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Clinical Trial
. 2022 Jul 1;40(19):2128-2137.
doi: 10.1200/JCO.21.02631. Epub 2022 Mar 11.

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma

Marc-Oliver Grimm  1 , Bernd Jürgen Schmitz-Dräger  2   3 , Uwe Zimmermann  4 , Christine Barbara Grün  5 , Gustavo Bruno Baretton  6   7   8 , Marc Schmitz  7   8   9 , Susan Foller  1 , Katharina Leucht  1 , Martin Schostak  10 , Friedemann Zengerling  11 , Ulrike Schumacher  12 , Wolfgang Loidl  13 , Johannes Meran  14
Affiliations
Clinical Trial

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma

Marc-Oliver Grimm et al. J Clin Oncol. .

Abstract

Purpose: Several anti-programmed cell death (ligand)-1 (PD-[L]1) immune checkpoint inhibitors are approved in advanced/metastatic urothelial carcinoma (mUC). Recently, improved activity of an anti-PD-1/anticytotoxic T-cell lymphocyte-4 (CTLA-4) combination versus anti-PD-1 monotherapy has been reported. We report a response-based approach starting treatment with nivolumab monotherapy with nivolumab/ipilimumab as immunotherapeutic boost.

Methods: After four doses of nivolumab induction, responders continued with nivolumab maintenance therapy. Patients with stable/progressive disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for 2 doses followed by nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 2 doses, if not responding to the initial boost. Responders to boosts continued with nivolumab maintenance. Between July 2017 and April 2019, 86 patients were enrolled. The median follow-up is 7.7 months. The primary end point is objective response rate (ORR) per RECIST1.1. Secondary end points include efficacy of nivolumab induction, remission rate with nivolumab/ipilimumab boosts, overall survival, and safety.

Results: Of all patients, 42, 39, and five were first- (1L), second- (2L), and third-line (3L), respectively. The median age was 68 years. The ORR with nivolumab monotherapy (assessed at week 8) was 29% in 1L and 23% in 2/3L, respectively. Forty-one patients received early (week 8) and 11 received later nivolumab/ipilimumab boosts. ORRs with nivolumab with or without nivolumab/ipilimumab (best overall response) were 45% and 27% in 1L and 2/3L, respectively. In 1L, 7 of 17 patients receiving boosts at week 8 improved, compared with 2 of 24 in 2/3L.

Conclusion: The tailored approach of TITAN-TCC shows meaningful clinical activity supporting dual checkpoint inhibition in 1L mUC. However, starting therapy with nivolumab exclusively appears inadequate given the aggressive nature of mUC. In 2/3L, nivolumab/ipilimumab boosts with escalating ipilimumab dose did not improve efficacy outcomes versus nivolumab monotherapy. An independent 2L cohort of TITAN-TCC receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 4 doses is ongoing.

Trial registration: ClinicalTrials.gov NCT03219775.

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Conflict of interest statement

Marc-Oliver GrimmHonoraria: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Ipsen, Merck Serono, EUSA PharmaConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Pfizer, Astellas Pharma, EUSA Pharma, Merck Serono, Roche Pharma AG, Takeda, Eisai, Bayer/VitalResearch Funding: Bristol Myers Squibb (Inst), Intuitive Surgical (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Serono Bernd Jürgen Schmitz-DrägerConsulting or Advisory Role: Hexal, Astellas Pharma, Janssen Oncology, Bayer Health, AtheneumResearch Funding: Cepheid/Danaher (Inst), Nucleix (Inst), Concile (Inst), Arquer Diagnostics (Inst), Nextage (Inst) Gustavo Bruno BarettonConsulting or Advisory Role: MSD/AstraZeneca, Bristol Myers Squibb/Pfizer, RocheResearch Funding: BMS (Inst)Travel, Accommodations, Expenses: BMS Susan FollerHonoraria: Roche Pharma AG, MSD, Bristol Myers Squibb, Novartis, Pfizer, Ipsen, PROCEPT BioRoboticsConsulting or Advisory Role: Roche, MSD, Ipsen, Merck/Pfizer Katharina LeuchtOther Relationship: Bristol Myers Squibb (Inst) Martin SchostakHonoraria: Bayer, Merck, AstraZeneca/MedImmune, Janssen Oncology, PfizerConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Ipsen, EDAP TMS, Sanofi, Janssen Oncology, Astellas PharmaResearch Funding: Bristol Myers Squibb Foundation (Inst), AstraZeneca (Inst), Ipsen (Inst), MSD Oncology (Inst), Janssen Oncology (Inst), Sanofi (Inst), Bayer (Inst)Travel, Accommodations, Expenses: AstraZeneca, MSD Oncology, Bristol Myers Squibb/Pfizer, Sanofi, Merck, EDAP TMS, Pfizer, Bayer Friedemann ZengerlingHonoraria: Ipsen, Pfizer, Merck Serono, Astellas Pharma, JanssenConsulting or Advisory Role: Bristol Myers Squibb, Sanofi/Aventis, Merck Serono, IPSEN, Merck Sharp & Dohme, Bayer Health, Apogepha, Pfizer, Janssen, Roche Wolfgang LoidlConsulting or Advisory Role: Roche Pharma AG, Merck Sharp & Dohme, Bristol Myers Squibb, NovartisTravel, Accommodations, Expenses: Bristol Myers Squibb, Janssen Oncology Johannes MeranConsulting or Advisory Role: MSD, Astellas PharmaTravel, Accommodations, Expenses: JanssenNo other potential conflicts of interest were reported.

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