Pembrolizumab maintenance after initial enfortumab vedotin plus pembrolizumab for frontline metastatic urothelial cancer

Pembrolizumab Maintenance After Enfortumab Vedotin/Pembrolizumab Induction in Front-Line Metastatic Urothelial Carcinoma

This trial will test whether continuing pembrolizumab after an 18-week course of enfortumab vedotin plus pembrolizumab helps people with previously untreated metastatic urothelial carcinoma.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 97 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fox Chase Cancer Center (other)
• Drugs / interventions: enfortumab, immunotherapy, radiation, prednisone, pembrolizumab
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT07221942 on ClinicalTrials.gov

What this trial studies

This is a single-arm, open-label Phase 2 trial enrolling about 97 patients with treatment-naïve metastatic or unresectable urothelial carcinoma. Participants receive induction therapy with enfortumab vedotin plus pembrolizumab for six 21-day cycles (approximately 18 weeks) with radiographic assessments after cycles 3 and 6. Patients who achieve a complete or partial response transition to maintenance pembrolizumab given either 400 mg every 6 weeks or 200 mg every 3 weeks for up to two years, with imaging every 12 weeks. Treatment continues until disease progression, unacceptable toxicity, or completion of maintenance, and participants enter long-term follow-up as appropriate.

Who should consider this trial

Good fit: Ideal candidates are adults with measurable, previously untreated metastatic or unresectable urothelial carcinoma, ECOG 0–2, who have not received prior systemic therapy for metastatic disease (prior perioperative ICI allowed if completed ≥12 months earlier).

Not a fit: Patients who progress during induction, who cannot tolerate the combination due to toxicity, or who have already received systemic therapy for metastatic disease are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could extend the time patients remain on disease control while limiting continued exposure to enfortumab vedotin.

How similar studies have performed: Earlier-phase studies of enfortumab vedotin combined with pembrolizumab have shown promising response rates, so the combination is not entirely novel but using pembrolizumab as defined maintenance after this induction is being specifically tested.

Eligibility criteria

Inclusion Criteria:

* Patients must have histologically and radiographically confirmed locally advanced, unresectable urothelial carcinoma.
* Patients should not have received prior systemic therapy for metastatic disease.
* Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v1.1
* Patients may have received prior neoadjuvant or adjuvant immune checkpoint inhibitor therapy for localized disease and are eligible if they completed the treatment ≥12 months prior to initiating treatment on this clinical trial.
* ECOG performance status 0-2
* Ability to understand and willingness to sign a written informed consent and HIPAA consent document
* Archival tumor biospecimen (when available) must be procured for correlative evaluation. If tumor tissue is not available or accessible despite good faith efforts, patient may still be treated on study. Formalin fixed, paraffin embedded (FFPE) tissue block(s) or at least 25 unbaked, unstained slides are required. Tissue samples taken from a metastatic lesion prior to the start of screening are acceptable.
* Normal organ and marrow function as defined below.

  * Absolute neutrophil count \> 1,000/mm3 unless patient has constitutional neutropenia
  * Platelets \> 100,000/µl
  * Hemoglobin \> 8.0 g/dL
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5 x upper limit of normal (ULN) or \<3.5 x ULN if liver metastases
  * Creatinine Clearance \>20 ml/min

Exclusion Criteria:

* Patients who have received prior monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) for urothelial cancer.
* Grade 2 or higher baseline sensory or motor neuropathy.
* Uncontrolled diabetes (HbA1c \>8%)
* Patients with uncontrolled and untreated central nervous system (CNS) metastases.

  * Prior radiation to CNS metastases is permitted.
  * Prior history of CNS disease that has responded to previous systemic therapy is permitted only if no recurrence.
  * Patient should not have leptomeningeal disease
  * CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis.
  * If requiring steroid treatment for CNS metastases, the patient is on stable dose \< 10 mg/day of prednisone or equivalent for at least 2 weeks prior to starting treatment
* Uncontrolled intercurrent illness including, but not limited to ongoing or active untreated infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would substantially impair the patient's ability to comply with study requirements. Efforts should be made to provide reasonable accommodations before determining exclusion based on social limitations.
* Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug that cannot be watched and requires treatment, or any evidence of residual disease from a previously diagnosed malignancy that cannot be watched and requires treatment. Adjuvant hormonal therapy for breast cancer is allowed.
* Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted.
* Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with enfortumab vedotin.
* History of idiopathic pulmonary fibrosis; organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
* Prior allogeneic stem cell or solid organ transplant.
* Other underlying medical condition that, in the opinion of the investigator, would impair the ability of the patient to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
* Patients with active tuberculosis.
* Pregnant or breast feeding
* History of autoimmune diseases. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., use of disease modifying agents, corticosteroids, or immunosuppressive drugs).

  * Patients with vitiligo or residual autoimmune hypothyroidism on stable doses of hormone replacement are permitted to enroll.
  * Patients with type 1 diabetes mellitus (T1DM) on a stable dose of insulin are permitted to enroll.
  * Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
* On high dose steroids at the time of study enrollment, defined as \>10 mg prednisone (or bioequivalent), including steroids used for management of intracranial lesions. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
* Patients who received prior immunotherapy for mUC or for an alternative malignancy are eligible unless they developed an immune related adverse event while on therapy requiring cessation of therapy or use of disease modifying agents, corticosteroids, or immunosuppressive drugs.

Where this trial is running

Philadelphia, Pennsylvania

• Fox Chase Cancer Center - Philadelphia — Philadelphia, Pennsylvania, United States (RECRUITING)

Study contacts

• Principal investigator: Pooja Ghatalia, MD — Fox Chase Cancer Center
• Study coordinator: Ryan Romasko, MBA

Conditions: Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma, Advanced Urothelial Carcinoma, Urothelial carcinoma