To learn if sacituzumab tirumotecan can help to control advanced or metastatic SMARCB1-deficient RMC in patients whose disease has progressed after receiving at least 1 treatment.

Primary Objectives

To determine the objective response rate (ORR) at any time and disease control rate (DCR) through 18 weeks from treatment initiation, as assessed by independent reviewer per RECIST 1.1, of sacituzumab tirumotecan in participants with locally advanced or metastatic SMARCB1-deficient RMC who have progressed on at least one prior line of therapy.

Secondary Objectives

To determine the efficacy and safety of sacituzumab tirumotecan in participants with locally advanced or metastatic SMARCB1-deficient RMC who have progressed on at least one prior line of therapy. Efficacy will be measured by overall survival (OS), progression-free survival (PFS), and duration of response (DOR).

Inclusion Criteria:

1. Participants with locally advanced or metastatic RMC histologically confirmed by expert pathology review and loss of SMARCB1 staining by IHC. Participants with advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a rare SMARCB1 negative RMC variant occurring in individuals without sickle hemoglobinopathies) are also eligible.

2. Participants will be eligible regardless of whether they have had prior nephrectomy or still have their primary tumor in-situ.

3. Participants must have at least one measurable site of disease, defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) and measures. 15 mm with conventional techniques or . 10 mm with more sensitive techniques such as MRI or CT scan. If the participant has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.

4. Participants must have progressed on at least one line of prior therapy.

5. There must be evidence of progression on or after last treatment regimen received.

6. ECOG performance status 0-1

   a. NOTE: If participant is unable to walk due to paralysis, but is mobile in a wheelchair, participants considered to be ambulatory for the purpose of assessing their performance status.

7. Age (at the time of consent/assent): . 18 years

8. Consent to MD Anderson companion laboratory protocols LAB02-152, PA17-0577 and PA11-1045.

9. Participants must have adequate organ and marrow function as defined below:

   Hemoglobina ≥9 g/dl (treatment allowed) Absolute neutrophil countb ≥1,500/.L Platelets ≥100,000/.L Total bilirubin ≤1.5 mg/dl AST(SGOT) or ALT (SGPT) ≤2.5 X institutional ULN,except in known hepatic metastasis, wherein may be ≤5 x ULN Estimated GFR (eGFR) >30 mL/kg/1.73 m2 by Cockcroft- Gault methods or local institutional standard Coagulation: INR or PT aPTT ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants May receive transfusion within the screening period Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days

10. Participants with controlled brain metastases are allowed on protocol if the brain metastases were surgically resected or treated with radiosurgery or Gamma knife, and are radiologically stable without recurrence or edema for at least 1 month (4 weeks) as confirmed by repeat imaging performed during study screening. Participants actively requiring glucocorticoids for uncontrolled brain or leptomeningeal metastases are not eligible.

11. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of the study drug.

12. Women must not be breastfeeding.

13. WOCBP must agree to follow instructions for method(s) of contraception from the time of registration for treatment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30days (duration of ovulatory cycle) for a total of 5 months post treatment completion. Men must agree to effective contraception from the time of registration for treatment to 210 days post last protocol treatment.

    Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male participants who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% per year when used consistently and correctly. Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Patient/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 120 days after completion of sacituzumab tirumotecan administration:

    • Refrain from donating sperm
    • Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive metho as a condom may break or leak

    The effects of sacituzumab tirumotecan on the developing human fetus are unknown. For this reason and because immunotherapy agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female participants, between the onset of menses (as early as 8 years of age) and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following:

    • Postmenopausal (no menses in greater than or equal to 12 consecutive months).
    • History of hysterectomy or bilateral salpingo-oophorectomy.
    • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
    • History of bilateral tubal ligation or another surgical sterilization procedure.

14. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Participants must not have any other malignancies within the past 2 years except for in situ carcinoma of any site, or adequately treated (without recurrence post-resection or post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, ductal carcinoma in situ of the breast or low-risk early stage prostate adenocarcinoma with negligible risk of metastasis or death

2. Participants previously treated with a topoisomerase 1 inhibitor-containing ADC or TROP2-targeted ADCs such as sacituzumab govitecan are excluded.

3. Participants currently receiving anticancer therapies or who have received anticancer therapies (including chemotherapy and targeted therapies such as tazemetostat) within 2 weeks (14 days) prior to study Day 1 are excluded. Participants who have completed palliative radiation therapy more than 14 days prior to the first dose of the combination immunotherapy are eligible.

4. Participants must not be scheduled to receive another experimental drug while on this study.

5. Participants

   • Note: A list of strong inducers/inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactionstable- substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally-approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor of CYP3A4.

6. Participants with persistent grade .2 adverse events from prior systemic therapies that would confound timely detection of immune-related adverse events due to sacituzumab tirumotecan or otherwise hinder participant participation in the clinical trial.

7. Participants, who have had a major surgery or significant traumatic injury (injury requiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of study drug, participants who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).

8. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency.

   • Participants with HIV who have controlled infection (undetectable viral load with the exception of clinically insignificant blips and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted.
   • Participants with hepatitis B surface antigen positive (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted.
   • Participants with HBsAg negative but total HBV core antibody positive (HBc Ab+) are permitted with the following requirements: Serum HBV DNA PCR should be tested and if it is above the limit of detection at screening then antiviral therapy for HBV must be initiated prior to study entry. If serum HBV DNA PCR is below the limit of detection periodic monitoring of HBsAg must be performed every 12 months +/- 3 months.
   • Participants who are Hepatitis C virus antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.

9. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.

10. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

11. Any underlying medical condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea, uncontrolled nausea or vomiting.

12. Participants who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

    • Symptomatic congestive heart failure of New York heart Association Class III or IV
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled symptomatic cardiac arrhythmia, prolongation of QTcF interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention.
    • Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement) despite appropriate antibiotics or other treatment.
    • Participants with a history of major psychiatric illness judged unable to fully understand the investigational nature of the study and the risks associated with the therapy.

13. Participants must not have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of sacituzumab tirumotecan or that might affect the interpretation of the results of the study or render the participant at high risk from treatment complications.

14. Participants should not receive immunization with attenuated live vaccines within 30 days of planned start of study medication.

    • Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-MistR) are live attenuated vaccines and are not allowed.

15. Female participants who are pregnant or breast feeding, or adults of reproductive potential who are not willing to use effective birth control methods as defined above.

16. Any participants who cannot be compliant with the appointments required in this protocol must not be enrolled in this study.

17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to sacituzumab tirumotecan.

18. Participants with psychiatric illness/social situations that would limit compliance with study requirements.