Pembrolizumab Plus Chemotherapy Shows Preliminary Activity in Advanced Penile Cancer

The addition of pembrolizumab (Keytruda) to platinum-based chemotherapy led to an investigator-assessed objective response rate (ORR) of 39.4% (95% CI, 22.9%-57.9%) as frontline therapy in patients with advanced penile squamous cell carcinoma (PSCC), according to findings from the phase 2 nonrandomized HERCULES trial (NCT04224740) published in JAMA Oncology.1

At a median follow-up of 24.0 months (95% CI, 13.5-26.4) and among efficacy-evaluable patients (n = 33), the median progression-free survival (PFS) was 5.4 months (95% CI, 2.7-7.2) and the median overall survival (OS) was 9.6 months (95% CI, 6.4-13.2). The estimated 6-month PFS and OS rates were 40.6% (95% CI, 23.8%-56.8%) and 69.7% (95% CI, 51.0%-82.4%), respectively.

Best responses included 1 complete response (3.0%), 12 partial responses (36.4%), 7 cases (21.2%) of stable disease lasting at least 12 weeks, and 11 cases (33.3%) of disease progression. Two patients were not evaluated for best response due to early treatment cessation, reflecting a clinical benefit rate (CBR) of 45.5% (95% CI, 28.1%-63.7%).

“These findings suggest that pembrolizumab combined with chemotherapy may be a first-line treatment option for patients with advanced PSCC, and that the treatment had a manageable toxic effects profile,” lead study author Fernando Cotait Maluf, PhD, of the Hospital Beneficência Portuguesa de São Paulo and the Hospital Israelita Albert Einstein in Brazil, and coauthors wrote in the study publication.

Efficacy With Pembrolizumab Plus Platinum-Based ChemotherapyThe objective response rate was 39.4% (95% CI, 22.9%-57.9%).The median progression-free survival was 5.4 months (95% CI, 2.7-7.2).The median overall survival was 9.6 months (95% CI, 6.4-13.2).What Served as the Basis for the Study?

Advanced PSCC is a rare and aggressive cancer that is associated with poor survival. Although most cases will present as localized or locally advanced for which surgical treatment may be curative, approximately 30% of patients will develop recurrent disease.

Platinum-based chemotherapy has retained its role as the standard of care for patients with advanced or metastatic disease due to a lack of clinical advances in the past decade. The combination of PD-(L)1 inhibitors and chemotherapy has proven effective in human papillomavirus (HPV)–associated cancers such as cervical and head and neck squamous cell carcinoma, the latter of which has shown genomic similarity to PSCC.

How Was the Trial Designed and What Patients Were Included?

The trial was conducted at 11 sites in Brazil. Eligible patients included those 18 years of age or older with histologically confirmed PSCC. Patients had to have metastatic disease, locally advanced disease at diagnosis, or recurrent disease, neither of which could be eligible for curative-intent therapy. Additional trial criteria required that patients have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and normal organ function. Prior systemic therapy precluded enrollment unless recurrence developed after 12 months of therapy completion.1,2

Eligible patients received 200 mg of intravenous (IV) pembrolizumab on day 1; 70 mg/m2 of IV cisplatin or IV carboplatin at area under the curve 5 on day 1 per investigator discretion; and 1000 mg/m2 of IV fluorouracil per day with continuous infusion on days 1 to 4, every 3 weeks for 6 cycles.1 Patients without disease progression received 200 mg of maintenance pembrolizumab every 3 weeks for up to 34 cycles. Treatment was discontinued for disease progression or unacceptable adverse effects (AEs).

The primary end point was investigator-assessed ORR per RECIST 1.1 criteria. Secondary end points included ORR by central review, CBR, duration of response (DOR), PFS, OS, safety, and health-related quality of life (HRQOL).

A total of 37 patients were enrolled and received at least 1 dose of study therapy. Four patients were excluded from the efficacy-evaluable population because of major protocol violations (n = 3, active infection at enrollment; n = 1, progressed on prior chemotherapy within 4 months). Of the 33 evaluable for efficacy, 30 discontinued study therapy due to disease progression (n = 19), death (n = 6), toxicity (n = 4), and nonadherence (n = 1). Three completed treatment, 2 were ongoing treatment, and 2 were lost to follow-up.

Baseline characteristics revealed that the median age was 56 years (range, 30-76). Most patients had an ECOG performance status of 1 (n = 27; 73.0%), were Black or African American (n = 22; 59.5%), and were never smokers (n = 24; 64.9%); 29.7% (n = 11) were current or former smokers.

Regarding disease stage, 64.9% (n = 24) had metastatic disease, 21.6% (n = 8) had recurrent disease, and 13.5% (n = 5) had locally advanced disease. The predominant PD-L1 combined positive score and tumor mutational burden status was at least 1 in 78.4% (n = 29) and less than 10 mutations/megabase in 64.9% (n = 24) of patients, respectively. Twenty-two patients (56.5%) had negative HPV status and 83.8% (n = 31) of patients had proficient mismatch repair status.

What Other Efficacy Data Were Shared in the Publication?

The ORR according to central assessment was 42.4% (95% CI, 25.5%-60.8%).

Among patients who experienced a response, the median time to response was 1.4 months (95% CI, 1.3-1.8) and the median DOR was 5.9 months (95% CI, 4.4-9.0). The estimated 12- and 24-month OS rates were 41.4% (95% CI, 24.4%-57.6%) and 19.4% (95% CI, 7.5%-35.5%), respectively.

Was the Regimen Well Tolerated?

Of the 37 patients treated, any-grade AEs occurred in 97.3% (grade ≥3, 83.8%). Serious AEs also occurred (any grade, 70.3%; grade ≥3, 67.6%). Treatment-related AEs occurred in 91.9% of patients (grade ≥3, 51.4%). Events that occurred in at least 10% of patients in order of frequency included anemia, nausea, hypercalcemia, lymphopenia, thrombocytopenia, leukopenia, neutropenia, decreased appetite, diarrhea, vomiting, stomatitis, mucosal inflammation, constipation, deep vein thrombosis, hyponatremia, asthenia, fatigue, groin pain, hyperglycemia, and peripheral edema.

Immune-related AEs of any grade and grade 3 or higher were reported in 21.6% (n = 8) and 5.4% (n = 2) of patients, respectively. Immune-mediated AEs included adrenal insufficiency (any grade, n = 1; grade ≥3, n = 1), anemia (any grade, n = 1; grade ≥3, n = 1), increase alanine aminotransferase levels (any grade, n = 1; grade ≥3, n = 0), increased blood alkaline phosphatase levels (any grade, n = 1; grade ≥3, n = 0), drug hypersensitivity (any grade, n = 1; grade ≥3, n = 0), hyperthyroidism (any grade, n = 1; grade ≥3, n = 0), hypothyroidism (any grade, n = 3; grade ≥3, n = 1), pruritus (any grade, n = 1; grade ≥3, n = 0), rash (any grade, n = 1; grade ≥3, n = 0), and thrombocytopenia (any grade, n = 1; grade ≥3, n = 0).

No deaths were related to study therapy.

Was Health-Related Quality of Life Maintained?

Improvements in the HRQOL from baseline to week 24 were seen in global health status and all functional scales: physical, role, emotional, cognitive, and social functioning. Patients also experienced improvements in symptom scales for pain and insomnia. Less than 10-point changes in scores were considered stable and were seen with respect to fatigue, nausea and/or vomiting, appetite loss, and constipation during the first 18 weeks, with observed clinical improvement at week 24. Diarrhea and financial burden also remained stable.

“To our knowledge, this is the first phase 2 study to evaluate the role of an anti–PD-1 inhibitor combined with chemotherapy in first-line treatment of advanced PSCC. This trial met its primary end point and showed encouraging PFS and OS results, demonstrating the efficacy of immunotherapy in this rare disease,” the authors concluded.

ReferencesMaluf FC, Trindade K, Preto D, et al. Pembrolizumab plus platinum-based chemotherapy for patients with advanced penile cancer. The nonrandomized HERCULES (LACOG 0218) clinical trial. JAMA Oncol. Published online September 18, 2025. doi:10.1001/jamaoncol.2025.3266Pembrolizumab combined with cisplatin-based chemotherapy as first-line systemic therapy in advanced penile cancer (HERCULES). Clinicaltrials.gov. Updated March 13, 2024. Accessed October 2, 2025. https://clinicaltrials.gov/study/NCT04224740