Subcutaneous nivolumab under review in EU for solid tumor indications

The European Medicines Agency (EMA) has validated an extension application for a subcutaneous formulation of nivolumab (Opdivo), which if accepted would introduce a new route of administration (subcutaneous) in a new pharmaceutical form (solution for injection) and a new strength (600 mg/vial) across all previously approved indications in solid tumors in the European Union (EU).¹

The CheckMate-67T study is currently ongoing, with expected completion in January 2026.

The application spans all indications of nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx). Specifically, these indications include in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

Currently, nivolumab is approved in those indications under intravenous (IV) administration.

“Subcutaneous nivolumab has the potential to change the way patients living with cancer receive Opdivo treatment and to significantly reduce administration time by utilizing a single injection in 3 to 5 minutes. By providing patients the same quality of care as IV Opdivo in a fraction of the time, patients can focus on what is important to them rather than spending a longer wait time at the infusion center,” said Susan Parker, vice president and global program lead of product design & development at Bristol Myers Squibb, in the news release.¹ “We are committed to advancing medicines that improve the patient experience and are evaluating innovative formulations across our broad portfolio. We look forward to working with the EMA to advance this application with the goal of introducing the subcutaneous option of Opdivo.”

Subcutaneous nivolumab is also under review in the United States. In May 2024, the FDA accepted a Biologics License Application (BLA) for the therapy in all previously approved solid tumor indications. The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.²

The validation of the extension application in the EU and the BLA in the United States were supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to IV nivolumab regarding time average nivolumab serum concentration over 28 days (C_avgd28; geometric mean ratio [GMR], 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C_minss; GMR, 1.774; 90% CI, 1.633-1.927) in patients with advanced or metastatic clear cell RCC (ccRCC).

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,³ also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the trial’s key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR) compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received 2 or more prior lines of systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus recombinant human hyaluronidase (rHuPH20) every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C_avgd28 and C_minss of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

The CheckMate-67T study is currently ongoing, with expected completion in January 2026.⁴

References

1. European Medicines Agency validates Bristol Myers Squibb’s application for subcutaneous nivolumab. News release. Published online and accessed June 21, 2024. https://news.bms.com/news/corporate-financial/2024/European-Medicines-Agency-Validates-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. May 21, 2024. Accessed June 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. J Clin Oncol. doi:10.1200/JCO.2024.42.4_suppl.LBA360

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated June 3, 2024. Accessed June 21, 2024. https://clinicaltrials.gov/study/NCT04810078