BACKGROUND: Data in East Asian patients and in other epithelial skin cancers, including extramammary Paget's disease (EMPD) and adnexal carcinomas, are scarce. Therefore, we conducted a phase II trial of nivolumab in Japanese patients with advanced non-melanoma skin cancers (NMSCs).
PATIENTS AND METHODS: This multicentre, open-label, single-arm phase II study enrolled adults (≥ 20 years) with histologically confirmed unresectable or recurrent epithelial cutaneous malignancies, Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion (RECIST v1.1). Nivolumab 480 mg was administered intravenously every 4 weeks for up to 26 cycles. The primary endpoint was overall response rate (ORR), assessed by blinded independent central review (BICR; RECIST v1.1). Secondary endpoints included progression-free survival, overall survival, and safety.
RESULTS: Thirty-one patients were enrolled (20 cSCC, 4 EMPD, 2 BCC, 5 other NMSCs); median age was 73 years (range 58-86), and 71% were male. ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31). Responses were durable, with a median duration of 21.3 months. In the cSCC cohort, median tumour mutational burden (TMB) was 9.0 mut/Mb, lower than in Western series; among three patients with TMB ≥ 30 mut/Mb, two achieved objective responses. Common adverse events included pyrexia, hypothyroidism, adrenal insufficiency, and pruritus.
CONCLUSIONS: Nivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC. The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy.
CLINICAL TRIAL REGISTRATION: jRCT2031190048; registered 2 July 2019.
ORR by BICR was 22.6% (7/31), and the disease control rate was 54.8% (17/31).
centrally reviewed descriptive estimates with wide uncertainty in a small heterogeneous cohort
Nivolumab showed durable antitumour activity with manageable toxicity in Japanese patients with advanced NMSCs, including rare non-cSCC.
uncontrolled treatment evidence and sparse rare-subtype responses limit the combined activity and durability conclusion
Responses were durable, with a median duration of 21.3 months.
duration is estimated only among seven responders in a small single-arm trial, with a 3.7–NR confidence interval
The lower ORR compared with Western trials may reflect intrinsic biological differences and support biomarker-driven, region-specific immunotherapy.
uncontrolled cross-trial comparisons cannot identify intrinsic regional biology or establish a treatment-selection strategy
two of three cases with TMB ≥ 30 mutations/Mb achieved an objective response
post hoc subgroup selection in three patients cannot establish predictive biomarker utility
Derived from the full evaluation — not a separate score.
Strengths
The multicentre trial supplies centrally reviewed response data in a population underrepresented in the cited PD-1 studies and includes rare non-cSCC cancers.
↳ Introduction; Results, Efficacy; Table 2
BICR provides the prespecified primary estimate, and unevaluable patients are counted as non-responders. The paper also reports the higher investigator-assessed response rate rather than substituting it for the primary result.
↳ Methods, Endpoints and assessments; Results, Efficacy
The Discussion reports that the data contributed to Japanese approval of nivolumab for epithelial cutaneous malignancies in 2024, identifying a concrete route from the study to treatment access.
↳ Discussion, regulatory approval paragraph
Limitations
The Discussion says the trial confirms efficacy despite the absence of a concurrent comparator and without establishing why the 5% response threshold is clinically comparable.
↳ Methods, Study design; Discussion, paragraph 1
Overall PFS confidence intervals differ between text and Table 2, and the Discussion reverses the Results' cSCC and non-cSCC TMB medians. The headline response count of 7/31 remains consistent.
↳ Results, Efficacy and TMB and MSI; Table 2; Discussion, TMB paragraph
The highlighted TMB ≥30 observation rests on three patients, one unevaluable by BICR. Cross-trial response comparisons cannot isolate intrinsic biological differences from differences in populations, treatment history, or measurement.
↳ Abstract, Results and Conclusions; Results, TMB and MSI; Discussion, Western-trial comparison
The trial's main contribution is a prospective, centrally reviewed response estimate in Japanese patients with advanced epithelial skin cancers. Registration, non-responder handling of unevaluable patients, and systematic safety collection support its execution, but the Discussion's efficacy-confirmation claim exceeds an uncontrolled comparison with an unexplained 5% benchmark. The post hoc three-patient TMB subgroup and Western-trial comparisons do not establish biomarker selection or intrinsic regional biology. Numerical conflicts require reconciliation without invalidating the consistent headline response count of 7/31, while reported Japanese regulatory uptake gives the findings a concrete clinical pathway.
Nabu’s assessment, alongside the field’s view.
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Sound3.1
Confidence mediumProspective, centrally reviewed Japanese treatment data extend the predominantly Western evidence base and include rare non-cSCC cancers. The contribution remains bounded by 31 participants and very small histology-specific groups.
Registration, BICR, conservative handling of NE patients, and systematic safety collection support execution. The unexplained clinical benchmark cannot support efficacy confirmation, and the highlighted post hoc TMB subgroup further limits inference.
The primary response estimate and safety findings are presented in a followable sequence. Efficacy-confirming and region-specific treatment language conveys more certainty than the uncontrolled and exploratory evidence supports.
The paper engages the pivotal Western trials and explains the limitations of rare-subtype analyses. It does not address the missing concurrent comparator and unestablished benchmark comparability when interpreting efficacy.
Caveats4 of 4 checks
Ethics approval, written consent, and prospective registration are declared. Unavailable external materials and absent availability statements do not establish a conduct concern in the supplied text.
Ethics approval: declared · Preregistration: declared
38 references in manuscript 38 of 38 checkable references found in an index
References not verified automatically are resolved manually within 24 hours.
No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Reported regulatory uptake places the findings closer to clinical use than proof-of-concept alone. The evidence does not establish equivalent readiness across broader populations or individual rare histologies.
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