This trial is a multi-site, single-arm, phase 2 trial of neoadjuvant combination of enfortumab vedotin and pembrolizumab in patients with high-grade localized/locally advanced cT1-4 N0-1 M0 upper tract urothelial cancer who are deemed eligible for curative-intent surgery (radical nephroureterectomy or distal ureterectomy) followed by adjuvant pembrolizumab.
Patients must have a diagnosis of high-grade upper tract (renal pelvis and/or ureter) urothelial carcinoma proven by biopsy or cytology within 60 days prior to registration with the following (cT1-4 N0-1 M0): a. Upper urinary tract mass on cross-sectional imaging or Tumor directly visualized during upper urinary tract endoscopy before referral to medical oncology. b. No regional lymph node metastasis, a single regional lymph node metastasis, or multiple regional lymph node metastases (no distant lymph node metastases)
Patients must not have any component of small cell carcinoma. Other variant histologic types are permitted provided the predominant (≥50%) subtype is urothelial carcinoma.
Patients must be considered to be a candidate for definitive surgery (nephroureterectomy or distal ureterectomy) with curative intent by the treating urologist. Lymph node dissection is strongly encouraged but its scope and determination will be at the discretion of the treating urologist. Details of the surgery such as bladder cuff removal are left to the discretion of the treating urologist. Robotic or open approaches are allowed.
Prior local endoscopic therapy for upper tract urothelial cancer is permitted if completed at least 6 months prior to the initiation of study treatment and if all toxicities from such therapy have improved to grade 1 or resolved.
Prior exposure to immune-mediated therapy, including but not limited to, other anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), anti-PD1, anti-PD-L1, anti-PD-L2 antibodies, and therapeutic anticancer vaccines.
Prior exposure to monomethyl auristatin E antibody-drug conjugates (MMAE ADC).
Patient is currently on or used immunosuppressive medication within 14 days prior to the first dose of pembrolizumab. The following are exceptions to this criterion: o Intranasal, inhaled, intra-auricular, topical steroids, or local steroid injections (e.g., intra-articular injection). o Use of chronic immunosuppressive agents at baseline at doses not to exceed more than prednisone 10 mg/day or equivalent. o Steroids as premedications for hypersensitivity reactions (e.g., CT scan premedication).
Active or prior documented autoimmune or inflammatory disorders requiring immunosuppressive therapy within 2 years prior to registration. Exceptions are well-controlled hyper/hypothyroidism, celiac disease controlled by diet alone, diabetes mellitus type 1, alopecia, psoriasis, eczema, lichen planus, vitiligo, or similar skin/mucosa conditions.
Single group
Enfortumab vedotin
Drug1.25 mg/kg IV
Pembrolizumab
Drug200 mg IV
Efficacy of the combination of enfortumab vedotin and pembrolizumab as neoadjuvant therapy in patients based off pathological response
This trial will estimate the efficacy of combination enfortumab vedotin and pembrolizumab given as neoadjuvant therapy in patients with localized/locally advanced upper tract urothelial cancer (cT2-4 N0-1 M0) followed by definitive surgery. The historic pT0/Ta/Tis/T1 (termed 'response' herein) rate with definitive surgery alone for a comparable patient population (H0) is approximately 20%. This study targets an improvement of 20% in the response proportion to a target 40% response rate (H1) with the combination of enfortumab vedotin and pembrolizumab. Patients who are unable to undergo definitive surgery within 16 weeks from the last dose of neoadjuvant chemotherapy will be considered non-responders for the primary endpoint.
Assess the safety and toxicity of the combination of enfortumab vedotin and pembrolizumab as neoadjuvant therapy in UTUC
CTCAE v5 criteria will be used to assess the safety and toxicity of combination enfortumab vedotin and pembrolizumab in eligible UTUC patients. Safety and toxicity will be reported in all patients who receive treatment with any therapy on trial. Toxicity by grade and attribution will be described using counts and proportions.
Assess whether patients who receive the combination of enfortumab vedotin and pembrolizumab as neoadjuvant therapy have increased surgical complications.
Surgical complications will be assessed by the Clavien-Dindo classification. Grade 1 to Grade 5 (Grade 1 being no deviation and Grade 5 being death).
Estimate secondary measures of efficacy of neoadjuvant combination enfortumab vedotin and pembrolizumab and pembrolizumab adjuvant therapy (if tolerated) in response evaluable patients with UTUC by measuring RECIST v1.1 measurable disease.
Overall response in the subset of patients with RECIST v1.1 measurable disease in response evaluable patients with UTUC who receive neoadjuvant combination enfortumab vedotin and pembrolizumab will be measured. The ORR (Overall Response Rate) will be calculated from the partial responses and complete responses in the subset of subjects with have RECIST 1.1 measurable disease at baseline.
Estimate secondary measures of efficacy of neoadjuvant combination enfortumab vedotin and pembrolizumab and pembrolizumab adjuvant therapy (if tolerated) in response evaluable patients with UTUC by measuring 2-year recurrence-free survival (RFS).
2-year recurrence-free survival (RFS) proportions and 95% confidence intervals will be estimated using Kaplan-Meier methods.
Assess comprehensive profiling of tumor and host characteristics (including genomics and assessment of tumor mutational burden) as predictors of response to treatment.
Integrative Next Generation Sequencing: We plan to perform integrative Next Generation Sequencing by the Michigan Center for Translational Pathology (MCTP) including but not limited to RNA-seq, PD-L1 status by the 22C3 assay, and tumor mutational burden assessment from tissue obtained at the time of diagnosis or surgery to correlate with response to treatment. Optional tumor biopsy at recurrence may be obtained for integrative next generation sequencing
Explore circulating biomarkers as early detectors of cancer recurrence
Early detection of cancer recurrence, ResBio ctDNA will be obtained prior to starting neoadjuvant therapy (cycle 1, day 1), on the last day of neoadjuvant therapy (cycle 4, day 8), after surgery at 4-6 weeks, after surgery at 12 weeks then at 3 month intervals for 24 months (after surgery).
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