The researchers are doing this study to find out whether stereotactic body radiation therapy (SBRT) in combination with immunotherapy (cemiplimab with or without fianlimab) before cystectomy is an effective and safe treatment for people with muscle-invasive bladder cancer (MIBC).

Patients will be assigned to neoadjuvant SBRT and cemiplimab (Cohort 1) until Cohort 1 completes accrual and then enrollment for Cohort 2 will begin with those patients receiving neoadjuvant SBRT plus cemiplimab and fianlimab.

Inclusion Criteria:

• Age ≥ 18 years at the time of informed consent

• ECOG 0-1

• Histologically confirmed diagnosis of urothelial carcinoma.

  ° Variant histology is acceptable if there is a predominant urothelial component. Any neuroendocrine / small cell components are excluded (Investigators are encouraged to discuss with study team and PI)

• Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease per American Joint Committee on Cancer Staging Manual, 8th edition.

  • Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.
  • Clinically node-negative pelvis (cN0) on CT or MRI within 56 days: no pelvic lymph node ≥15 mm short-axis. Pelvic nodes 10-14 mm are permitted if not suspicious by GU radiology morphology; if deemed suspicious, biopsy or repeat imaging in 4-6 weeks must confirm cN0 prior to enrollment. PET may inform adjudication but is not required.

• Patients declines cisplatin-based therapy or is ineligible for cisplatin-based therapy based on any of the following criteria:

  • Estimated or calculated creatinine clearance ≥ 30ml/min but < 60 ml/min
  • Grade 2 or above audiometric hearing loss (per CTCAE v5.0)
  • Grade 2 or above peripheral neuropathy (per CTCAE v5.0)

• Availability of tumor specimen block or 20 unstained slides from diagnosis of muscle-invasive disease. Patients with fewer than 20 slides available may be enrolled after discussion with the Principal Investigator.

• Medically appropriate candidate for radical cystectomy, as per MSK Attending Urologic Oncologist

• Life expectancy ≥ 12 weeks at randomization

• Required initial laboratory values:

  • Absolute neutrophil count ≥ 1.0 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Bilirubin ≤1.5 times the upper limit of normal (x ULN)
  • AST and ALT ≤ 3 x ULN
  • Partial thromboplastin time (PTT)/prothrombin time (PT) ≤1.5 x ULN or international normalized ratio (INR) < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.

• For women of childbearing potential: agreement to remain abstinent (i.e., refrain from heterosexual intercourse) or use contraception, as defined below:

  • Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period plus 6 months after the last dose of cemiplimab with or without fianlimab.
  • Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices
  • A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

• Male subjects must be willing to use contraception during the study and until 6 months after the last dose of study treatment.

Exclusion Criteria:

• Evidence of metastatic disease on standard staging CT and/or MR imaging

• Evidence of nodal metastasis (cN+), defined as any pelvic node ≥15 mm short-axis on CT/MRI or biopsy-proven nodal disease of any size.

• Prior systemic chemotherapy or non-BCG immunotherapy (e.g., T cell co-stimulation or targeting of immune checkpoint pathways with anti-PD-1, anti-PD-L1, anti-LAG-3, anti-PD-L2, anti-CTLA-4, anti-CD137, IL-15 superagonist, or other medicines specifically targeting T cells other than prior IL-2 therapy) for the treatment of bladder cancer

• Prior therapy with intravesical BCG within 6 weeks of treatment.

• Prior pelvic RT

• Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment.

• Patients using immunosuppressive doses (≥ 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement will not be eligible for the study. It is recommended that patients do not receive systemic corticosteroids such as hydrocortisone, prednisone, prednisolone (Solu-Medrol®) or dexamethasone (Decadron®) at any time throughout the study except in the case of a life-threatening emergency and/or to treat an immune-mediated adverse event.

  °Immunosuppressive doses (≥ 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement must be discontinued within 14 days of initiating neoadjuvant SBRT.

• Received a live vaccine within 30 days of planned start of study medication.

  • Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing.
  • Live vaccines are also prohibited during neoadjuvant therapy and for 90 days after completing neoadjuvant therapy.

• Has had an allogenic tissue/solid organ transplant

• Unstable angina.

• New York Heart Association (NYHA) Grade II or greater congestive heart failure.

• History of myocardial infarction within 6 months.

• History of stroke within 6 months.

• Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose.

• Major surgical procedure within 28 days prior to the study other than transurethral resection of bladder tumor.

• Serious, non-healing wound, ulcer, or bone fracture.

• Other prior malignancy active within the previous 2 years except for local or organ-confined early-stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study.

• Uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection.

• Notes:

  • Patients with known HIV who have controlled infection (undetectable viral and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards.
  • Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
  • Patients who are known 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.
  • Patients with HIV or hepatitis must be reviewed by a qualified specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial.

• Participants with a history of myocarditis.

• Troponin T (TnT) or troponin I (TnI) > 2x institutional ULN at baseline.

  • TnT or Tnl levels between > 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN.
  • If TnT or Tnl levels are > 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the judgement in the patient's best interest.

• Known hypersensitivity to the active substances or to any of the excipients.

• WOCBP* must have a negative serum (beta-hCG) at screening.

  • WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

    • A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the CTFG guidance.

Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

• Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence.

• Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.

• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together.

  • WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment
  • All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose
  • Pregnant or breastfeeding women.
  • Women of childbearing potential (WOCBP)* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:

• stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;

• intrauterine device; intrauterine hormone-releasing system;

• bilateral tubal occlusion/ligation;

• vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or

• sexual abstinence

• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

• Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together.

  • Active infection requiring therapy.
  • Subjects who are compulsorily detained for treatment of a psychiatric illness.
  • History or current evidence of significant (CTCAE grade ≥ 2) local or systemic infection (e.g, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.