In the RESPONDER study, the role of the immune evasive mechanisms combined with genomic characterization will be explored in urothelial cancer patients treated with second-line treatment with pembrolizumab.

Combined profiling of immune and molecular status is novel and may contribute to improved patient stratification and provide rationale for future treatment strategies containing pembrolizumab.

Antibodies that target the crosstalk between immune and cancer cells by inhibiting programmed death 1 (PD-1, Pembrolizumab and Durvalumab) or programmed death-ligand 1 (PD-L1, Atezolizumab) have shown promising results as second-line treatments in phase II studies with response rates of about 30%.

Although urothelial cancer is prone to immune checkpoint blockade, better understanding of the underlying mechanisms is necessary to improve patient selection. The efficacy of immune checkpoint inhibitors in urothelial cancer may be affected by both tumor specific and environmental factors. In order to improve the efficacy of immunotherapy in urothelial cancer, drivers of local immune suppression need to be identified.

In this prospective translational multicenter study, clinical data, peripheral blood and sequential tumor biopsies are collected from urothelial cancer patients treated with second-line treatment with pembrolizumab to identify the role of immune evasive mechanisms combined with genomic characterization. A pre-treatment tumor biopsy and blood sample will be obtained and subsequently whole genome sequencing and whole genome RNA sequencing is performed. Both tumor tissue as well as peripheral blood will be investigated for immune and molecular profiling. A biopsy will also be taken after start of treatment (at 6 weeks) and at progression (optional)

For future research projects, longitudinal blood samples will be collected for isolation of immune cells, cytokine/chemo-attractants and circulating tumor DNA (ctDNA).

Inclusion Criteria:

1. Should have signed informed consent for CPCT-02 (this is another clinical trial, NCT01855477)

2. Be willing and able to provide written informed consent for the trial.

3. Be >= 18 years of age on day of signing informed consent.

4. Have histologically or cytologically-confirmed urothelial cancer that is not amenable to curative treatment with local and/or systemic therapies.

5. Have progressive disease after platinum containing chemotherapy as defined by:

   1. Disease progression after treatment with a platinum-containing regimen for recurrent (disease not amenable to curative treatment)/metastatic disease
   2. Recurrence/progression within 12 months of prior therapy containing platinum

6. Have measurable disease based on RECIST 1.1. Tumor lesions located in a previously irradiated area are considered measurable if progression has been demonstrated in these lesions.

7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.

8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

9. Demonstrate adequate organ function according to screening labs, which should be performed within 10 days of treatment initiation.

10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. lf the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

11. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in protocol - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

12. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in protocol- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Treatment with an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

2. Has a diagnosis of immunodeficiency or is receiving high dose systemic steroid therapy (defined as >=; 20 mg prednisone or equivalent per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

3. Has a known history of active TB (Tuberculosis Bacillus).

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., :S Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., :S Grade 1 or at baseline) from adverse events due to a previously administered agent

   • Note: Subjects with Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

7. Has a known additional malignancy that is progressing or requires active treatment Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using high dose steroids (defined as >=; 20 mg prednisone or equivalent per day) for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

10. Has known history of, or any evidence of active, (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.

11. Has an active infection requiring systemic therapy.

12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subjects participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 120 days after the last dose of trial treatment.

15. Has received prior therapy with an anti-PD-1, anti-PD-L 1, or anti- PD-L2 agent.

16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

17. Has a known history ofor is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected). Note: Without known history, testing needs to be performed to determine eligibility.

    Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care.

18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed

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