Indirect Trial Comparison Suggests Retifanlimab Edges Out Avelumab in Metastatic Merkel Cell Carcinoma

Merkel cell carcinoma is one of the rarest and most lethal skin cancers known to medicine, and a new statistical analysis has now offered clinicians their first quantitative glimpse at how two leading immunotherapies stack up against each other in treating it. Because no clinical trial has ever directly compared the checkpoint inhibitors retifanlimab and avelumab in patients with metastatic Merkel cell carcinoma, researchers turned to a sophisticated technique called a matching-adjusted indirect comparison, or MAIC, to extract a comparative signal from two separate single-arm trials. The results, published in the journal Advances in Therapy, generally favor retifanlimab, including a statistically significant advantage in progression-free survival, though the authors and the methodology itself demand careful interpretation.

The stakes in this comparison are high. Merkel cell carcinoma carries a five-year survival rate of roughly 40 to 45 percent in the United States and between 28 and 48 percent in Europe. The disease predominantly strikes men and patients aged 70 and older, and its incidence is climbing as populations age. In most cases, Merkel cell polyomavirus can be detected in the tumor, a viral signature that distinguishes this cancer from melanoma and other skin malignancies. While about 65 percent of patients present with disease confined to the original site, roughly 8 percent already harbor distant metastases at diagnosis, and among those with localized disease, distant spread occurs in nearly half of cases within a single year and in virtually all patients within five years. Once the cancer metastasizes, chemotherapy may initially shrink tumors, but responses typically last only three to six months, and the toxicities are often severe in an elderly patient population.

That therapeutic vacuum opened the door to immunotherapy. Avelumab, a monoclonal antibody that blocks the programmed death-ligand 1 protein, or PD-L1, became the first approved immunotherapy for metastatic Merkel cell carcinoma, gaining accelerated approval in the United States and authorization in the European Union in 2017 on the strength of the phase 2 JAVELIN Merkel 200 trial. Retifanlimab, a humanized immunoglobulin G4 antibody targeting the PD-1 receptor itself, followed more recently, receiving accelerated US approval in 2023 and European approval in 2024 based on the phase 2 POD1UM-201 trial, in which 101 patients with locally advanced or metastatic disease achieved an objective response rate of 54.5 percent. Both drugs work by releasing a molecular brake on T cells, allowing the immune system to recognize and attack tumor cells, but they have never been tested against each other in the same study.

The research team, led by Camilla Porta, Gianni Ghetti, and Massimiliano Povero of the health economics firm AdRes in Turin, Italy, confronted a fundamental problem in evidence-based medicine: how to compare treatments when only separate, single-arm trials exist. Traditional network meta-analyses require a connected web of trials sharing a common comparator, an assumption of consistency across studies, and broadly exchangeable patient populations. None of those conditions held here. Instead, the team used the MAIC approach, first formalized by James Signorovitch and colleagues, which applies statistical weights to individual patient data from one trial until its baseline characteristics match those reported for the aggregate population of another trial. The method directly balances observed covariates between populations and avoids the outcome-model misspecification biases that can afflict alternative techniques such as simulated treatment comparisons, which is why the authors selected it for these time-to-event endpoints.

The mechanics of the analysis were intricate. Individual patient data came from POD1UM-201, with a data cutoff of July 2024 and a median follow-up of 35.7 months, restricted to patients with metastatic disease to align with the eligibility criteria of the comparator. For avelumab, the researchers used aggregate data from part B of JAVELIN Merkel 200, a cohort of 116 previously untreated patients with metastatic disease, digitizing the published Kaplan-Meier survival curves and reconstructing pseudo-individual patient data using an algorithm developed by Pierre Guyot and colleagues. Matching covariates were chosen based on their established prognostic value in Merkel cell carcinoma: age below or above 65 years, Eastern Cooperative Oncology Group performance status, PD-L1 positivity, Merkel cell polyomavirus status, site of the primary tumor, and the presence or absence of visceral metastases at baseline.

Weighting came at a price. After the adjustment, the effective sample size of the retifanlimab population shrank to approximately 42 patients, just 47 percent of the original trial enrollment, a consequence of the right-skewed weight distribution in which a small number of patients carried disproportionate statistical influence. Some covariates simply could not be balanced. Ethnicity data showed an apparent imbalance, with Hispanic or Latino patients representing 1.1 percent of the retifanlimab trial but 25 percent of the avelumab trial, and adjusting for it would have collapsed the effective sample size to unusable levels. Geographic region posed a similar obstacle, since 10.3 percent of avelumab patients came from Australia or Asia, regions absent from the retifanlimab dataset. Race, sex, and time since initial diagnosis were explored in scenario analyses to test the robustness of the base case findings.

The headline result concerns progression-free survival, the length of time patients live without their disease worsening. After adjustment, the weighted hazard ratio of 0.590, with a 95 percent confidence interval of 0.396 to 0.881, statistically significantly favored retifanlimab, translating to roughly a 40 percent lower hazard of progression or death. Intriguingly, the proportional hazards assumption was violated for this endpoint, meaning the treatment effect changed over time. A stratified analysis revealed that the entire advantage was concentrated in the first two months of treatment, with no significant difference thereafter, so the overall hazard ratio should be read as a time-averaged summary rather than a constant benefit. For overall survival, the hazard ratio of 0.800 numerically favored retifanlimab but carried wide uncertainty and did not reach statistical significance, and exploratory piecewise modeling suggested the survival benefit, if real, emerged after the first five months. The odds ratio for overall response rate, 1.871, also pointed toward retifanlimab without achieving significance in the base case, though a scenario analysis found the odds of complete or partial response were approximately 2.4 times higher with retifanlimab.

The authors are candid about the limitations. An unanchored MAIC, used here because no common comparator links the two trials, rests on strong assumptions, including the conditional constancy of absolute treatment effects and adequate adjustment for every prognostic factor and effect modifier, assumptions that cannot be fully verified. Residual confounding by unmeasured characteristics remains possible, and the reduced effective sample size, together with sparse events in the tails of the survival curves, limits statistical precision. Differences in follow-up duration between the trials could also skew time-to-event estimates in either direction, although the authors argue these effects are likely confined to the curve tails. Post-progression therapies, which about 40 percent of patients in each trial received, could theoretically influence overall survival, but the broadly similar distribution of subsequent treatments, including somewhat more frequent subsequent immunotherapy in the avelumab trial, suggests any imbalance would if anything have attenuated rather than inflated the observed advantage for retifanlimab. The findings, the researchers conclude, should be treated as hypothesis-generating rather than confirmatory.

Nevertheless, the analysis carries real-world weight. A companion cost-utility analysis conducted in Italy, drawing on an earlier MAIC, found retifanlimab to be a cost-effective option relative to avelumab, with an incremental cost of 12,228 euros per patient and an incremental cost-utility ratio of 5,037 euros per quality-adjusted life year gained. Practical considerations reinforce the clinical picture: retifanlimab is administered once every four weeks, while avelumab requires infusions every two weeks, a meaningful difference for elderly patients who often face long travel distances to reach the specialist centers equipped to manage this rare cancer. For a disease in which diagnosis is frequently delayed and access to optimal care is constrained, a therapy that combines favorable efficacy signals with a convenient dosing schedule could reshape treatment decisions. As population-adjusted indirect comparisons become increasingly embedded in regulatory, reimbursement, and health technology assessment frameworks, this study offers both a template and a caution: statistical ingenuity can squeeze comparative insight from unconnected trials, but the resulting estimates are only as trustworthy as the assumptions beneath them. For now, the evidence tilts toward retifanlimab, pending the head-to-head data that rare-disease oncology so rarely delivers.

Subject of Research: Comparative effectiveness of the immune checkpoint inhibitors retifanlimab and avelumab in metastatic Merkel cell carcinoma using matching-adjusted indirect comparison methodology

Article Title: Retifanlimab Versus Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma: A Matching-Adjusted Indirect Comparison Analysis

Article References: Porta, C., Ghetti, G., & Povero, M. (2026). Retifanlimab Versus Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma: A Matching-Adjusted Indirect Comparison Analysis. Advances in Therapy. https://doi.org/10.1007/s12325-026-03802-1

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03802-1

Keywords: Merkel cell carcinoma, retifanlimab, avelumab, immune checkpoint inhibitors, matching-adjusted indirect comparison, PD-1, PD-L1, immunotherapy, progression-free survival, POD1UM-201, JAVELIN Merkel 200, rare skin cancer