A Study Comparing the Combination of Pembrolizumab and Sacituzumab Govitecan Versus Sacituzumab Govitecan Alone in the Treatment of Advanced Urothelial Cancer

This phase III trial compares the effectiveness of pembrolizumab and sacituzumab govitecan to sacituzumab govitecan alone in treating patients with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a chemotherapy drug called govitecan. Sacituzumab attaches to TROP2 positive tumor cells in a targeted way and delivers govitecan to kill them. Giving pembrolizumab and sacituzumab govitecan may be more effective than sacituzumab govitecan alone in treating patients with locally advanced or metastatic urothelial cancer.

PRIMARY OBJECTIVE:

I. To compare overall survival (OS) between the sacituzumab govitecan monotherapy arm and the sacituzumab govitecan + pembrolizumab arm.

SECONDARY OBJECTIVES:

I. To compare the progression free survival (PFS) between the sacituzumab govitecan monotherapy arm and the sacituzumab govitecan + pembrolizumab arm.

II. To evaluate overall response rate (ORR) between the sacituzumab govitecan monotherapy arm and the sacituzumab govitecan + pembrolizumab arm.

III. To evaluate clinical benefit rate (complete response \[CR\]/partial response \[PR\] /stable disease \[SD\]) between the sacituzumab govitecan monotherapy arm and the sacituzumab govitecan + pembrolizumab arm.

IV. To evaluate duration of response (DoR) between the sacituzumab govitecan monotherapy arm and the sacituzumab govitecan + pembrolizumab arm.

V. To evaluate toxicity of the sacituzumab govitecan + pembrolizumab arm using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

CORRELATIVE OBJECTIVE:

I. To evaluate the potential association between tumor tissue-based, blood and urine-based biomarkers with clinical endpoints (e.g., OS, PFS, ORR) in each arm.

EXPLORATORY OBJECTIVE:

I. To assess clinical outcomes (OS, PFS, ORR, clinical benefit rate) in prespecified subsets based on 1) prior checkpoint inhibitor therapy response primary versus (vs.) secondary resistance 2) prior enfortumab vedotin 3) prior platinum-based chemotherapy (cisplatin/carboplatin) and 4) Bellmunt score / risk factors.

EXPLORATORY HEALTH RELATED QUALITY OF LIFE (HRQOL) OBJECTIVES:

I. To compare HRQOL, as assessed by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBISI-18) summary score between patients on the sacituzumab govitecan arm versus the sacituzumab govitecan + pembrolizumab arm at 6 months.

II. To compare HRQOL change from baseline, as assessed by the FBISI-18 summary score, for patients on the sacituzumab govitecan arm versus the sacituzumab govitecan + pembrolizumab arm at baseline, 3, 6, and 12 months.

III. To compare the change in patient-reported fatigue from baseline and across 3, 6, and 12 months as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) summary score; change from baseline will be compared between patients on the sacituzumab govitecan arm versus the sacituzumab govitecan + pembrolizumab arm.

IV. To compare quality-adjusted survival (overall survival x health utility score assessed by the European Quality of Life Five Dimension Five Level \[EQ-5D-5L\]) between patients on the sacituzumab govitecan arm versus the sacituzumab govitecan + pembrolizumab arm.

V. To compare time to HRQOL deterioration in global HRQOL, as measured by the FBISI-18 disease-related physical symptom subscale (FBISI-18 disease-related symptoms (DRS) in the physical emotional domains \[DRS-P\]), between patients on the sacituzumab govitecan arm versus the sacituzumab govitecan + pembrolizumab arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive sacituzumab govitecan intravenously (IV) over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study.

ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 and sacituzumab govitecan IV over 1-3 hours on days 1 and 8 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients additional undergo blood sample collection, and CT or MRI throughout the study.

After completion of study treatment, patients are followed up for 5 years from the date of randomization.

Eligibility Criteria:
Inclusion Criteria:

* Patient must be ≥ 18 years of age
* Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Patient must have locally advanced or metastatic urothelial cancer
* Patient must have histologically proven conventional urothelial carcinoma (UC) of any urinary tract origin \[any histologic subtype except neuroendocrine (small or large cell)\] are permitted so long as tumors include ≥ 1% urothelial histology). NOTE: Pure non-urothelial histology is excluded
* Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Baseline imaging must be obtained ≤ 35 days prior to randomization
* Patient must have the following prior treatment. Patient must have had progression on or after the immediate prior therapy
* Patient must have had prior exposure to anti-PD(L)1 therapy \[anti -PD(L)1 monotherapy or as a combination regimen in any disease/therapy setting for UC. Patient must have received at least 1 dose of anti-PD(L)1 therapy

  * NOTE: Anti-PD(L)1 therapy does not need to be the most recent therapy received prior to enrollment on this protocol
  * NOTE: Prior platinum-based chemotherapy and/or enfortumab vedotin is allowed in any prior disease/therapy setting
* Patient must have had ≤ 2 lines of systemic therapy given in the advanced/metastatic disease setting for tumors with no known FGFR2 or FGFR3 (-) susceptible alteration (for erdafitinib) OR ≤ 3 lines of systemic therapy given in the advanced/metastatic disease setting for tumors harboring susceptible FGFR2 or FGFR3 susceptible alteration (for erdafitinib)
* Patient must have had no prior exposure to sacituzumab govitecan or other TROP-2 directed therapies or antibody-drug conjugate that contains topo-isomerase I inhibitor
* Patient must not have any history of grade 3 or higher immune-related adverse events on prior anti-PD1/L1, with the exception of endocrinopathies on adequate hormone repletion and clinically insignificant laboratory abnormalities
* Patient must have recovered (i.e., ≤ grade 1) from clinically significant AEs due to previously administered systemic therapy agent.

  * NOTE: Patients with ≤ grade 2 neuropathy, any grade of alopecia, or any grade of non-clinically significant laboratory abnormality are exceptions to this criterion and are allowed in this trial.
  * Examples of non-clinically significant laboratory abnormalities include, but are not limited to:

    * Grade 2-3 lymphopenia
    * Monocytosis
    * Increase in amylase or lipase with no clinical correlation
    * Any other grade 2-3 abnormal laboratory findings that have no clinical relevance per the treating investigators.
  * NOTE: If patient has undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to randomization
* Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Patient must not nurse infants while on protocol treatment and for 4 months after the last dose of protocol treatment
* Patient must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Patients of childbearing potential must continue contraceptive method(s) or abstain for 6 months after the last dose of protocol treatment. Patients with partners who could become pregnant should use effective contraception during therapy and for 3 months after the last dose of protocol treatment
* Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (obtained ≤ 14 days prior to randomization)
* Platelets ≥ 100,000/mcL (obtained ≤ 14 days prior to randomization)
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 14 days prior to randomization)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN or ≤ 5.0 x institutional ULN if known liver metastases (obtained ≤ 14 days prior to randomization)
* Creatinine clearance (CrCl) or estimated glomerular filtration rate (GFR) ≥ 30 ml/min (obtained ≤ 14 days prior to randomization) NOTE: CrCl is measured by 24- hour urine collection or other validated instruments (e.g., Modification of Diet in Renal Disease \[MDRD\] equation) and estimated (e)GFR estimated by the Cockcroft-Gault formula
* Patient must not have a known genetic UGT1A1 deficiency (Gilbert's syndrome). Patients with variant type UGT1A1\*28 allele may have increased levels of SN-38 metabolite (due to reduced SN-38 metabolism and clearance) and are at higher risk for severe adverse events when compared to wild-type.

  * NOTE: If a patient's UGT1A1 status is unknown, they are eligible to enroll (the study does not require this test as part of screening)
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression and are not using steroids \> 20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to randomization
* Patients with a prior or concurrent malignancy that is not considered clinically significant and whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (at the discretion of the treating physician) are eligible for this trial
* Patient must not be on immunosuppressive medication, including steroids (if doses exceed the equivalent of prednisone 10 mg daily, except those with treated brain metastases, where up to 20 mg/day is allowed). Short courses of steroids which are discontinued prior to randomization are acceptable. Patients on inhaled, intranasal and/or topical steroids are eligible
* Patient must be English or Spanish speaking to be eligible for the HRQOL component of the study.

  * NOTE: Sites cannot translate the associated HRQOL forms