Neoadjuvant and/or Adjuvant Immune Checkpoint Inhibitors Combined with Chemotherapy for Locally Advanced Resectable Penile Squamous Cell Carcinoma

First prospective trial of perioperative chemoimmunotherapy in locally advanced PSCC reports 53% response rate in 17 evaluable patients

Journal: Frontiers in Immunology | Published: 2026-03-19 | Type: Prospective non-randomized cohort study | PMID: 41939893 Authors: Xu Shanshan, Chen Feiran, Diao Lei, et al. — Tianjin Medical University Cancer Institute & Hospital and Tianjin First Central Hospital Funding/COI: Funding not disclosed. Authors declare no commercial or financial conflicts of interest.

Summary

This is a preliminary report from an ongoing prospective trial testing sintilimab (a PD-1 inhibitor) combined with nab-paclitaxel and cisplatin as neoadjuvant and/or adjuvant therapy in 25 patients with locally advanced penile squamous cell carcinoma (N2/N3 disease). Among the 17 patients evaluable for neoadjuvant response, 52.9% had an objective response; 2 of 12 who reached surgery achieved pathological complete response. The 18-month overall survival rate for the whole cohort was 90.0%, with grade ≥3 adverse events in 20% of patients. The authors characterize this as "durable antitumor activity," which is a stretch for a non-randomized 25-patient dataset with no comparator arm.

Claims

• Objective response rate (ORR) to neoadjuvant therapy: 52.9% (9/17; 95% CI 31.0–73.8%), including 2 complete responses and 7 partial responses
• Disease control rate (DCR): 76.5% (95% CI 52.7–90.4%)
• Treatment-naive subgroup ORR: 66.7% (8/12)
• Pathological complete response (pCR) rate among those reaching surgery: 2/12 (16.7%); major pathological response (MPR): 3/12 (25%)
• 18-month PFS for full cohort: 71.4%; 18-month OS: 90.0%
• Neoadjuvant-adjuvant group 18-month PFS: 68.8%, OS: 85.7%
• Adjuvant-only group 18-month PFS: 75.0%, OS: 100%
• Patients achieving radiological CR/PR after neoadjuvant therapy had significantly better PFS than SD/PD (P = 0.005)
• PD-L1 CPS ≥20 was not significantly associated with PFS
• Grade ≥3 treatment-related adverse events: 20% (5/25)

Study Quality

This is a prospective, two-center, non-randomized cohort study — not a randomized controlled trial — with 25 analyzable patients, and the study is still enrolling (planned N=28). Patient assignment to neoadjuvant vs. adjuvant-only pathways was determined by clinical assessment and imaging, not randomization, which introduces selection bias by design: the sicker, less resectable patients received neoadjuvant therapy. Comparing outcomes between arms is therefore almost meaningless. There is no control arm, so the survival figures cannot be attributed to the intervention without a comparator against historical chemotherapy-only data.

The efficacy analysis population varies across endpoints (17 evaluable for neoadjuvant ORR, 12 for surgical outcomes, 24 for safety, 25 for survival) due to withdrawals, discontinuations, and protocol exits — with only 25 patients to start, each dropout materially shifts the numbers. The 18-month survival rates are descriptive estimates from a small, heterogeneous cohort; confidence intervals are not reported for these figures. The study is registered (ChiCTR2400094629), which is to its credit, and the 20-month median follow-up is adequate for preliminary assessment of PFS.

Red Flags

• 25 patients total. This is proof-of-concept territory, not evidence of efficacy.
• No randomization, no control arm. The two cohorts differ systematically in disease severity by design.
• Preliminary analysis of an ongoing trial — the final dataset will have only 3 more patients (planned N=28), which will not materially change statistical power.
• Funding not disclosed. Sintilimab is manufactured by Innovent Biologics (China); the absence of any funding declaration for a sponsored drug trial is a gap.
• Published in Frontiers in Immunology, a journal known for lower peer-review thresholds than top-tier oncology outlets.
• Generalizability is limited: sintilimab is not approved outside China; the PSCC patient population at two Tianjin centers may not represent other populations.
• PD-L1 expression showed no predictive value — the study lacks a validated biomarker for patient selection despite testing for it.
• One patient discontinued after grade IV myelosuppression (excluded from efficacy analysis, included in safety) — a serious event in an already tiny cohort.

Strengths

• First prospective trial of perioperative chemoimmunotherapy specifically in locally advanced PSCC — an area with essentially no RCT-level evidence to date
• Prospective design with pre-specified endpoints and RECIST-based independent response assessment
• Registered trial with protocol transparency
• Adequate median follow-up of 20 months for a preliminary report
• Biomarker analysis (PD-L1 CPS, P16, NLR) in 76% of patients, enabling future correlative work
• Rare disease: PSCC represents <1% of male genitourinary cancers; a 25-patient prospective cohort is realistically near the ceiling of what's achievable without multi-national coordination

Verdict

This paper deserves attention as a registered first-in-class prospective effort in a disease so rare that most evidence is retrospective case series. The 53% ORR and 71% 18-month PFS numbers are interesting signals. But "preliminary analysis" is doing a lot of work here: 25 patients, no control arm, a Frontiers journal, and no funding disclosure add up to early-phase hypothesis generation, not clinical evidence. The paper's own conclusion — "warrant further validation in larger cohorts" — is the correct read. Treat the numbers as a promising biological signal, not a treatment benchmark.