Neoadjuvant PD‑1/LAG‑3 Bispecific (tobemstomig) Matches Efficacy but Improves Safety Versus Nivolumab‑Ipilimumab in Resectable Stage III Melanoma: Insights from Morpheus‑Melanoma

Highlights

– Tobemstomig (anti‑PD‑1/anti‑LAG‑3 bispecific) achieved a pathological response rate (pRR) of 80% versus 77.3% with nivolumab plus ipilimumab in resectable stage III melanoma in Morpheus‑Melanoma.

– Major pathological response (MPR) was slightly less frequent with tobemstomig (62.5% vs 72.7%), but grade ≥3 treatment‑related adverse events (TRAEs) and treatment discontinuations were substantially reduced with tobemstomig.

– Combinations with anti‑TIGIT (tiragolumab) and PD‑L1 (atezolizumab) plus tiragolumab showed lower pRRs than nivolumab‑ipilimumab in this trial.

Background

Patients with resectable stage III melanoma remain at considerable risk of recurrence despite surgery. Immune checkpoint inhibitors (ICIs) have transformed outcomes in metastatic disease, and the neoadjuvant setting—delivering systemic therapy before surgical resection—has emerged as a promising strategy to increase pathological response, reduce micrometastatic disease, and potentially improve long‑term outcomes. Randomized data from neoadjuvant studies have suggested benefits over adjuvant therapy for some regimens. However, the optimal agent or combination that maximizes tumor eradication while minimizing immune‑related toxicity remains an active area of investigation.

Study design

The Morpheus‑Melanoma study (phase 1b/2, randomized umbrella trial; ClinicalTrials.gov NCT05116202) evaluated neoadjuvant immune strategies in patients with resectable stage III melanoma. The trial compared four experimental arms against a control regimen of nivolumab (anti‑PD‑1) plus ipilimumab (anti‑CTLA‑4):

• Tobemstomig (anti‑PD‑1/anti‑LAG‑3 bispecific antibody; n = 40)
• Tobemstomig + tiragolumab (anti‑TIGIT monoclonal antibody; n = 20)
• Atezolizumab (anti‑PD‑L1) + tiragolumab (n = 20)
• Control: nivolumab + ipilimumab (n = 22)

The primary endpoint was pathological response assessed by independent pathological review. Secondary and exploratory endpoints included safety (treatment‑related adverse events), major pathological response (MPR), biomarker correlates (tumor‑infiltrating lymphocytes, IFNγ and effector T cell gene signatures, tumor mutational burden), and circulating tumor DNA (ctDNA) dynamics prior to surgery.

Key findings

Pathological responses

Tobemstomig produced a pathological response rate (pRR) of 80.0% (32/40), which was broadly similar to the control nivolumab‑ipilimumab arm pRR of 77.3% (17/22). The frequency of major pathological responses (typically defined as ≤10% viable tumor) was lower with tobemstomig (62.5% [25/40]) compared with nivolumab‑ipilimumab (72.7% [16/22]).

Combination arms that included tiragolumab showed lower pRRs: tobemstomig + tiragolumab 60.0% (12/20) and atezolizumab + tiragolumab 45.0% (9/20). These findings indicate that adding anti‑TIGIT to either the bispecific PD‑1/LAG‑3 agent or to PD‑L1 blockade did not improve—and may have reduced—the pathological response rates in this cohort.

Safety and tolerability

A key strength of the tobemstomig arm was a markedly improved safety profile compared with nivolumab + ipilimumab. Grade ≥3 TRAEs occurred in 2.5% (1/40) of patients treated with tobemstomig versus 22.7% (5/22) with nivolumab + ipilimumab. Similarly, no patients in the tobemstomig cohort discontinued treatment for TRAEs, compared with 13.6% (3/22) discontinuations in the nivolumab + ipilimumab arm.

For the combination arms, grade ≥3 TRAEs were reported in 15% (3/20) with tobemstomig + tiragolumab and in none of the patients treated with atezolizumab + tiragolumab. Overall, the bispecific PD‑1/LAG‑3 construct appeared to separate efficacy from the high immune‑related toxicity that characterizes CTLA‑4–containing regimens.

Biomarker correlates

Across treatment arms, several baseline and on‑treatment biomarkers correlated with pathological response. Higher baseline CD8+ and CD3+ tumor‑infiltrating T cell density, elevated IFNγ pathway and effector T cell gene expression signatures, higher tumor mutational burden (TMB), and detectable pre‑surgery ctDNA correlated with response. These findings align with prior work linking an inflamed tumor microenvironment and higher neoantigen load to improved ICI responsiveness.

Interpretation of effect sizes and clinical meaning

The near‑equivalent overall pRR between tobemstomig and nivolumab‑ipilimumab suggests that targeting PD‑1 and LAG‑3 with a single bispecific agent can recapitulate the clinical activity of a PD‑1 plus CTLA‑4 combination in the neoadjuvant setting. Importantly, the substantially lower rate of high‑grade TRAEs with tobemstomig may offer a therapeutic index advantage—reducing perioperative morbidity, avoiding treatment discontinuations, and improving tolerability for patients and surgical workflows.

Expert commentary and contextualization

Neoadjuvant strategies aim to leverage intact tumor antigenicity and a more complete immune priming environment. The modestly lower MPR with tobemstomig suggests that while overall pRR is preserved, the depth of tumor eradication in a subset may be less than with CTLA‑4 combination therapy. However, the clinical relevance of differences in MPR versus pRR must be considered in light of safety trade‑offs and longer‑term endpoints such as recurrence‑free survival (RFS) and overall survival (OS), which were not reported here.

Mechanistically, dual PD‑1/LAG‑3 blockade targets complementary inhibitory axes implicated in T cell exhaustion and may potentiate reinvigoration with less systemic immune activation than CTLA‑4 blockade. The negative signal from adding TIGIT blockade in this trial stands in contrast with mixed results from other contexts and may reflect complex biological interactions, timing, dosing, or patient selection factors.

Limitations of the Morpheus‑Melanoma trial include its phase 1b/2 design and modest sample sizes across arms, which limit precision and stratified subgroup analyses. The follow‑up duration and mature survival endpoints were not reported; these will be essential to establish whether pRR and MPR translate into durable RFS/OS benefit. Finally, the biomarker analyses are hypothesis‑generating and will require validation in larger cohorts.

Clinical implications

For clinicians managing resectable stage III melanoma, the Morpheus‑Melanoma results suggest that PD‑1/LAG‑3 bispecific therapy could be a viable neoadjuvant option that preserves high pathological response rates while reducing severe immune‑related toxicity compared with nivolumab plus ipilimumab. Choices about neoadjuvant regimens should weigh the potential for deeper pathological responses from CTLA‑4 combos against higher toxicity, and consider patient comorbidity, surgical timing, and preferences.

Pending maturation of survival data and randomized comparisons powered for RFS/OS, tobemstomig may be particularly attractive for patients at elevated risk from treatment‑related complications or those in whom preserving perioperative fitness is critical.

Conclusion and future directions

Morpheus‑Melanoma provides important randomized neoadjuvant data indicating that a PD‑1/LAG‑3 bispecific antibody (tobemstomig) achieves comparable pathological response rates to nivolumab plus ipilimumab while substantially improving tolerability in resectable stage III melanoma. The trial underscores the value of neoadjuvant platforms to rapidly evaluate novel immunotherapy approaches and identify biomarker signatures associated with response.

Key next steps include reporting longer‑term outcomes (RFS and OS), validating biomarker predictors, refining patient selection, and exploring optimal sequencing or combination strategies. Larger randomized trials will be needed to confirm whether the improved safety profile of tobemstomig translates into net clinical benefit compared with established neoadjuvant regimens.

Funding and clinicaltrials.gov

The Morpheus‑Melanoma study is registered as NCT05116202. Funding and sponsor information are reported in the primary publication (Long et al., Nat Med 2025).

References

Long GV, Nair N, Marbach D, Scolyer RA, Wilson S, Cotting D, Staedler N, Amaria RN, Ascierto PA, Tarhini AA, Robert C, Hamid O, Gaudy‑Marqueste C, Lebbe C, Munoz‑Couselo E, Menzies AM, Pages C, Curigliano G, Mandala M, Jessop N, Bader U, Perdicchio M, Teichgräber V, Muecke M, Markert C, Blank C. Neoadjuvant PD‑1 and LAG‑3‑targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus‑Melanoma trial. Nat Med. 2025 Sep 24. doi: 10.1038/s41591-025-03967-2 IF: 50.0 Q1 B1. Epub ahead of print. PMID: 40993242 IF: 50.0 Q1 B1.