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.

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.

FUNDING

Bristol Myers Squibb.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests MOG reports institutional research grants from Bristol Myers Squibb, Intuitive Surgical, and Bayer Vital; personal consulting fees from AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Pfizer, Astellas Pharma, EUSA Pharma, Merck Serono, Roche Pharma, Eisai, Bayer Vital, Janssen, Gilead, and Novartis; personal honoria from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, Janssen, Astellas Pharma, and Takeda; and travel expenses from Merck Serono, Bristol Myers Squibb, Bayer, Pfizer, and AstraZeneca. PB reports grants from Bristol Myers Squibb, Ipsen, MSD, Pfizer, Merck, AstraZeneca, Janssen, and Gilead; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, AAA Pharma, Novartis, Gilead, and Bayer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Suibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, Bayer, AAA Pharma, and Novartis; and travel expenses Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas Pharma. ManS reports personal consulting fees for advisory boards from Bristol Myers Squibb, MSD, Eisai, Ipsen, and Exelixis; personal honoria for lectures from Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca; and personal participation on advisory boards for Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca. JB reports an educational grant from Astellas Pharma; consulting fees from Bristol Myers Squibb, MSD, Merck, Ipsen, and Pfizer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen and Merck; travel expenses from Ipsen and Merck; and participation on a data safety monitoring board or advisory board for MSD, Pfizer, and Ipsen. BPV reports consulting fees from Bristol Myers Squibb, MSD Oncology, Astellas Pharma, AstraZeneca, Novartis, Bayer, and Advanced Accelerator Applications-Novartis; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, Roche, EUSA Pharma, Pfizer, Merck, Astellas Pharma, AstraZeneca, and Bayer; and travel expenses from Merck, Pfizer, Advanced Accelerator Applications-Novartis, and Roche. KL payment for medical writing (to their institution) for manuscript writing from Bristol Myers Squibb and Intuitive Surgical; and travel expenses from Ipsen. ID reports institutional research grants from Roche and AstraZeneca; honoria for lectures, presentations, or educational events from Bristol Myers Squibb, MSD, Ipsen, Roche Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, and Bayer; travel expenses from Merck-Pfizer, Ipsen, Janssen, Bayer, and AstraZeneca; participation on an advisory board for Bristol Myers Sqibb, MSD, Ipsen, Roche Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclics, and Gilead; is the cofounder of GO NORTE (GU cooperative group, unpaid); is Vice President of Germ Cell Spanish Group (unpaid); is an executive board member of the GUARD consortium (GU cooperative group, unpaid); has received institutional medical writing support from Roche Genentech; and has procured substances for preclinical research purposes from Jansen (institutional research group). GdV reports consulting fees from Bristol Myers Squibb, Astellas Pharma, MSD, Merck, and Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Roche, Novartis, Ipse, Pfizer, Astellas Pharma, Pierre Fabre, MSD, Merck, and Janssen; travel expenses from Roche and MSD; and participation on a data safety monitoring board or advisory board for AstraZeneca. FP reports participation on a data safety monitoring board or advisory board for Daiichi and Novartis. PM reports payment or honoria for lectures, presentation, speaker bureaus, manuscript writing or educational events from Bayer; payments for expert testimony from Amgen; travel expenses from Bayer; and reports participation on a data safety monitoring board or advisory board for Pfizer, Novartis, and Astellas Pharma. LA reports consulting fees, paid to their institution, from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. EE, NC, MarS, US, SF, and GB declare no competing interests.