Pembrolizumab plus platinum-based therapy shows safety, efficacy in penile cancer


“The HERCULES trial is the first trial to demonstrate the efficacy of immune checkpoint inhibitors in [patients with] advanced penile cancer with [a] manageable safety profile," says Fernando Cotait Maluf, MD.

Treatment of penile squamous cell carcinoma (PSCC) with pembrolizumab (Keytruda) plus platinum-based therapy was associated with safety and efficacy, according to results from the single-arm phase 2 HERCULES (NCT04224740) trial.1

Blur image of hospital corridor | Image Credit: © zephyr_p -

Confirmed ORR by central review was 42.4% (95% CI, 25.5%-60.8%).

Fernando Cotait Maluf, MD, of Hospital Beneficência Portuguesa de São Paulo and Hospital Israelita Albert Einstein, São Paulo, Brazil, presented the data at the 2024 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois. In his presentation, Maluf noted that PSCC has up to a 10 times higher incidence in low-income countries in Africa, Asia, and Latin America.2 He added that advanced PSCC is a disease for which no improvements have been made of late, and prognosis is poor, with an overall survival (OS) of approximately 6 to 7 months.

“Platinum-based chemotherapy has been considered the standard of care…Immune checkpoint inhibitors have been associated with efficacy in different tumor types, including HPV16-positive tumors, such as cervical and head and neck squamous cell carcinoma,”3,4 Maluf explained.

Maluf and his coauthors hypothesized that the addition of pembrolizumab to platinum-based chemotherapy for first-line treatment of advanced penile cancer would be safe and associated with improved outcomes for patients.

Eligible patients were required to have an ECOG Performance Status of 0-1, have metastatic (de novo or recurrent) disease, locally advanced disease (TanyN3M0 or T4NanyM0) that is not amenable to curative-intent therapy, loco-regional recurrence that is not amenable to curative-intent therapy, and no prior exposure to chemotherapy for advanced disease; however, prior neoadjuvant chemotherapy was allowed if disease progressed after 12 months.

Patients received cisplatin 70 mg/m2 or carboplatin AUC 5 D1 plus 5-FU 1000 mg/m2/day D1-D4 plus pembrolizumab 200 mg IV Q3W for 6 cycles. This was followed by maintenance pembrolizumab 200 mg IV Q3W for up to 34 cycles. The primary outcome was confirmed overall response rate (ORR) (RECIST 1.1) per investigator assessment. Secondary end points included confirmed ORR by central review, progression-free survival (PFS), OS, safety, and translational research analysis.

A total of 37 patients were included in the study, of whom 5 (13.5%) had locally advanced disease and 8 (21.6%) had loco-regional recurrence. Thirty-three patients were eligible for efficacy analysis. Confirmed ORR by investigator was 39.4% (95% CI, 22.9%-57.9%). Of these, 1 was a complete response (3.0%) and 12 (36.4%) were partial responses. Confirmed ORR by central review was 42.4% (95% CI, 25.5%-60.8%). Clinical benefit rate by investigator over 24 weeks was 45.5% (95% CI, 28.1%-63.7%).

Maluf reported that tumor shrinkage of any magnitude was seen in 75.8% of patients. After a median follow-up of 24 months, median duration of response was 5.9 months (95% CI, 4.4-9.0), and median time to response was 1.4 months (95% CI, 1.3-1.8). Median PFS was 5.4 months (95% CI, 2.7-7.2), and median OS was 9.6 months (95% CI, 6.4-13.2).

“Our biomarker exploratory analysis showed a potential correlation between response with TMB as well as HPV16 status,” Maluf reported.

Regarding treatment-related adverse events (AEs), Maluf reported 19 AEs (51.4%) of grade 3 or higher, and noted that only 6 patients (16.2%) experienced neutropenia. Two (5.4%) immune-related AEs of grade 3 or higher were observed.

“The HERCULES trial is the first trial to demonstrate the efficacy of immune checkpoint inhibitors in [patients with] advanced penile cancer with [a] manageable safety profile. We are proud to say that pembrolizumab plus platinum-based therapy is a new treatment option for [patients with] advanced penile cancer,” Maluf said in his concluding remarks.


1. Maluf FC, Trindade K, Almeida Preto DD, et al. A phase II trial of pembrolizumab plus platinum-based chemotherapy as first-line systemic therapy in advanced penile cancer: HERCULES (LACOG 0218) trial. Presented at: 2024 American Society of Clinical Oncology Annual Meeting. May 31-June 4, 2024. Chicago, Illinois. Abstract 5009.

2. Coelho RWP, Pinho JD, Moreno JS, et al. Penile cancer in Maranhão, Northeast Brazil: the highest incidence globally? BMC Urol. 2018;18(1):50. doi:10.1186/s12894-018-0365-0

3. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7

4. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435

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