Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial - 14/10/23

Doi : 10.1016/S1470-2045(23)00449-7

Marc-Oliver Grimm, ProfMD ^a,⁎ , Emilio Esteban, MD ^c, Philippe Barthélémy, MD ^d, Manuela Schmidinger, ProfMD ^e, Jonas Busch, ProfMD ^f, Begoña P Valderrama, MD ^g, Natalie Charnley, MD ^h, Marc Schmitz, ProfMD ^i,^k,^l,^m, Ulrike Schumacher, PhD ^b, Katharina Leucht, PhD ^a, Susan Foller, MD ^a, Gustavo Baretton, ProfMD ^j, Ignacio Duran, MD ⁿ, Guillermo de Velasco, MD ^o, Frank Priou, MD ^p, Pablo Maroto, MD ^q, Laurence Albiges, ProfMD ^r
for the
TITAN-RCC study group
Carlo Barone, Daniel Castellano, Christine Chevreau, Pablo Gajate Borau, Srinavasan Gopalakrishnan, Enrique Grande, Abdel Hamid, Julia Heinzelbecker, Martin Janssen, Jindřich Kopecký, Eugen Kubala, Wolfgang Loidl, Anja Lorch, Bohuslav Melichar, Nuria Lainez Milagro, Günter Niegisch, Carsten Ohlmann, Anne Sacré, Naveed Sarwar, Giovanni Schinzari, Dirk Schrijvers, Sophie Tartas, Manfred Wirth, Pascal Wolter, Milanda Zemanova

^a Department of Urology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
^b Center for Clinical Studies, Jena University Hospital, Friedrich-Schiller University, Jena, Germany
^c Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain
^d Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
^e Department of Urology, Medical University of Vienna, Vienna, Austria
^f Department of Urology, University Hospital Charité Berlin, Berlin, Germany
^g Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain
^h Department of Oncology, Royal Preston Hospital, Preston, UK
ⁱ Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
^j Institute of Pathology, Faculty of Medicine Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
^k National Center for Tumor Diseases, Dresden, Germany
^l German Cancer Consortium, Dresden, Germany
^m German Cancer Research Center, Heidelberg, Germany
ⁿ Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla, Santander, Spain
^o Department of Oncology, Hospital 12 de Octubre, Madrid, Spain
^p Centre Hospitalier Départemental Vendee, Hopital Les Oudairies, La Roche Sur Yon, France
^q Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
^r Department of Cancer Medicine, Gustave Roussy, University of Paris Saclay, Villejuif, France

^*Correspondence to: Prof Marc-Oliver Grimm, Department of Urology, Jena University Hospital, Friedrich-Schiller University, Jena 07747, GermanyDepartment of UrologyJena University HospitalFriedrich-Schiller UniversityJena07747Germany

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 14 October 2023
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Summary

Background

Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma.

Methods

TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete.

Findings

Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5–34·8), 39 (36%, 90% CI 28–44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24–40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3–4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia.

Interpretation

In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy.