Metastatic Renal Cell Carcinoma - First Line

Metastatic, measurable clear cell RCC without prior systemic tx in any setting.
Tumor tissue available for RNA-sequencing (metastatic preferred, no bone)
Calculated creatinine clearance ≥30 mL/min per the Cockcroft Gault
No immunosuppressive meds or prednisone equivalent > 10mg/d
**FYI time from consent to first treatment day likely 3-4 weeks

Key Eligibilty Criteria:
Inclusion:
1. Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
a. One bone lesion on bone scan (tec99 or sodium fluoride [NaF] PET/CT, CT or MRI) for the bone-only cohort.
b. Histologically confirmed diagnosis of one of the following metastatic cohorts:
- Small cell/ neuroendocrine carcinoma of the bladder (Cohort A)- All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded
- Squamous cell carcinoma of the bladder (Cohort C) - must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma)
- Plasmacytoid urothelial carcinoma (Cohort D) - Tumor should show predominantly > or equal ~ 50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well)
- Sarcomatoid urothelial carcinoma (Cohort H) - Tumor should show predominantly ~ 50% sarcomatoid differentiation
- Bone-only metastatic GU tumors (non-prostate) (Cohort J) - All genitourinary histologies, except prostate are eligible
- Urethra carcinoma (Cohort L) - May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder
c. H&E slides from diagnostic tumor tissue for retrospective central pathology review
2. Patients may have received up to 2 systemic anti-cancer treatments or be treatment naive. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin-eligible)
3. Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed.
4. No prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors with the exception of patients with "urothelial carcinoma" histology (cohorts D, H, J, L)
5. The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment

Key Eligibility Criteria:

Inclusion Criteria:
1. Histological or cytological evidence of renal cell carcinoma having a clear cell component.
2. Advanced (not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma
3. Treatment naïve for systemic therapy for renal cell carcinoma including no prior neo/adjuvant systemic therapy
4. Archival tissue available.

Exclusion Criteria:
1. Prior systemic therapy against renal cell carcinoma in the neo/adjuvant or metastatic setting
2. Participants with a history of myocarditis.

For pre-screening, please contact: Message Basket: VICC RESEARCH UROTHELIAL

Key Eligibility Criteria:

Inclusion Criteria:
1. Confirmed diagnosis of unresectable locally advanced/metastatic RCC with clear cell component.
2. Has received no other prior systemic therapy for treatment of advanced/metastatic ccRCC, except for adjuvant anti-PD-(L)1 therapy.
3. Has disease recurrence during adjuvant anti-PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy.
4. Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.

Exclusion Criteria:
1. Deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
2. Prolongation of QTcF interval to >480 ms.
3. Received prior treatment with HIF-2alpha and/or VEGF/TKI inhibitors.
4. Have been previously allocated/randomized to study intervention in any sub-study of protocol MK-3475-U03.
5. Has any of the following:
a. A pulse oximeter reading <92% at rest, or
b. Requires intermittent supplemental oxygen, or
c. Requires chronic supplemental oxygen.

For pre-screening, please contact: Message Basket: VICC RESEARCH UROTHELIAL