Writing—original draft, Writing—review & editing.All authors approved the final submission.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.