This is a phase II clinical trial evaluating activity, safety and patients reported outcomes of first-line pembrolizumab plus cisplatin (or carboplatin) plus 5-FU for patients with advanced penile squamous cell carcinoma.

The primary endpoint is overall responsa rate according to RECIST v1.1 at week 24.

Advanced penile squamous cell carcinoma is associated with dismal survival rates and a major impact on the quality of life. To date, unresectable or metastatic disease is managed by systemic therapy with platinum-based chemotherapy for patients with good performance status. The median PFS and OS on first-line platinum-based chemotherapy vary between 3-4 and 7-15 months, respectively. Chemotherapy induces objective responses in only 20-30% of penile cancer patients with rare complete responses and systemic treatment has not changed for decades. Therefore, this study's rationale is to explore the efficacy and safety of pembrolizumab combined with standard-of-care cisplatin(or carboplatin) plus 5-fluorouracil as part of the first-line therapy. Patients will receive pembrolizumab 200mg IV every three weeks with a maximum duration of 2 years (34 cycles-counting the combination with chemotherapy) in case of no progressive disease or intolerance. The investigators hypothesized that the combination of immunotherapy with standard cytotoxic chemotherapy may improve the overall response rate by RECIST v1.1 in this patient population.

INCLUSION

1. Male participants who are at least 18 years of age on the day of signing informed consent will be enrolled in this study.

2. Patients with penile squamous cell carcinoma with either:

   • metastatic disease (de novo or recurrent), or
   • recurrent locally advanced disease not amenable to curative intent therapy (e.g. surgery, radiotherapy, chemoradiotherapy, etc), or
   • anyT N3 M0 or T4 anyN M0 (stage IV - AJCC 8th) not amenable to curative-intent therapy (e.g. surgery, radiotherapy, chemoradiotherapy, etc).

3. Histologically confirmed diagnosis of penile squamous cell carcinoma (PSCC).

4. Patients with advanced or metastatic PSCC without prior treatment or that progressed after 12 months of (neo) adjuvant chemotherapy completion.

5. Participant must agree to use a contraception.

6. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

7. Have measurable disease based on RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

   Newly obtained biopsies are preferred to archived tissue.

9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of enrollment.

10. Have adequate organ function (see Table 1). Specimens must be collected within 10 days prior to the start of study treatment.

11. Have a life expectancy of at least 12 weeks.

EXCLUSION

1. Primary tumor arising from urethra.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to enrollment.
4. Has received prior radiotherapy within 3 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
5. Has received a live vaccine within 30 days prior to the first dose of study drug.
6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of non-penile skin or carcinoma in situ that have undergone potentially curative therapy are not excluded.
9. Has known symptomatic uncontrolled CNS metastases and/or carcinomatous meningitis.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of Human Immunodeficiency Virus (HIV).
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. Is expecting to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
20. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subject who are MSD employees directly involved in the conduct of the trial.