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Efficacy and Safety of Immune Checkpoint Blockade in Locally Advanced or Metastatic Penile Cancer: A Systematic Review and Meta-Analysis - Beyond the Abstract

Rationale

Locally advanced or metastatic penile squamous cell carcinoma (LA/mPC) is a rare malignancy with a poor prognosis.1 Systemic therapy for LA/mPC centers on platinum-based chemotherapy, largely extrapolated from other tumors, and associated with significant toxicity and responses that are short-lived.2 While Immune Checkpoint Blockade (ICB) has changed the treatment landscape for various genitourinary cancers, its role in LA/mPC remains preliminary and not fully established.3,4 Thus, we conducted the first systematic review and meta-analysis to synthesize much-needed evidence regarding the efficacy and safety of ICB in LA/mPC.5

Key Results
We included 12 cohorts (including two arms of the PERICLES trial) comprising 488 patients who were treated with ICB-based regimens.6-16 The pooled results indicated a promising clinical activity that appears to exceed historical controls for chemotherapy alone:

  • Objective Response Rate (ORR): Pooled ORR for all ICB regimens was 34.1% (95% CI,
  • 20.6%–56.5%).
  • Survival Outcomes: Survival data were encouraging, with a median progression-free survival of 5.7 months (CI 4.8-6.5), and the median overall survival of 13.6 months (CI 12-16). The 12month OS was ~80%.
  • Safety: The safety profile was manageable, with a pooled incidence of grade 3 or higher immun-related adverse events of 13.8%.
The Critical Role of Combination Therapy

Our study findings revealed heterogeneity in therapeutic outcomes based on specific treatment regimens (e.g., ICI monotherapy and ICI-chemotherapy) and disease burden. Subgroup analyses revealed that ICB combined with chemotherapy yielded a marked ORR of 60.7%, whereas ICB monotherapy demonstrated a much more modest ORR of 16.7%. This suggests that the immunogenic effects of chemotherapy may be necessary to prime the tumor microenvironment in penile cancer, enhancing sensitivity to checkpoint inhibition. Also, the ALPACA Trial, recently presented at ESMO 2025, and not included in our analyses, adds new evidence to this patient population. The ALPACA trial was a phase II, multicenter, single-arm trial that evaluated avelumab monotherapy in LA/mPC, and reported modest outcomes (ORR 17%, mPFS 1.7 mo, mOS 3.9 months), which are lower than reported in our pooled analyses, which in turn, are consistent with our findings for ICB given in monotherapy (16.7% ORR, mPFS 2.9 months, mOS 9.3 months). Notably, a heavily pretreated cohort of patients was enrolled in the ALPACA study. Landmark first-line trials such as HERCULES and EPIC-A, included in our study, investigated ICB combined with platinum-based chemotherapy, revealing higher response rates (39.4% and 51.7%) and improved survival outcomes (9.6 and 15.5 months), respectively.

Future Directions

Moving to Earlier Lines: The discrepancy between the modest outcomes in the refractory setting and the increased responses seen in combinatorial, earlier-line studies suggests that the optimal window for ICB intervention in penile cancer is early in the disease course. Thus, the current data support a hypothesis for evaluating ICB-chemotherapy combinations not only in the first line, but also potentially in the neoadjuvant settings, and future trials are warranted to elucidate the best treatment sequencing.

Biomarker-Driven Patient Selection: Human papillomavirus (HPV) infection is a well-established risk factor in penile cancer, but whether its identification is associated with the predictive value of ICB therapy remains widely unknown.17 In our review, retrospective cohort data and the PERICLES trial suggested that patients with LA/mPC and HPV-positive achieved superior survival outcomes compared to patients who were HPV-negative.9,14 Similar findings have been reported in other HPV-associated malignancies.18 Interestingly, in an exploratory subgroup analysis restricted to studies leveraging sequencing for high-risk HPV strains, we observed significant improvements in both PFS (HR = 0.32) and OS (HR = 0.16) among HPV-positive patients. By contrast, studies leveraging surrogate markers for HPV infection (e.g., p16 IHC) did not demonstrate statistically significant improvements in survival outcomes. Additionally, while PD-L1 overexpression is observed in ~40–60% of patients with penile cancer, its role in stratifying patients who may derive greater benefit from ICB therapy remains uncertain. In summary, future research efforts should aim to elucidate the role of biomarkers that can aid in complex treatment decision-making in this heterogeneous and rare cancer population.

Written by: Mariana Macambira Noronha1 and Erick F. Saldanha2,3

  1. Department of Medical Sciences, Universidade Federal do Ceará, CE, Brazil
  2. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
  3. Department of Medicine, University of Toronto, Toronto, ON, Canada 
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