Avelumab Delivers Responses but Not Survival Benefits in Penile Cancer

Avelumab (Bavencio) demonstrated modest but durable activity in a small subset of patients with advanced penile cancer, according to findings from the single-arm, multicenter phase 2 ALPACA trial (NCT03391479).^1,2

The primary end point, objective response rate (ORR), was met, with an investigator-assessed ORR of 17% (n = 4/23).¹ This consisted of 0 complete responses, 4 partial responses, 1 case of stable disease, and 18 cases of progressive disease. Notably, the responses were durable, with a median duration of 15.9 months (range, 14-16.2). The disease control rate was 21%.

However, the survival benefit was limited. The median progression-free survival (PFS) was 1.7 months (95% CI, 1.5-1.8), and the median overall survival (OS) was 3.9 months (95% CI, 2.6-9.9), leading to the conclusion that the data, while promising for a select few, are not transformative for the patient population as a whole.

The safety profile of avelumab was manageable and consistent with its known profile, with no new safety signals or treatment-related deaths reported. The most common adverse events (AEs) were infusion-related reactions (grade 1/2, 22%; grade 3+, 4%), edema in limbs (13%, 0%) fatigue (9%, 4%), nausea (13%, 0%), anemia (4%, 4%), chills (9%, 0%), and dry mouth (9%, 0%).

Immune-related AEs included myalgia/arthralgia/arthritis (grade 1/2, 13%; grade 3+, 4%), maculopapular rash (9%, 4%), diarrhea (4%, 4%), increased alanine aminotransferase/aspartate aminotransferase (9%, 0%), increased lipase (4%, 0%), and hyperthyroidism (4%, 0%).

Background and Study Rationale

Penile cancer is a rare and aggressive malignancy, with approximately 38,000 new cases diagnosed worldwide annually. It is more prevalent in regions such as Latin America, Africa, and India. The disease has established links to human papillomavirus (HPV), with up to 50% of cases being HPV-related, and 30% to 60% of tumors expressing PD-L1.

For patients with metastatic disease, the prognosis is poor, with a median survival of less than 1 year. The standard first-line treatment, platinum-based chemotherapy, offers limited efficacy, with an ORR of approximately 30% and a median PFS of only 3 months, and is often poorly tolerated. There are no established standard second-line treatment options, creating a significant unmet need for this patient population.

Given that immune checkpoint inhibitors (ICIs) have demonstrated activity in other HPV-related cancers, the investigator-initiated ALPACA trial was designed to evaluate the efficacy and tolerability of the PD-L1 inhibitor avelumab in this specific context.

The ALPACA Study Design

The study was a multicenter, single-arm, phase 2 trial conducted under a Simon 2-stage design, which targeted an ORR greater than 12.5%. The trial accrued patients between August 2018 and January 2025.

Patients had locally advanced inoperable or metastatic penile cancer refractory to or unfit for platinum chemotherapy. Key criteria included an ECOG performance status of 0 to 2 and no prior ICI therapy. A total of 25 patients were enrolled across 3 Canadian centers, with 23 deemed evaluable for analysis. Six patients were HPV positive, 5 were HPV negative, and 12 had unknown status. The median patient age was 58 (range, 41-72).

Patients were administered avelumab at 10 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. The primary end point was ORR assessed by investigators per iRECIST criteria. Secondary end points included PFS, OS, safety, and tolerability.

Correlative Science and Biomarker Analysis

Preliminary correlative studies did not establish a clear correlation between HPV status and patient outcomes, though this analysis was limited by the high number of patients with unknown HPV status. Another finding suggested that a high neutrophil to lymphocyte ratio may be predictive of worse outcomes. Additional correlative studies are ongoing to further explore potential biomarkers.

“Future studies will need to consider if these agents should be evaluated in earlier disease settings, or in combination with novel therapeutic strategies,” said Srikala S. Sridhar, MD, MSc, FRCPC, Princess Margaret Cancer Center, Toronto, Canada, during a presentation of the data. “Ultimately, large-scale collaborations, innovative study designs, and increased funding will be essential to accelerate drug development to improve outcomes for patients with rare tumors, including penile cancer.”

REFERENCES

1. Sridhar S. A phase II study of avelumab in locally advanced or metastatic penile cancer patients unfit for platinum-based chemotherapy or progressed on or after platinum-based chemotherapy (ALPACA). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA37.

2. A study of avelumab in penile cancer who are unfit for or have progressed after platinum-based chemotherapy. ClinicalTrials.gov. Updated October 10, 2024. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT03391479