A Study of the Safety and Efficacy of Various Combinations of Avelumab as Therapy in Locally Advanced or Metastatic Urothelial Carcinoma (JAVELIN Bladder Medley)

• Avelumab (Drug), also known as MSB0010718C: Participants received intravenous infusion of Avelumab at a dose of 800 mg once every 2 weeks until unacceptable toxicity, withdraw consent or initiation of a new treatment.
• Sacituzumab Govitecan (SG) (Drug), also known as IMMU-132, Trodelvy™, GS-0132: Participants received intravenous infusion SG at dose of 10 mg/kg of bodyweight once a week on Day 1 and 8 of each 21-daytreatment cycles until unacceptable toxicity, withdraw consent or initiation of a new treatment.
• M6223 (Drug): Participants intravenous infusion of M6223 at dose of 1600 mg once every 2 weeks until unacceptable toxicity, withdraw consent or initiation of a new treatment.
• NKTR-255 (Drug): Participants intravenous infusion of NKTR-255 at a dose of 3 mcg/kg of body weight once every 4 weeks until unacceptable toxicity, withdraw consent or initiation of a new treatment.
• JB100 (Drug): As per the Clinical Study Protocol, the control group (avelumab alone) was extended by data from an external control, i.e. the JAVELIN Bladder 100 study (JB100) (NCT02603432). Participants received an intravenous infusion of 10 mg/kg of Avelumab along with best supportive care (BSC), on Day 1 and 15 of each 28 days treatment cycle, until confirmed disease progression, participant refusal, lost to follow up, unacceptable toxicity, or study termination by the sponsor, whichever occurred first. BSC was administered asper the treating physician. Participants were followed up until death, end of the study or withdrawal of consent, whichever comes first, regardless of initiation of new anticancer therapy.

Primary outcomes

• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + Sacituzumab Govitecan Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to first documentation of progressive disease (PD) or death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: PFS:defined as time from date of randomization to first documentation of progressive disease (PD) or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. PD:at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline/ appearance of 1/more new lesions. The propensity score (PS)-based weighted Kaplan-Meier estimated median PFS times. PS were used as weights to minimize impact of confounding factors on estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with sum of weights adding up to number of participants in randomized control arm. PFS Efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + M6223 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to first documentation of progressive disease (PD) or death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: PFS:defined as time from date of randomization to first documentation of progressive disease (PD) or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. PD:at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline/ appearance of 1/more new lesions. The propensity score (PS)-based weighted Kaplan-Meier estimated median PFS times. PS were used as weights to minimize impact of confounding factors on estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with sum of weights adding up to number of participants in randomized control arm. PFS Efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to first documentation of progressive disease (PD) or death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: PFS:defined as time from date of randomization to first documentation of progressive disease (PD) or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. PD:at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline/ appearance of 1/more new lesions. The propensity score (PS)-based weighted Kaplan-Meier estimated median PFS times. PS were used as weights to minimize impact of confounding factors on estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with sum of weights adding up to number of participants in randomized control arm. PFS Efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events, and AEs of Special Interest (AESIs) [Up to 32 months and 12 days (Current study) and 61 months and 11 days (JB100 extended control group)]: Adverse Event (AE): any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE: AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as events with onset date or worsening during the on-treatment period, defined as the time from the first dose of study intervention administration days to the last administration day + 30 days, or the start day of subsequent anticancer therapy - 1 day, whichever occurred first. TEAEs included serious AEs and non- serous AEs. AESIs included Infusion-related reactions (IRRs), Immune-related AEs (irAEs), Thromboembolic events, Cytokine release syndrome, QT interval prolongation.

Secondary outcomes

• Overall Survival (OS) -Avelumab + Sacituzumab Govitecan Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: OS: time from date of randomization to death. OS was analyzed by using PS-based weighted product-limit (Kaplan-Meier) estimates. PS were used as weights to minimize the impact of confounding factors on the estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with the sum of weights adding up to number of participants in randomized control arm. Pre-chosen baseline covariates with possible impact on OS outcome was used to calculate the preference score, i.e., a prevalence adjusted PS defined as the conditional probability of being a participant of the JB100 study in contrast to being a participant of current study given observed baseline covariates. OS efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Overall Survival (OS) - Avelumab + M6223 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: OS: time from date of randomization to death. OS was analyzed by using PS-based weighted product-limit (Kaplan-Meier) estimates. PS were used as weights to minimize the impact of confounding factors on the estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with the sum of weights adding up to number of participants in randomized control arm. Pre-chosen baseline covariates with possible impact on OS outcome was used to calculate the preference score, i.e., a prevalence adjusted PS defined as the conditional probability of being a participant of the JB100 study in contrast to being a participant of current study given observed baseline covariates. OS efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Overall Survival (OS) - Avelumab + NKTR-255 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) [Time from date of randomization to death, assessed up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: OS: time from date of randomization to death. OS was analyzed by using PS-based weighted product-limit (Kaplan-Meier) estimates. PS were used as weights to minimize the impact of confounding factors on the estimation of causal treatment effects. Each participant from randomized study was assigned a weight of 1, while participants from external control received a PS-based weight with the sum of weights adding up to number of participants in randomized control arm. Pre-chosen baseline covariates with possible impact on OS outcome was used to calculate the preference score, i.e., a prevalence adjusted PS defined as the conditional probability of being a participant of the JB100 study in contrast to being a participant of current study given observed baseline covariates. OS efficacy analysis was prespecified to use a pooled control population comprising the avelumab control arm and JB100 external control cohort; therefore, results are reported for combined control population.
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator- Avelumab + Sacituzumab Govitecan Versus Avelumab [Time from randomization to first observation of progression disease (PD), assessed up to 32 months and 12 days]: ORR is defined as percentage of participants who achieved either a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST v1.1 from randomization to first observation of progression disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + M6223 Versus Avelumab [Time from randomization to first observation of progression disease (PD), assessed up to 32 months and 12 days]: ORR is defined as percentage of participants who achieved either a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST v1.1 from randomization to first observation of progression disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab [Time from randomization to first observation of progression disease (PD), assessed up to 32 months and 12 days]: ORR is defined as percentage of participants who achieved either a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST v1.1 from randomization to first observation of progression disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + Sacituzumab Govitecan Versus Avelumab [Time from first documented objective response to PD or death due to any cause, assessed up to 32 months and 12 days]: DoR was defined as time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator Avelumab + M6223 Versus Avelumab [Time from first documented objective response to PD or death due to any cause, assessed up to 32 months and 12 days]: DoR was defined as time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab [Time from first documented objective response to PD or death due to any cause, assessed up to 32 months and 12 days]: DoR was defined as time from first documentation of objective response (Complete Response \[CR\] or Partial Response \[PR\]) to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or randomization. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
• Serum Concentrations of Avelumab in Avelumab Monotherapy [C1D1 and C3D29 (pre-dose and end of infusion); C2D15, C6D71, C9D113, C12D155, C18D239, C24D323, C30D407, C36D491, C42D575, C48D659, and C54D743 (pre-dose) (each cycle is of 2 weeks)]: Serum concentrations of Avelumab were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Serum Concentrations of Avelumab- Avelumab + Sacituzumab Govitecan (SG) [C1D1 and C2D29 (pre-dose and end of infusion); C1D15, C3D43, C5D85, C7D127, C9D169, C13D253, C17D337, C21D421, C25D505, C29D589, C33D673, and C37D757 (pre-dose) (each cycle is of 4 weeks)]: Serum concentrations of Avelumab in investigational arm (Avelumab + Sacituzumab Govitecan (SG) were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Serum Concentrations of Avelumab- Avelumab + M6623 [C1D1, C2D15 and C3D29 (pre-dose and end of infusion); C1D2, C2D16 (24 hour) C1D8, C2D22 (168 hours); C6D71, C9D113, C12D155, C18D239, C24D323, C30D407, C36D491, C42D575, C48D659 and C54D743 (Pre-dose) (each cycle is of 2 weeks)]: Serum concentrations of Avelumab in investigational arm (Avelumab + M6623) were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day"
• Serum Concentrations of Avelumab- Avelumab + NKTR-255 [C1D1, C2D29, C3D57 and C5D113 (pre-dose and end of infusion); C1D2, C2D30 (24 hour) C1D8, C2D36 (168 hours); C7D169, C10D253, C13D337, C16D421, C19D505, C22D589, C25D673 and C28D757(Pre-dose) (each cycle is of 4 weeks)]: Serum concentrations of Avelumab in investigational arm (Avelumab + NKTR-255) were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Serum Concentrations of Total Antibody of Sacituzumab Govitecan (SG) [C1D1 and C2D22 (Pre-dose and end of infusion); C1D8, C2D29, C3D43, C5D85, C5D92, C7D127, C7D134, C9D169, C9D176, C13D253, C17D337, C21D421, C21D428, C25D505, C29D589 and C33D673 (Pre-dose) (each cycle is of 4 weeks)]: Serum concentrations of SG were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Serum Concentrations of M6223 [C1D1, C2D15 and C3D29 (pre-dose and end of infusion); C1D2, C2D16 (24 hour) C1D8, C2D22 (168 hours); C6D71, C9D113, C12D155, C18D239, C24D323, C30D407, C36D491, C42D575, C48D659 and C54D743 (Pre-dose) (each cycle is of 2 weeks)]: Serum concentrations of M6223 were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Serum Concentration of NKTR-255 [C1D1, C2D29, C3D57 and C5D113 (pre-dose and end of infusion); C1D2, C2D30 (24 hour) C1D8, C2D36 (168 hours); C7D169, C10D253, C13D337, C16D421, C19D505, C22D589, C25D673 and C28D757(Pre-dose) (each cycle is of 4 weeks)]: Serum concentrations of NKTR-255 were measured. "C" in the timeframe below refers to "Cycle" and D refers to "Day".
• Number of Participants With Positive Anti-Drug Antibody (ADA) of Avelumab and Combination Drugs [Up to 32 months and 12 days (current study) and 41 months (JB100 extended control group)]: Number of participants with positive ADA of Avelumab and combination drugs (Sacituzumab Govitecan \[SG\], M6223 and NKTR-255) were reported.
• Change From Baseline in National Comprehensive Cancer Network- Functional Assessment of Cancer Therapy (NCCN-FACT) Bladder Symptom Index- 18 (FBlSI-18) Disease Related Symptoms-Physical Subscale (DRS-P) Scores at Week 13 - Avelumab + SG Versus Avelumab [Baseline, Week 13]: The NCCN FACT FBlSI-18 is designed to be a stand-alone instrument to measure symptoms and quality of life in participants with urothelial carcinoma and was created using inputs from participants and oncologists. The disease-related symptoms - physical (DRS-P) subscale uses a subset of physical symptoms which are specific to urothelial carcinoma, i.e., pain, weight loss, urination, weakness, dizziness, meeting family needs, appetite, erection in males, and sleep. Each question offers 5 answers: not at all (0), a little bit (1), somewhat (2), quite a bit (3), very much (4). The overall summary range is 0-36. The scores of negatively stated items (e.g., pain) are reversed and added together with the positively stated scores. The sum of these item scores are multiplied by the number of items in the subscale, i.e., by 9, and divided by the number of items answered. In general, higher scores are better than lower scores.
• Change From Baseline in NCCN FACT FBlSI-18 DRS-P Scores at Week 13 - Avelumab + M6223 Versus Avelumab [Baseline, Week 13]: The NCCN FACT FBlSI-18 is designed to be a stand-alone instrument to measure symptoms and quality of life in participants with urothelial carcinoma and was created using inputs from participants and oncologists. The disease-related symptoms - physical (DRS-P) subscale uses a subset of physical symptoms which are specific to urothelial carcinoma, i.e., pain, weight loss, urination, weakness, dizziness, meeting family needs, appetite, erection in males, and sleep. Each question offers 5 answers: not at all (0), a little bit (1), somewhat (2), quite a bit (3), very much (4). The overall summary range is 0-36. The scores of negatively stated items (e.g., pain) are reversed and added together with the positively stated scores. The sum of these item scores are multiplied by the number of items in the subscale, i.e., by 9, and divided by the number of items answered. In general, higher scores are better than lower scores.
• Change From NCCN FACT FBlSI-18 DRS-P Scores at Week 13 -Avelumab + NKTR-255 Versus Avelumab [Baseline, Week 13]: The NCCN FACT FBlSI-18 is designed to be a stand-alone instrument to measure symptoms and quality of life in participants with urothelial carcinoma and was created using inputs from participants and oncologists. The disease-related symptoms - physical (DRS-P) subscale uses a subset of physical symptoms which are specific to urothelial carcinoma, i.e., pain, weight loss, urination, weakness, dizziness, meeting family needs, appetite, erection in males, and sleep. Each question offers 5 answers: not at all (0), a little bit (1), somewhat (2), quite a bit (3), very much (4). The overall summary range is 0-36. The scores of negatively stated items (e.g., pain) are reversed and added together with the positively stated scores. The sum of these item scores are multiplied by the number of items in the subscale, i.e., by 9, and divided by the number of items answered. In general, higher scores are better than lower scores.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participants with histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology
* Participants has documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
* The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study
* Estimated life expectancy of at least 3 months
* Participants without progressive disease as per RECIST v1.1 guidelines following completion of 4 to 6 cycles of 1L chemotherapy. Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* Adequate hematological, hepatic, and renal function as defined in the protocol
* Other protocol defined inclusion criteria could apply

Exclusion Criteria:

* Participants with prior immunotherapy with Interleukin-2 (IL-2), IL-15, interferon alfa (IFN-α), or an anti programmed death receptor-1 (PD-1), anti programmed death-ligand 1 (PD-L1), anti PD-L2, anti CD137, or cytotoxic T cell lymphocyte-4 (CTLA-4) antibody (including ipilimumab), anti TROP2, anti-T-cell-immuno-receptor with Ig and ITM domains (anti-TIGIT) any other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways, agents targeting Nectin-4, or any of the investigational drugs used in combination with avelumab.
* Participants with active infection 48 hours before randomization requiring systemic therapy
* Participants with known prior or suspected hypersensitivity to study drugs or any component in their formulations
* Participants with prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization
* Participants with vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines) administered >= 2 weeks prior first dose of study treatment. All severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccines approved or authorized by local Health Authorities are allowed
* Other protocol defined exclusion criteria could apply

Participant flow

Outcome results

• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + Sacituzumab Govitecan Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Primary), Median, months: Avelumab + Sacituzumab Govitecan (SG) 11.17 (7.62 to 17.64); Avelumab + JB100 (NCT02603432) 3.75 (3.32 to 5.65)
• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + M6223 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Primary), Median, months: Avelumab + M6223 5.42 (3.78 to 7.43); Avelumab + JB100 (NCT02603432) 4.50 (3.45 to 7.20)
• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Primary), Median, months: Avelumab + NKTR-255 5.59 (3.75 to 12.91); Avelumab + JB100 (NCT02603432) 4.50 (3.48 to 7.20)
• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events, and AEs of Special Interest (AESIs) (Primary), Count of participants, Participants: Avelumab + Sacituzumab Govitecan (SG) 73; Avelumab + M6223 68; Avelumab + NKTR-255 70; Avelumab 33; JB100 (NCT02603432) 303
• Overall Survival (OS) -Avelumab + Sacituzumab Govitecan Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Secondary), Median, months: Avelumab + Sacituzumab Govitecan (SG) NA (18.37 to NA); Avelumab + JB100 (NCT02603432) 22.05 (16.92 to 28.78)
• Overall Survival (OS) - Avelumab + M6223 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Secondary), Median, months: Avelumab + M6223 NA (19.45 to NA); Avelumab + JB100 (NCT02603432) 23.23 (17.68 to 30.82)
• Overall Survival (OS) - Avelumab + NKTR-255 Versus Avelumab Monotherapy (Avelumab [Control Group] + JB 100 [External Control]) (Secondary), Median, months: Avelumab + NKTR-255 NA (19.19 to NA); Avelumab + JB100 (NCT02603432) 23.23 (17.08 to 30.82)
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator- Avelumab + Sacituzumab Govitecan Versus Avelumab (Secondary), Number, percentage of participants: Avelumab + Sacituzumab Govitecan (SG) 25.7 (16.2 to 37.2); Avelumab 2.7 (0.1 to 14.2)
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + M6223 Versus Avelumab (Secondary), Number, percentage of participants: Avelumab + M6223 8.3 (3.1 to 17.3); Avelumab 2.7 (0.1 to 14.2)
• Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab (Secondary), Number, percentage of participants: Avelumab + NKTR-255 8.2 (3.1 to 17.0); Avelumab 2.7 (0.1 to 14.2)
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + Sacituzumab Govitecan Versus Avelumab (Secondary), Median, months: Avelumab + Sacituzumab Govitecan (SG) 12.0 (5.6 to NA); Avelumab NA (NA to NA)
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator Avelumab + M6223 Versus Avelumab (Secondary), Median, months: Avelumab + M6223 NA (5.6 to NA); Avelumab NA (NA to NA)
• Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Assessed by Investigator - Avelumab + NKTR-255 Versus Avelumab (Secondary), Median, months: Avelumab + NKTR-255 9.2 (3.9 to NA); Avelumab NA (NA to NA)
• Serum Concentrations of Avelumab in Avelumab Monotherapy (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab NA +/- NA
• Serum Concentrations of Avelumab- Avelumab + Sacituzumab Govitecan (SG) (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab + Sacituzumab Govitecan (SG) NA +/- NA
• Serum Concentrations of Avelumab- Avelumab + M6623 (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab + M6223 NA +/- NA
• Serum Concentrations of Avelumab- Avelumab + NKTR-255 (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab + NKTR-255 NA +/- NA
• Serum Concentrations of Total Antibody of Sacituzumab Govitecan (SG) (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab + Sacituzumab Govitecan (SG) NA +/- NA
• Serum Concentrations of M6223 (Secondary), Mean, microgram per milliliter (mcg/mL): Avelumab + M6223 NA +/- NA
• Serum Concentration of NKTR-255 (Secondary), Mean, nanogram per milliliter (ng/mL): Avelumab + NKTR-255 NA +/- NA
• 4 more outcome measures not shown.

Adverse events

Time frame: Up to 32 months and 12 days (Current study) and 61 months and 11 days (JB100 extended control group)

Serious adverse events by term

94 more terms not shown.

Other adverse events by term

26 more terms not shown.

• Results publication: Naing A, McKean M, Tolcher A, Victor A, Hu P, Gao W, Nogueira Filho MAF, Kitzing T, Gleicher S, Holland D, Richter E, Tadjalli-Mehr K, Siu LL. TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial. J Immunother Cancer. 2025 Feb 10;13(2):e010584. doi: 10.1136/jitc-2024-010584. PMID 39929671
• Results publication: Hoffman-Censits J, Grivas P, Powles T, Hawley J, Tyroller K, Seeberger S, Guenther S, Jacob N, Mehr KT, Hahn NM. The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma. Future Oncol. 2024 Feb;20(4):179-190. doi: 10.2217/fon-2023-0492. Epub 2023 Sep 6. PMID 37671748

• Study Protocol (PDF, 2025-07-31)
• Statistical Analysis Plan (PDF, 2025-04-02)

• Medical Responsible, Study director, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

NIH grants: 2023