Amivantamab in Patients With Metastatic/Recurrent Penile Squamous Cell Carcinoma

Amivantamab in Patients With Metastatic/Recurrent Penile Squamous Cell Carcinoma Who Progressed to First-line Platinum-Based Chemotherapy: APOLO TRIAL (LACOG 2425)

This is a collaborative, multicenter, open-label, Phase 2 clinical trial (APOLO TRIAL / LACOG 2425) designed to evaluate the efficacy, safety, and tolerability of subcutaneous amivantamab monotherapy in adult patients with histologically confirmed recurrent or metastatic penile squamous cell carcinoma (PSCC). Eligible participants must have experienced disease progression on or after receiving at least one platinum-based chemotherapy regimen (with or without immunotherapy). The study allocates participants into two parallel non-randomized cohorts based on their human papillomavirus (HPV) status (HPV-positive and HPV-negative).

Penile squamous cell carcinoma (PSCC) is a rare and aggressive disease with near-universal EGFR protein overexpression and frequent MET activation, representing a significant unmet medical need following the failure of first-line platinum-based chemotherapy. Amivantamab is a fully human bispecific antibody targeting both EGFR and MET. Study Design & Administration: Participants receive subcutaneous amivantamab monotherapy across 21-day cycles. Dosing is weight-based (1,600 mg for $<80\text{ kg}$; 2,240 mg for $\ge80\text{ kg}$ on Cycle 1 Day 1, followed by 2,400 mg or 3,360 mg on Days 8 and 15 of Cycle 1, and every 3 weeks starting from Cycle 2 onwards). Treatment continues during the core treatment phase for up to 24 weeks or until disease progression, unacceptable toxicity, or consent withdrawal. Patients without progression at 24 weeks may enter an extension phase. Primary Endpoint: Objective Response Rate (ORR) assessed by the investigator per RECIST v1.1. Secondary Endpoints: Independent Central Review ORR (ORR-ICR), Disease Control Rate (DCR), Duration of Response (DoR), Progression-Free Survival (PFS), Overall Survival (OS), safety/tolerability (NCI-CTCAE v6.0), treatment compliance, post-progression therapies, and Patient-Reported Outcomes (EORTC QLQ-C30). Exploratory Biomarker Research: Evaluation of baseline tissue/blood biomarkers (HPV status, EGFR/MET expression), longitudinal tracking of ctDNA and HPV copy numbers, and exploration of acquired resistance mechanisms. Sample Size & Design: Using Simon's two-stage design, each cohort aims to enroll 27 evaluable patients (up to 29 patients per cohort to account for non-evaluable participants, totaling up to 58 patients overall). Each cohort includes a Stage 1 futility analysis after enrolling 13 patients.

Inclusion Criteria:

1. Histologically confirmed diagnosis of penile squamous cell carcinoma.

2. Metastatic or locally advanced disease not amenable to therapy of curative intent (e.g., surgery, radiotherapy, chemoradiotherapy) in the opinion of the investigator.

3. Measurable disease per RECIST v1.1 as assessed by the local site investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

4. Have received up to 2 lines of previous systemic therapy. Documented disease progression on or after first-line or second-line platinum-based chemotherapy for locally advanced/metastatic disease. Disease progression within 12 months of (neo) adjuvant chemotherapy completion is considered first-line of therapy. Previous anti-PD-1/anti-PD-L1 therapy is allowed.

5. Participants must have tumor tissue available for HPV testing. HPV status will be determined by IHC for p16 or FISH (both are acceptable) assessed by the local laboratory or central laboratory. Note: A copy of the local test report documenting the HPV status must be included in the participant records and must also be submitted to the sponsor.

6. Male participant aged at least 18 years and no more than 85 years at the time of signing the informed consent form.

7. Male Participants (Reproductive Potential). If capable of producing sperm, the participant agrees to the following from the first dose of study intervention and for at least 120 days after the last dose:

   • Refrain from donating sperm.
   • Use a penile/external condom when engaging in penile-vaginal intercourse with a partner of childbearing potential who is not currently pregnant, PLUS the partner must use an additional highly effective contraceptive method. Note: A condom alone is not considered highly effective, as breakage or leakage may occur. If the participant is azoospermic (vasectomized or due to medical cause, documented by medical records, examination, or history), no contraception is required. Contraceptive use must be consistent with local regulations for participants in clinical studies. If local label requirements for amivantamab are more stringent, those must be followed.

8. The participant (or legally acceptable representative, if applicable) provides written informed consent for the study.

9. Life expectancy of at least 12 weeks in the opinion of the investigator.

10. Willing and able to provide an archival tumor tissue sample or newly obtained core/incisional/excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred; newly obtained biopsies are preferred to archived tissue (minimum 10-15 unstained slides recommended).

11. Adverse events due to previous anticancer therapies must have recovered to ≤ Grade 1 or baseline (except for alopecia and vitiligo). Participants with endocrine-related AEs adequately managed on stable hormone replacement therapy are eligible.

12. Adequate organ function defined by the laboratory values in Table 2 (specimens collected within 14 days prior to the start of study intervention). This population definition ensures a homogeneous group of platinum-refractory patients with measurable disease while maintaining broad applicability across age, race, and ethnicity, in line with the orphan nature of the disease and the universal EGFR overexpression observed in penile squamous cell carcinoma.

13. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Evaluation is to be performed within 7 days prior to the start of study intervention.

14. Be willing and able to adhere to the study visit schedule and other protocol requirements, including the completion of all scheduled study procedures, laboratory tests, tumor assessments, and patient-reported outcome questionnaires.

15. Participants with chronic hepatitis B virus (HBV) infection (HBsAg positive) are eligible if they have received HBV antiviral therapy for at least 4 weeks and have an undetectable HBV viral load prior to the start of study intervention. Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy after completion of study intervention. Note: Hepatitis B serology testing at screening is not required unless if there is a known history of HBV infection.

16. Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening and they have completed curative antiviral therapy at least 4 weeks prior to the start of study intervention. Note: Hepatitis C serology/viral load testing at screening is not required unless if there is a known history of HCV infection.

Exclusion Criteria:

1. History of interstitial lung disease (ILD)/pneumonitis/pulmonary fibrosis that required systemic steroids, or current ILD/pneumonitis (including radiation pneumonitis).

2. Any evidence of active or suspected ILD/pneumonitis/pulmonary fibrosis on screening chest imaging (CT preferred).

3. Participant with untreated brain metastases Note: Participants with definitively, locally treated metastases that are clinically stable and asymptomatic for at least 8 weeks and who are off or receiving low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 4 weeks prior to the first dose of study treatment are eligible.

4. Participant has a medical history or known presence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.

5. Uncontrolled illness, including but not limited to (applicable to all participants):

   1. Diabetes.
   2. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment]) or diagnosed or suspected viral infection.
   3. Active bleeding diathesis.
   4. Impaired oxygenation requiring continuous oxygen supplementation.

6. Known allergies, hypersensitivity, or intolerance to excipients of amivantamab or rHuPH20 (refer to the IB).

7. Participant has a history of clinically significant cardiovascular disease including, but not limited to the following:

   • Diagnosis of deep vein thrombosis or pulmonary embolism within 8 weeks prior to the first dose of study treatment or any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary.
   • Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). Note: Participants with cardiac pacemakers who are clinically stable are eligible.
   • Uncontrolled (persistent) hypertension: systolic blood pressure >180 mm Hg; diastolic blood pressure >100 mm Hg.
   • Congestive heart failure defined as NYHA Class III, IV or Hospitalization for congestive heart failure (any NYHA Class) within 6 months of the first dose of study treatment.
   • Pericarditis/clinically significant pericardial effusion.
   • Myocarditis.
   • Clinically significant arrhythmias requiring medication

8. Participant has, or will have, any of the following:

   1. An invasive operative procedure with entry into a body cavity, within 4 weeks or without complete recovery before the first administration of study treatment. Thoracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to the first administration of study treatment, as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator.
   2. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to Day1).
   3. Expected major surgery while the investigation agent is being administered or within 6 months after the last dose of study treatment.

9. HIV-positive participants are not eligible if they meet any of the following:

   1. Detectable viral load (ie, >50 copies/mL) at screening.
   2. CD4+ count <300 cells/mm3 at screening.
   3. AIDS-defining opportunistic infection within 6 months of screening.
   4. Not receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening. Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to enrollment).

10. Active hepatitis of infectious origin.

    1. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg negative with anti-HBc with or without the presence of anti-HBs) must be screened using RT-PCR measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR.
    2. Positive hepatitis C antibody test result at screening or within 3 months prior to the first dose of study treatment. Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative HCV RNA test is obtained.
    3. Positive hepatitis C RNA test result at screening or within 3 months prior to the first dose of study treatment. Note: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
    4. Other clinically active liver diseases of infectious origin.

11. Prior treatment with any EGFR×MET bispecific antibody.

12. Severe or uncontrolled ocular disorders including severe dry eye syndrome, severe Meibomian gland dysfunction, severe blepharitis, or corneal disease that may preclude safe administration of amivantamab (e.g., history of corneal ulceration, persistent epithelial defect).

13. Prior systemic anticancer therapy (including investigational agents) within 14 days or 4 half-lives (whichever is longer) prior to first dose. The maximum required washout is 28 days.

14. Prior radiotherapy within 14 days prior to first dose or unresolved radiation-related toxicity requiring corticosteroids. Note: Limited palliative radiotherapy (≤10 fractions) to non-target lesions is allowed if completed ≥7 days before first dose.

15. Requires prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study; see Section 6.6 Concomitant Therapy for prohibited therapies.

16. Received an investigational treatment (including investigational vaccines, but not including anticancer therapy) or used an invasive investigational medical device within 6 weeks before the planned first dose of study treatment.

17. Any medical, psychiatric, social or other condition that, in the opinion of the investigator, would preclude safe participation or compliance with study procedures.