Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial

Marc-Oliver Grimm; Martin Schostak; Christine Barbara Grün; Wolfgang Loidl; Martin Pichler; Uwe Zimmermann; Bernd Schmitz-Dräger; Thomas Steiner; Florian Roghmann; Günter Niegisch; Christian Bolenz; Marc Schmitz; Gustavo Baretton; Katharina Leucht; Ulrike Schumacher; Susan Foller; Friedemann Zengerling; Johannes Meran

doi:10.1001/jamaoncol.2024.0938

. 2024 May 9;10(6):755–764. doi: 10.1001/jamaoncol.2024.0938

Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma

A Nonrandomized Clinical Trial

Marc-Oliver Grimm ^1,^✉, Martin Schostak ², Christine Barbara Grün ³, Wolfgang Loidl ⁴, Martin Pichler ⁵, Uwe Zimmermann ⁶, Bernd Schmitz-Dräger ^7,⁸, Thomas Steiner ⁹, Florian Roghmann ¹⁰, Günter Niegisch ¹¹, Christian Bolenz ¹², Marc Schmitz ^13,^14,¹⁵, Gustavo Baretton ¹⁶, Katharina Leucht ¹, Ulrike Schumacher ¹⁷, Susan Foller ¹, Friedemann Zengerling ¹², Johannes Meran ¹⁸, for the TITAN-TCC Study Group

¹Department of Urology, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany

²Department of Urology, Magdeburg University Hospital, Magdeburg, Germany

³Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany

⁴Department of Urology, Elisabethinen Hospital, Linz, Austria

⁵Department of Oncology, Graz University Hospital, Graz, Austria

⁶Department of Urology, Greifswald University Hospital, Greifswald, Germany

⁷Urologie 24, St Theresien-Krankenhaus, Nuremberg, Germany

⁸Department of Urology and Pediatric Urology, University Hospital, Erlangen, Germany

⁹Department of Urology, Helios Hospital Erfurt, Erfurt, Germany

¹⁰Department of Urology, University Hospital of Ruhr University Bochum, Marien Hospital Herne, Herne, Germany

¹¹Department of Urology, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

¹²Department of Urology, Ulm University Hospital, Ulm, Germany

¹³Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany

¹⁴National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

¹⁵German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany

¹⁶Institute of Pathology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;

¹⁷Center for Clinical Studies, Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany

¹⁸Department of Internal Medicine, Hematology, and Internal Oncology, Hospital Barmherzige Brueder, Vienna, Austria

Group Information: The members of the TITAN-TCC Study Group appear in Supplement 5.

Accepted for Publication: November 10, 2023.

Published Online: May 9, 2024. doi:10.1001/jamaoncol.2024.0938

Correction: This article was corrected on October 3, 2024, to fix errors in the CONSORT flow diagram.

^✉

Corresponding Author: Marc-Oliver Grimm, MD, Department of Urology, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany (marc-oliver.grimm@med.uni-jena.de).

Author Contributions: Prof Grimm had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Grimm, Schumacher.

Acquisition, analysis, or interpretation of data: Grimm, Schostak, Grün, Loidl, Pichler, Zimmermann, Schmitz-Dräger, Steiner, Roghmann, Niegisch, Bolenz, Schmitz, Leucht, Schumacher, Foller, Zengerling, Meran.

Drafting of the manuscript: Grimm, Leucht.

Critical review of the manuscript for important intellectual content: Grimm, Schostak, Grün, Loidl, Pichler, Zimmermann, Schmitz-Dräger, Steiner, Roghmann, Niegisch, Bolenz, Schmitz, Schumacher, Foller, Zengerling, Meran.

Statistical analysis: Schumacher.

Obtained funding: Grimm, Schostak.

Administrative, technical, or material support: Grün, Pichler, Schmitz-Dräger, Steiner, Roghmann, Niegisch, Bolenz.

Supervision: Grimm, Roghmann, Meran.

Conflict of Interest Disclosures: Prof Grimm reported grants from Bristol Myers Squibb (BMS), Intuitive Surgical, and Bayer Vital; and personal fees from AstraZeneca, BMS, Ipsen, MSD, Pfizer, Astellas, EUSA Pharma, Merck Serono, Roche Pharma AG, Eisai, Bayer Vital, Janssen, Gilead, Novartis, and Takeda outside the submitted work. Prof Schostak reported sponsored studies from BMS, MSD, Pfizer, and Ferring outside the submitted work. Prof Pichler reported receiving speaker fees from or serving on advisory boards for BMS, MSD, Merck, Pfizer, Jannsen, Astellas, AstraZeneca, Eisai Co, Ipsen, and Vaccentis outside the submitted work. Prof Schmitz-Dräger reported grants from Cepheid, Concile GmbH, NextAge, Nucleix, and Arquer Diagnostics; and personal fees from Sandoz and Atheneum outside the submitted work. Prof Roghmann reported personal fees from Hoffmann–La Roche, MSD, Merck, AstraZeneca, and Pfizer outside the submitted work. Prof Niegisch reported study case fees from AIO-Studien-gGmbH during the conduct of the study; personal fees from Roche lectures, personal fees from Merck, BMS, Pfizer, AstraZeneca, Janssen, Ingress Health AG, Astellas, and Ipsen. Prof Bolenz reported grants from AstraZeneca, Cepheid, and Janssen-Cilag; nonfinancial support from Erbe Elektromedizin; speaker honoraria from Roche, AstraZeneca, Bayer, Janssen-Cilag, and Medac; and consulting for BMS outside the submitted work. Dr Leucht reported medical writing (institutional) for BMS and Intuitive Surgical outside the submitted work. Dr Foller reported personal fees from BMS, AstraZeneca, MSD, IPSEN Pharma, Merck, Pfizer, and Roche outside the submitted work. Prof Zengerling reported personal fees from Astellas Pharma GmbH, AstraZeneca Germany, Janssen-Cilag GmbH, BMS, Merck Healthcare Germany, Merck Sharp & Dohme, Roche Pharma AG, Amgen GmbH, Apogepha Pharma GmbH, Bayer Vital GmbH, Ipsen Pharma GmbH, and Novartis Pharma AG outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by BMS.

Role of the Funder/Sponsor: The funder approved the study design, but had no role in the collection, management, analysis, and interpretation of the data. The funder reviewed the manuscript but had no role in its preparation, final approval, or the decision to submit the manuscript for publication.

Group Information: The members of the TITAN-TCC Study Group are listed in Supplement 5.

Meeting Presentation: This article was presented as a poster during the 2023 ESMO Congress; October 21, 2023; Madrid, Spain.

Data Sharing Statement: See Supplement 6.

Additional Contributions: We thank the patients and their families for granting permission to publish this information. We also thank the investigators (for a list of participating investigators and sites see eTable 1 in Supplement 3) and clinical study teams contributing to the study. We also thank the sponsor, AIO-Studien gGmbH (Berlin, Germany), and the Center for Clinical Studies (Jena, Germany). Participation in the study was compensated to the study centers by the sponsor. Personal fees were not paid.

^✉

Corresponding author.

PMCID: PMC11082753 PMID: 38722641

Key Points

Question

What is the efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for metastatic urothelial carcinoma?

Findings

In this phase 2 multicentric nonrandomized clinical trial of 169 patients, some patients showed improved objective response rates, including 20 (48%) receiving first-line nivolumab + dose escalation of ipilimumab, 12 (27%) receiving second-/third-line nivolumab + dose escalation of ipilimumab, and 27 (33%) receiving second-/third-line 1-mg/kg nivolumab + 3-mg/kg ipilimumab (high-dose).

Meaning

These findings suggest that second-/third-line nivolumab plus high-dose ipilimumab may benefit patients with metastatic urothelial carcinoma.

Abstract

Importance

Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab.

Objective

To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC.

Design, Setting, and Participants

In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1.

Interventions

All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression.

Main Outcomes and Measures

The primary end point was objective response rate.

Results

The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively.

Conclusions and Relevance

In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC.

Trial Registration

ClinicalTrials.gov Identifier: NCT03219775

This nonrandomized clinical trial evaluates the efficacy and safety of a tailored approach with nivolumab plus ipilimumab as an immunotherapeutic boost in patients with metastatic urothelial carcinoma.

Introduction

Immune checkpoint inhibitors are second-line treatment options after platinum-based chemotherapy in patients with metastatic urothelial carcinoma (mUC). Nivolumab, an anti–programmed cell death protein-1, is approved for this indication based on the single-arm phase 2 CheckMate-275 trial. Results indicated that 21% of patients achieved partial or complete response (PR or CR) and had a median overall survival (OS) of 8.6 months (95% CI, 6.1-11.3 months).¹

The phase 3 CheckMate-032 trial suggested improved outcomes for dual checkpoint inhibition with nivolumab + ipilimumab, the latter targeting cytotoxic T-lymphocyte protein–4. Objective response rates (ORRs), achieved with PR or CR, were 20/78 (26%) for 3-mg/kg nivolumab, 28/104 (27%) for 3-mg/kg nivolumab + 1-mg/kg ipilimumab, and 35/92 (38%) for 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Added high-dose ipilimumab showed the longest median OS: 9.9 months (95% CI, 7.3 to 21.1 months) for nivolumab, 7.4 months (95% CI, 5.6 to 11.0 months) for 3-mg/kg nivolumab + 1-mg/kg ipilimumab, and 15.3 months (95% CI, 10.1 to 27.6 months) for 1-mg/kg nivolumab + 3-mg/kg ipilimumab.² As with other tumor entities,^3,4 in CheckMate-032 grade 3 or 4 treatment-related adverse events (trAEs) were more frequent for dual checkpoint inhibition than for immune checkpoint inhibitor monotherapy: 27% (nivolumab), 31% (3-mg/kg nivolumab + 1-mg/kg ipilimumab), and 39% (1-mg/kg nivolumab + 3-mg/kg ipilimumab).²

The present TITAN-TCC trial followed a tailored approach. Patients started nivolumab induction monotherapy, and in patients with short-term nonresponse (stable disease [SD] or progressive disease [PD] in week 8) or later progression, nivolumab + ipilimumab was used as an immunotherapeutic boost. We aimed to improve efficacy while avoiding unnecessary exposure to excess toxic effects from dual checkpoint inhibition. In cohort 1, patients received boosts with escalating doses of ipilimumab (both first-line and second-/third-line). These individuals were compared with patients in cohort 2 receiving an immediate boost with high-dose ipilimumab (3 mg/kg, second-/third-line only).

Methods

Study Design and Participants

TITAN-TCC is a completed single-arm, open-label phase 2 adaptive trial with 2 separate cohorts. Patients in cohort 1 were treated according to version 3 of the trial protocol (Supplement 1), including patients with and without previous platinum-based therapy (first-line and second-/third-line). Cohort 2 received second-/third-line treatment only, according to version 5 of the trial protocol (Supplement 2). Adults aged 18 years and older with histologically confirmed metastatic or surgically unresectable cancer of the bladder, urethra, ureter, or renal pelvis were eligible (eFigure 1 in Supplement 3). All patients required a Karnofsky Performance Score of at least 70% (lower scores indicating worse survival) and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1), categorizing responses into CR, PR, SD, and PD. Exclusion criteria were previously reported^5,6 and appear in the protocols.

TITAN-TCC was approved by all relevant national competent authorities and independent ethics committees and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice, and local regulatory requirements. All patients provided written informed consent, and data were deidentified. Adherence to the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline was ensured (Figure 1).

Figure 1. — AE, adverse event; CR, complete response; irAE, immune-related adverse event; PD, progressive disease; PR, partial response; SD, stable disease.

^aIncluding patients with and without tumor assessment in week 8.

^bn = 7 Patients with later boost.

^cn = 2 Patients with later reboost.

^dn = 5 Patients with later boost.

^en = 5 Patients with later reboost.

Procedures

Patients in cohort 1 enrolled at 22 sites in Germany and Austria between August 8, 2017, and April 5, 2019. Patients in cohort 2 enrolled at 19 sites in the countries between April 9, 2019, and February 18, 2021 (eTable 1 in Supplement 3).^5,6 All patients initiated 4 doses of 240-mg nivolumab once every 2 weeks, intravenously. Nonresponders (SD or PD) at week 8 received nivolumab + ipilimumab boosts (once every 3 weeks, intravenously). Patients in cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab, if no response. Patients in cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders to nivolumab induction (PR or CR), suspected protocol-defined week-8 pseudo-progressors, or responders to the first/second (PR or CR) or third/fourth (PR, CR, or SD) boost doses continued with nivolumab maintenance (240-mg once every 2 weeks, intravenously) but could receive nivolumab + ipilimumab per aforementioned schedules for later progression. Tailored treatment was administered until immunotherapy resistance, unacceptable toxic effects, or patient-withdrawn consent occurred. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) until 100 days after final dose.

Outcomes

The primary end point was confirmed investigator-assessed ORR in the intention-to-treat population for each cohort. ORR was defined as the rate of patients with PR or CR. The final analysis was scheduled 24 months after the last patient's first treatment. Key secondary end points were remission rates during nivolumab induction and after nivolumab + ipilimumab boosts, progression-free survival (PFS), OS, duration of response, and safety.

Statistical Analysis

The a priori hypothesis was that ORRs would improve in the boost regimen compared with nivolumab monotherapy for patients with and without platinum pretreatment. For the statistical analysis plan, see Supplement 4. ORR assumptions were based on the results of the pivotal phase 2 single-arm CheckMate-275 trial and phase 1/2 CheckMate-032.^2,7 Independent assumptions were made using a Fleming single-stage phase 2 design. First-line cohort 1 required 108-patient sample size for 90% power to reject the null hypothesis of a true ORR of 24% or less if the true ORR was 37% or higher. Second-/third-line cohort 1 required 99 patients to test a true ORR of 20% or less against a 1-sided alternative hypothesis of 33% or higher. Cohort 2 required 77 evaluable patients to test a true ORR of 20% or less against a 1-sided alternative hypothesis of 35% or higher. For both cohorts, a 1-sided target error rate of 5% was applied. All end points were assessed in the intention-to-treat populations, defined as all patients who received at least 1 dose of the study medication.

Statistical analysis was performed with SAS, version 9.4 (SAS Institute, Inc). Demographics and baseline characteristics were summarized using descriptive statistics. The ORR derived from the best overall response was summarized with binomial response rates. Corresponding 2-sided 90% exact CIs were calculated using the Clopper-Pearson method matching the 1-sided test significance level of .05. Exact P values for the binomial proportion test are provided with a 1-sided significance threshold of .05. Time-to-event distributions were estimated using the Kaplan-Meier method. Descriptive statistics of safety were tabulated using the worst-grade criterion by preferred term, according to CTCAE 4.0.

Results

Baseline Characteristics

A total of 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years) were assigned to 2 cohorts, including 86 patients in cohort 1 (42 patients received first-line treatment; 44 patients received second-/third-line treatment). Of the latter, 39 (89%) received second-line treatment, and 5 (11%) received third-line treatment. Cohort 2 comprised 83 patients. Of these, 78 (94%) received second-line treatment, and 2 (2%) received third-line treatment. When source data were verified, 3 patients (4%) in cohort 2 were identified as not having prior platinum-based chemotherapy. All patients were treated. Demographic and baseline characteristics are detailed in Table 1. Most participants were men (first-line cohort 1: 29 individuals [69%]; second-/third-line cohort 1: 32 [73%]; cohort 2: 57 [69%]). Race was recorded by the investigator during screening.

Table 1. Baseline Characteristics.

Characteristic	No. (%)
	First-line cohort 1	Second-/third-line cohort 1	Cohort 2
	n = 42	n = 44	n = 83
Age, median (range), y	70 (45-84)	68 (45-80)	68 (37-84)
Age, y
<65	12 (29)	18 (41)	27 (33)
≥65	30 (71)	26 (59)	56 (67)
Sex
Female	13 (31)	12 (27)	26 (31)
Male	29 (69)	32 (73)	57 (69)
White race	42 (100)	44 (100)	82 (99)
Location of urothelial carcinoma^a
Bladder	35 (83)	33 (75)	72 (87)
Urethra	0	1 (2)	1 (1)
Ureter	2 (5)	3 (7)	5 (6)
Renal pelvis	5 (12)	7 (16)	5 (6)
Karnofsky performance status, %
100	18 (43)	19 (43)	42 (51)
90	9 (21)	13 (30)	23 (28)
80	8 (19)	8 (18)	15 (18)
70	7 (17)	4 (9)	3 (4)
Prior surgery related to current urothelial carcinoma	37 (88)	42 (95)	79 (95)
Prior radiotherapy for urothelial carcinoma	5 (12)	4 (9)	16 (19)
Prior systemic therapies related to current urothelial carcinoma
0	40 (95)	0	2 (2)
1	2 (5)	39 (89)	76 (92)
2	0	5 (11)	5 (6)
First-line systemic therapy agent
Gemcitabine/cisplatin	1 (2)	41 (93)	70 (84)
Gemcitabine/carboplatin	0	2 (5)	8 (10)
Other	1 (2)	1 (2)	3 (4)
Best response to first-line therapy
CR	0	2 (5)	5 (6)
PR	0	3 (7)	8 (10)
SD	0	6 (14)	19 (23)
PD	1 (2)	19 (43)	34 (42)
Unknown	1 (2)	14 (32)	15 (18)
PD-L1 expression ≥1%	24 (57)	17 (39)^b	28 (34)^c

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Abbreviations: CR, complete response; PD, progressive disease; PD-L1, programmed cell death ligand 1; PR, partial response; SD, stable disease.

^{^a}

Some patients may have had more than 1 location.

^{^b}

For 1 patient, PD-L1 status was not evaluable.

^{^c}

For 4 patients, PD-L1 status was not evaluable.

Treatment Exposure

Median (IQR) follow-up time for first-line cohort 1 was 10.4 (4.2-23.5) months; 7.5 (3.1-23.8) months for second-/third-line cohort 1; and 6.2 (3.2-22.7) months for cohort 2. Among survivors only, median (IQR) follow-up times for first-line cohort 1 were 14.4 (9.3-37.0) months; 22.0 (5.3-48.1) months for second-/third-line cohort 1; and 27.2 (8.7-34.4) months for cohort 2. In first-line cohort 1, 24 patients (57%) received at least 1 immunotherapy boost dose, including 17 (40%) after week 8 and 7 (17%) for later progression. This applied to 30 patients (68%) in second-/third-line cohort 1, including 24 (55%) after week 8 and 6 (14%) for later progression. In cohort 2, 51 (61%) patients received at least 1 immunotherapy boost dose, including 44 (53%) after week 8 and 7 (8%) for later progression. Overall, 2 (5%), 1 (2%), and 8 (10%) patients reached the planned study’s end for first-line cohort 1, second-/third-line cohort 1, and cohort 2, respectively (Figure 1).

Efficacy for Nivolumab ± Nivolumab + Ipilimumab (TITAN-TCC Approach)

Twenty patients (48%) responded to treatment in first-line cohort 1, including 3 patients (7%) achieving CR. The ORRs were significantly better than prespecified (Clopper-Pearson exact 90% CI, 0.34-0.61; 1-sided P < .001). Disease control rate (DCR) was 24/42 patients (57%) (eTable 2 in Supplement 3). Twelve patients (27%) responded to treatment in second-/third-line cohort 1 (Clopper-Pearson exact 90% CI, 0.17-0.40; 1-sided P = .15), including 3 patients (7%) achieving CR, and DCR was 20/44 patients (45%). A total of 27 patients (33%) responded to treatment in cohort 2, including 9 patients (11%) achieving CR. Again, the ORRs were significantly better than prespecified (Clopper-Pearson exact 90% CI, 0.24-0.42; 1-sided P = .005). DCR was 35/83 patients (42%).

Median time to first response was 3.3 months (95% CI, 2.5 months to not estimable [NE]) in first-line cohort 1. Median time to first response was not reached (95% CI, 4.5 months to NE) in second-/third-line cohort 1. Median time to first response was 19.5 months (95% CI, 4.8 months to NE) in cohort 2 (eFigure 2 in Supplement 3). Waterfall plots display the relative changes in the sum of target lesions at a time point of best overall response relative to the baseline assessment (eFigure 3 in Supplement 3). Median duration of response was 9.1 months (95% CI, 4.1 months to NE) for first-line cohort 1, 18.7 months (95% CI, 4.2-40.0 months) for second-/third-line cohort 1, and 18.0 months (95% CI, 6.9-34.9 months) for cohort 2 (eFigure 4 in Supplement 3).

Overall, 26 (62%), 34 (77%), and 53 (64%) patients had died until the study’s conclusion in first-line cohort 1, second-/third-line cohort 1, and cohort 2, respectively. In first-line cohort 1, median OS was 16.4 months (95% CI, 7.3-28.5 months) with 1-year, 2-year, and 3-year OS rates using the Kaplan-Meier method of 55% (95% CI, 38%-69%), 37% (95% CI, 21%-53%), and 32% (95% CI, 17%-49%), respectively. In second-/third-line cohort 1, median OS was 8.3 months (95% CI, 5.3-19.3 months) with 1-year, 2-year, and 3-year OS rates of 42% (95% CI, 27%-56%), 31% (95% CI, 17%-45%), and 19% (95% CI, 8%-33%), respectively. (Figure 2A). In cohort 2, median OS was 7.6 months (95% CI, 5.0-14.9 months) with 1-year, 2-year, and 3-year OS rates of 40% (95% CI, 29%-51%), 34% (95% CI, 23%-44%), and 34% (95% CI, 23%-44%), respectively. (Figure 2B). In terms of PFS, 37 patients (88%) in first-line cohort 1 had a first progression event (disease progression or death) before the end of the study compared with 39 patients (89%) in second-/third-line cohort 1 and 71 patients (86%) in cohort 2. Median PFS was 3.0 months (95% CI, 1.8-6.8 months) in first-line cohort 1; 1.9 months (95% CI, 1.7-5.8 months) in second-/third-line cohort 1 (Figure 2C); and 1.9 months (95% CI, 1.8-3.2 months) in cohort 2 (Figure 2D). Twelve patients responded to nivolumab induction in first-line cohort 1 with median PFS of 9.7 months (95% CI, 5.7-25.9 months). In contrast, 10 responded to nivolumab induction in second-/third-line cohort 1 with median PFS of 23.2 months (95% CI, 5.8-41.6 months) (eFigure 5A in Supplement 3). For 18 responders in cohort 2, median PFS was 31.3 months (95% CI, 6.2 months to NE) (eFigure 5B in Supplement 3).

Figure 2. — Progression-free survival (PFS) refers to the first progression event during the study, including disease progression or death. Several progression events were possible for each patient due to the tailored approach of the medication regimen in this trial.

Efficacy for Nivolumab Induction Monotherapy and Response to Nivolumab + Ipilimumab Boosts

Twelve patients (29%) responded to treatment at week 8 in first-line cohort 1, including 1 patient (2%) achieving CR, and DCR was 20/42 patients (48%) (eTable 2 in Supplement 3). Ten patients (23%) responded to treatment in second-/third-line cohort 1 at week 8, including 1 patient [2%] achieving CR. Seventeen patients (20%) responded to treatment in cohort 2 at week 8, including 2 patients [2%] achieving CR. DCR was 18/44 patients (41%) in second-/third-line cohort 1 and 28/83 patients (34%) in cohort 2.

Of patients in first-line cohort 1 boosted at week 8 for either SD or PD, 7/17 patients (41%) improved their best response, compared with 2/24 patients (8%) in second-/third-line cohort 1 and 10/44 patients (23%) in cohort 2. Table 2 details initial response data and response after immunotherapy boost. For patients in first-line cohort 1 who received an immunotherapy boost after week 8 for PD, 2/7 patients (29%) improved their best response; 2/6 (33%) improved their best response in second-/third-line cohort 1; and 5/7 (71%) improved their best response in cohort 2. Swimmer plots of patients boosted in week 8 are displayed in Figure 3. For patients without boosts or with later boosts, see eFigure 6 in Supplement 3.

Table 2. Best Confirmed Response to Boost At or After Week 8.

	No. (%)
	Cohort 1 receiving first-line treatment			Cohort 1 receiving second-/third-line treatment			Cohort 2
Time point of boost	Week 8	Week 8	>Week 8	Week 8	Week 8	>Week 8	Week 8	Week 8	>Week 8
Response to nivolumab induction^c	SD	PD	PR/CR^a	SD	PD	PR/CR	SD	PD	PR/CR ^b
Response to nivolumab induction^c	6/42 (14)	11/42 (26)	7/42 (17)	8/44 (18)	16/44 (36)	6/44 (14)	13/83 (16)	31/83 (37)	7/83 (8)
Response after boost
CR	1 (17)^d	0	0	0	1 (6)^d	0	1 (8)^d	1 (3)^d	2 (29)^d
PR	2 (33)^d	3 (27)^d	1 (14)^d	0	0	1 (17)^d	3 (23)^d	3 (10)^d	2 (29)^d
SD	3 (50)	1 (9)^d	1 (14)^d	5 (62)	1 (6)^d	1 (17)^d	2 (15)	2 (6)^d	1 (14)^d
PD	0	4 (36)	3 (43)	2 (25)	10 (62)	4 (67)	2 (15)	18 (58)	1 (14)
NE/NA	0	3 (27)	2 (29)	1 (12)	4 (25)	0	5 (38)	7 (23)	1 (14)

Open in a new tab

Abbreviations: CR, complete response; NA, not assessed; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.

^{^a}

One patient with SD as initial response (response after boost: PR).

^{^b}

Two patients with SD as initial response (response after boost: 1 with PR and 1 who was NA).

^{^c}

Time point assessment at week 8.

^{^d}

Improvement in response.

Figure 3. — Displayed response designates the best-confirmed response (first appearance, if different from the initial response) plus, eventually, subsequent progression and best-confirmed response to subsequent boost.

Safety

No new safety signals with the TITAN-TCC approach emerged in either cohort. Overall, 167/169 (99%) reported at least 1 adverse event of any grade. Any grade trAEs occurred in 125 patients (74%), with 62 patients (37%) having a grade 3 or 4 trAE. Grade 3 or 4 trAEs were slightly more common in the first-line treatment cohort (eTable 3 in Supplement 3). In 63 patients (37%), treatment was delayed due to trAEs, while treatment was discontinued in 45 patients (27%), both again with the highest incidences in first-line cohort 1. Reasons for discontinuation are detailed in eTable 5 in Supplement 3.

The most common trAEs of any grade that occurred in at least 1 cohort were generalized rash, fatigue, diarrhea, immune-mediated enterocolitis, pruritus, and hypothyroidism (eTable 4 in Supplement 3). The most common grade 3 or 4 trAEs were immune-mediated enterocolitis and diarrhea. Overall, 59 patients (35%) experienced at least 1 serious trAE, with the highest incidence in first-line cohort 1 (eTable 3 in Supplement 3). Overall, based on investigator assessment, 6 patients experienced grade 5 trAEs. In first-line cohort 1, immune-mediated enterocolitis occurred in 1 patient, and sepsis occurred in 1 patient. For second-/third-line cohort 1, the breakdown consisted of 1 patient with colitis and 2 patients with pneumonitis. In cohort 2, immune-mediated enterocolitis occurred in 1 patient.

Discussion

In TITAN-TCC, patients with mUC received a tailored approach with nivolumab induction ± nivolumab + ipilimumab as an immunotherapeutic boost with short-term nonresponse or later progression. Boosts involved either escalating doses of ipilimumab in cohort 1 or high-dose ipilimumab on first boost dose in cohort 2. Patients in cohort 1 received either first-line or second-/third-line therapy. Patients in cohort 2 received second-/third-line therapy only. We aimed to improve efficacy compared with nivolumab monotherapy, an approved second-line therapy for patients with mUC. Additionally, we intended to establish a standard to avoid excess toxic effects of dual immune checkpoint inhibition in responders to nivolumab monotherapy.

For first-line cohort 1, we observed clinically meaningful activity of the tailored approach. With an ORR of 48%, the primary study end point was met, designating significance toward literature-derived prespecification. Median OS was similar to platinum-based chemotherapy.^8,9,10 However, we observed substantial rates of primary progression and early deaths. When designing the study, we took the aggressiveness of mUC into account by scheduling nivolumab induction monotherapy for 8 weeks only. In similar adaptive trials for metastasized renal cell carcinoma, immunotherapeutic boosts with combination therapies were administered later,^11,12,13,14 acknowledging that time to response with nivolumab monotherapy is longer in patients with metastasized renal cell carcinoma than those with mUC (3.5 months and 1.9 months, respectively).^7,15 Even with the relatively short period of nivolumab monotherapy, cohort 1 was stopped due to safety concerns by the data monitoring committee, and first-line patients were excluded from cohort 2.

Regarding efficacy, the present findings aligned with the phase 3 DANUBE trial that compared durvalumab (anti–programmed cell death ligand 1 [anti-PD-L1]), durvalumab + tremelimumab (anti–cytotoxic T-lymphocyte associated protein 4), and first-line platinum-based chemotherapy in patients with mUC.¹⁰ ORR and median OS appeared to improve with the combination therapy compared with durvalumab monotherapy; however, this was not formally addressed in the statistical analysis. A considerable number of patients experienced primary progression with immune checkpoint inhibition (the highest number with durvalumab monotherapy). Excess mortality was also observed compared with platinum-based chemotherapy during the first 9 to 12 months. This might be further supported by the phase 3 CheckMate-901 trial, which randomized patients with mUC to first-line 1-mg/kg nivolumab + 3-mg/kg ipilimumab, nivolumab + platinum-based chemotherapy, or platinum-based chemotherapy alone. In the final analysis, OS, the primary end point of the main study, was not achieved for up-front 1-mg/kg nivolumab + 3-mg/kg ipilimumab in patients with PD-L1–positive tumors compared with platinum-based chemotherapy.¹⁶

Given the aggressiveness of mUC and the aforementioned observations, platinum-based chemotherapy has greater efficacy in first-line, and immune-checkpoint inhibition including the TITAN-TCC approach is not recommended, at least in patients who are eligible for cisplatin.¹⁷ Current research is concerned with immune checkpoint inhibition in combination with platinum-based chemotherapy or with antibody-drug conjugates. First-line enfortumab vedotin + pembrolizumab for patients with mUC who are ineligible for cisplatin had response rates of 68%. This therapy was granted accelerated approval in this setting by the US Food and Drug Administration.¹⁸ Recently in the phase 3 EV-302 trial, enfortumab vedotin + pembrolizumab had ORRs of 68% in first-line treatment of patients with mUC. Outstandingly, OS was significantly prolonged compared with platinum-based chemotherapy (hazard ratio, 0.47). Furthermore, median OS was nearly doubled.¹⁹ Although pending approval, enfortumab vedotin + pembrolizumab may represent a new standard of care.

For second-/third-line therapy, TITAN-TCC mimicked an initial standard approach because all patients received 4 doses of nivolumab induction monotherapy before any combination treatment. ORRs of 23% for second-/third-line cohort 1 and 20% for cohort 2 achieved during the first 8 weeks of treatment in TITAN-TCC were comparable to ORRs of other approved second-line ICI monotherapies in this setting (13%-21%).^20,21,22 Treatment response with nivolumab monotherapy may have improved over time if the study design had not engaged boost treatment in those who did not respond at a time point. This assumption is based on CheckMate-032, which reported a median (range) time to response for 3-mg/kg nivolumab of 2.0 (1.0-8.3) months,² indicating that, in TITAN-TCC, half of responses occurred when nonresponders to nivolumab induction had already received nivolumab + ipilimumab boosts.

Regarding this tailored approach, overall ORRs, with the limitation of cross-trial comparison, surpass those of currently approved second-line therapies. However, DCRs and PD rates did not improve.^20,21,22 In CheckMate-032, high-dose ipilimumab revealed improved ORRs compared with 3-mg/kg nivolumab + 1-mg/kg ipilimumab.² Similar results were found in TITAN-TCC when comparing second-/third-line cohort 1 with cohort 2, showing a tendency toward improved OS for 1-mg/kg nivolumab + 3-mg/kg ipilimumab vs nivolumab monotherapy as reported in the literature. Three-year OS in Checkmate-275 was 22.3% (95% CI, 17.3%-27.6%) for nivolumab monotherapy.¹ In our study, we reported OS of 19% for second-/third-line cohort 1 and 34% for cohort 2.

Regarding PFS, ipilimumab dosage during boost phases demonstrated no obvious effect. In TITAN-TCC, PFS refers to the first progression event, although due to the adaptive study design, several were possible. The therapeutic effect of the postprogression application of nivolumab + ipilimumab boosts, therefore, was not seen in the respective PFS curves and calculations. In cohort 1, numerous patients rapidly progressed within the first 2 months of nivolumab induction. Some progression events were later managed by the scheduled application of nivolumab + ipilimumab boost. Up-front nivolumab + ipilimumab administration may prevent some early progression events.

ORRs and 3-year OS rates suggest that 1-mg/kg nivolumab + 3-mg/kg ipilimumab may be a salvage therapy in second-line nivolumab. Presently, the antibody-drug conjugates enfortumab vedotin and sacituzumab govitecan were approved after platinum-based chemotherapy and an anti–PD-L1 immune checkpoint inhibitor.^23,24 Although ORRs (enfortumab vedotin, 44%; sacituzumab govitecan, 28%)^23,24 may be similar to those observed in our study with 1-mg/kg nivolumab + 3-mg/kg ipilimumab boosts, the higher DCR may support the use of antibody-drug conjugates, at least in patients with rapid progression. However, in TITAN-TCC, some patients achieved long-term response after 1-mg/kg nivolumab + 3-mg/kg ipilimumab boosts (Figure 3; eFigure 6 in Supplement 3).

No new safety signals emerged. Any grade and grade 3 or 4 trAEs occurred with similar incidences in up-front dual checkpoint inhibition in CheckMate-032 and second-/third-line treatment groups. However, 6 treatment-related deaths were recorded. Patients receiving second-/third-line treatment were often heavily pretreated, potentially contributing to the elevated treatment-related mortality rates.

Limitations

Limitations included subsequent cohorts rather than concurrent ones, which must be considered when interpreting the results comparatively. A central review was not done for the primary end point, which was at least partially mitigated by strict adherence to RECIST criteria. Additionally, racial and ethnic minority groups were underrepresented.

Conclusions

This nonrandomized clinical trial suggests that first-line escalated-dose nivolumab + ipilimumab treatment improved ORR and median OS, but considerable primary progression events and early deaths strongly suggest avoiding this approach as first-line therapy for patients with mUC. In the second-/third-line treatment cohorts, nivolumab + ipilimumab boosts with escalating ipilimumab dose did not improve the ORR compared with nivolumab monotherapy, as previously reported. However, second-/third-line boosts with high-dose ipilimumab had improved objective response and 3-year OS rates (34%). Nivolumab + ipilimumab might be considered salvage therapy when progression with nivolumab occurs in selected patients.

Supplement 1.

Trial Protocol, Version 3

jamaoncol-e240938-s001.pdf^{(1.3MB, pdf)}

Supplement 2.

Trial Protocol, Version 5

jamaoncol-e240938-s002.pdf^{(1.5MB, pdf)}

Supplement 3.

eTable 1. TITAN-TCC investigators

eTable 2. Best overall response (BOR) for nivolumab ± nivolumab+ipilimumab boosts (TITAN-TCC approach, primary end point), and anti-tumor activity for nivolumab induction monotherapy

eTable 3. Overview of adverse events

eTable 4. Treatment-related adverse events (trAEs)

eTable 5. Reasons for (premature) discontinuation of study medication

eFigure 1. Study design for (A) cohort 1 and (B) cohort 2

eFigure 2. Time to (first) response for (A) cohort 1 and (B) cohort 2

eFigure 3. Waterfall plot of relative change in sum of target lesions for (A) first-line cohort 1, (B) second-/third-line cohort 1, and (C) cohort 2

eFigure 4. Duration of response for (A) cohort 1 and (B) cohort 2

eFigure 5. Progression-free survival in patients with initial response to nivolumab

induction (week 8, initial effect) in (A) cohort 1 and (B) cohort 2

eFigure 6. Swimmer plots for patients with nivolumab maintenance therapy after week 8 and either no or later boost. (A) Cohort 1–1L, (B) cohort 1–2/3L, and (C) cohort 2

jamaoncol-e240938-s003.pdf^{(863.4KB, pdf)}

Supplement 4.

Statistical Analysis Plan

jamaoncol-e240938-s004.pdf^{(874.9KB, pdf)}

Supplement 5.

Nonauthor Collaborators

jamaoncol-e240938-s005.pdf^{(107.7KB, pdf)}

Supplement 6.

Data Sharing Statement

jamaoncol-e240938-s006.pdf^{(23.3KB, pdf)}

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Supplementary Materials