Neoadjuvant Enfortumab Vedotin and Pembrolizumab for the Treatment of Patients with Upper Tract Urothelial Cancer, NEPTUNE Trial

Inclusion Criteria

• 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): * Upper urinary tract mass on cross-sectional imaging or tumor directly visualized during upper urinary tract endoscopy before referral to medical oncology. * No regional lymph node metastasis or a single regional lymph node metastasis.
• 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.
• Patients must be eligible for cisplatin. Cisplatin eligibility is defined as meeting all of the following criteria: * Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or measured by 24-hour urine collection. * Absence of grade ≥ 2 peripheral neuropathy. * Absence of New York Heart Association class III or higher heart failure.
• 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 uro-oncologic history: * History of or active non-invasive carcinoma or carcinoma in situ of the bladder/urethra or upper tract is allowed. * Patients may have received prior intravesical chemotherapy or immunotherapy such as Bacillus Calmette-Guerin (BCG). * Prior neoadjuvant or adjuvant chemotherapy or antibody-drug conjugate for bladder cancer or invasive contralateral upper tract cancer is allowed but must have been completed ≥ 1 year prior to study registration.
• Patients must be age ≥ 18 on the date of registration.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Criteria for patients with hepatitis B or C are listed below. Hepatitis B and C screening tests are not required unless there is a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or as mandated by local healthy authority. * Hepatitis B positive subjects ** Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment. ** Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. * Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. ** Participants must have completed curative anti-viral therapy at least 4 weeks prior to enrollment.
• Absolute neutrophil count (ANC) ≥ 1500/uL (within 14 business days prior to start of study enrollment).
• Platelets ≥ 100 000/uL (within 14 business days prior to start of study enrollment).
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (within 14 business days prior to start of study enrollment). * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
• Creatinine clearance ≥ 45 mL/min (within 14 business days prior to start of study enrollment). * Creatinine clearance (CrCl) should be calculated by Cockcroft-Gault equation (using actual body weight) or measured by 24-hour urine collection.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 business days prior to start of study enrollment). * Total bilirubin ≤ 3 x ULN for patients with Gilbert's disease.
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x ULN (within 14 business days prior to start of study enrollment).
• International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 14 business days prior to start of study enrollment).
• aPTT ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 business days prior to start of study enrollment).
• Women and men of reproductive potential must agree to use an effective contraceptive method during treatment and for 4 months after the last dose of study drug for women and for 4 months after the last dose of study drug for men. Men must also refrain from donating sperm during this period.
• Women of reproductive potential must have a negative pregnancy test within 14 days prior to registration and are not breastfeeding.
• Patients must not have any other medical condition(s) that make(s) their participation in the study unadvisable in the opinion of the treating oncologist.
• All patients must be informed of the investigational nature of this study. The patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity who have a legally authorized representative or caregiver and/or family member available will also be considered eligible.

Exclusion Criteria

• 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: * Intranasal, inhaled, intra-auricular, topical steroids, or local steroid injections (e.g., intra-articular injection). * Use of chronic immunosuppressive agents at baseline at doses not to exceed more than prednisone 10 mg/day or equivalent. * 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.
• Evidence of metastasis (N2-3 or M1) on axial imaging at baseline.
• History of invasive, node positive, or metastatic bladder cancer OR invasive contralateral upper tract cancer within 2 years prior to registration.
• Enrolled in another interventional clinical trial at the time of registration.
• Patient has another active malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 1 year. The time requirement does not apply to participants who underwent successful definitive resection of non-melanoma skin cancers, superficial bladder cancer (described above in inclusion criteria 7), in situ cervical cancer, other in situ cancers, or either clinically insignificant per the investigator (e.g., ≤ Gleason 3+4) on surveillance or previously treated prostate cancer without rising prostate-specific antigen (PSA) and no plan to treat. * NOTE: Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patient has one kidney.
• Patient is pregnant or lactating.
• Has severe hypersensitivity (≥ grade 3) to enfortumab vedotin, pembrolizumab, and/or any of its excipients.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition 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.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of active TB (bacillus tuberculosis).
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Has had an allogenic tissue (e.g., hematopoietic stem cell transplant [HSCT])/solid organ transplant.
• Has any of the following: * Prior exposure to MMAE ADCs * Moderate or severe liver dysfunction (does not meet hepatic function laboratory criteria). * Uncontrolled diabetes mellitus as deemed by hemoglobin A1c of 8 or greater.