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Inclusion criteria
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1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible;
2. Subjects must have measurable disease by investigator assessment according to RECIST v1.1 (Appendix J):
Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy;
3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
(1) Subjects that received neoadjuvant chemotherapy with recurrence >;12 months from completion of therapy are permitted;
(2) Subjects that received adjuvant chemotherapy following cystectomy with recurrence > 12 months from completion of therapy are permitted;
4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigators judgment;
Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
(1) GFR < 60 mL/min but >= 30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine); Subjects with a GFR >= 50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigators clinical judgment;
(2) ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects);
(3) NCI CTCAE Grade >= 2 audiometric hearing loss;
(4) NYHA Class III heart failure;
5. Subjects must be aged 18 years or older;
6. Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed (see Section 7.5);
7. Subjects must have an ECOG Performance Status score of 0, 1, or 2 (see Appendix B for conversion of performance status using Karnofsky, if applicable);
Subjects with ECOG performance status of 2 must additionally meet the following criteria:
(1) Hemoglobin >= 10 g/dL;
(2) GFR >= 50 mL/min;
(3) May not have NYHA Class III heart failure
8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3;
9. A female subject of childbearing potential is anyone born female who has experienced menarche and who has not undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of amenorrhea in a person over age 45 in the absence of other biological, physiological, or pharmacological causes. Female subjects of childbearing potential must meet the following conditions:
(1) Agree not to try to become pregnant during the study and for at least 6 months after the final dose of study drug;
(2) Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [beta-hCG]) within 1 day prior to administration of study drug. Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation;
(3) If heterosexually active, must consistently use highly effective methods of birth control, with a failure rate of less than 1% (as described in Appendix L) starting at screening, throughout the study period, and for at least 6 months after the final dose of study drug;
(4) Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug;
10. A male subject who can father children is anyone born male who has testes and who has not undergone surgical sterilization (eg, vasectomy followed by a clinical test proving that the procedure was effective). Male subjects who can father children, must meet the following conditions:
(1) Must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug. Male subjects will be informed about the negative risk to reproductive function and fertility from the study treatment. Prior to treatment male subjects should be advised to seek information on fertility preservation and sperm cryoconservation;
(2) Must consistently use highly effective methods of birth control, with a failure rate of less than 1% (as described in Appendix L) starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug;
(3) Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid (as described in Appendix L) for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug;
11. Subjects must provide written informed consent.
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Exclusion criteria：
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1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs;
2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab);
3. Subjects who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists);
4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment (ongoing hormonal/anti hormonal treatment, eg, for breast cancer, is allowed, provided that the subject is eligible per exclusion criteria 14);
5. Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) >= 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained;
6. Subjects with an estimated life expectancy < 12 weeks;
7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher;
8. Subjects with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true:
(1) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis;
(2) The subject is on a stable dose of <= 10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment);
(3) Subject does not have leptomeningeal disease;
9. Subjects with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to <= Grade 1 or returned to baseline;
10. Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted;
11. Subjects who have known active hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] detected) infection, testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks;
12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority;
13. Subjects with conditions requiring high doses of steroids (> 10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency;
14. Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type (if complete resection was performed) are allowed.
(1) A history of prostate cancer (T2NXMX or lower with Gleason score <= 7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry is acceptable, provided that the subject is considered prostate cancer-free and the following criteria are met:
1) Participants who have undergone radical prostatectomy must have undetectable PSA for > 1 year and at screening;
2) Participants who have had radiation must have a PSA doubling time > 1 year (based on at least 3 values determined > 1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir);
(2) Participants with untreated low-risk prostate cancer (Gleason score <= 6) on active surveillance with PSA doubling time > 1 year (based on at least 3 values determined > 1 month apart) are also eligible;
15. Subjects with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization (Appendix D);
16. Subjects who have received radiotherapy within 2 weeks prior to randomization. Subject must have recovered adequately from the toxicity from the intervention prior to starting study treatment;
17. Subjects who have received major surgery within 4 weeks prior to randomization. Subject must have recovered adequately from complications from the intervention prior to starting study treatment;
18. Subjects with known severe (>= Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20). Subjects with known severe (>= Grade 3) hypersensitivity to any pembrolizumab excipient contained in the drug formulations of pembrolizumab. Subjects with known severe (>= Grade 3) hypersensitivity to the platinum agent selected by the investigator for study treatment. Subjects with known severe (>= Grade 3) hypersensitivity to the gemcitabine;
19. Subjects with active keratitis or corneal ulcerations. Subjects with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the investigator;
20. History of autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs);
(1) Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed;
(2) Brief (< 7 days) use of systemic corticosteroids is allowed when use is considered standard of care;
(3) Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded;
(4) Subjects requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded;
(5) Subjects with hypothyroidism that is stable with hormone replacement or Sjgren's syndrome will not be excluded;
21. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan;
22. Subjects who have received a prior allogeneic stem cell or solid organ transplant;
23. Subjects who have received a live attenuated vaccine within 30 days prior to randomization. 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, and typhoid vaccine; Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed;
24. Subjects with active tuberculosis;
25. Subjects with another underlying medical condition that, in the opinion of the investigator, would impair the ability of the subject 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.
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