EMA Validates Filings for Subcutaneous Formulation of Nivolumab in Solid Tumors

The European Medicines Agency (EMA) has validated an extension application for the subcutaneous formulation of nivolumab (Opdivo) to be administered as a solution for injection at a new strength of 600 mg/vial in previously approved solid tumor indications, including as monotherapy, as maintenance monotherapy following nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).¹

The decision was based on results from the phase 3 CheckMate-67T trial (NCT04810078) in which the agent demonstrated noninferior pharmacokinetics and efficacy vs the intravenous (IV) formulation.¹

The open-label, randomized, noninferiority trial enrolled patients with clear cell renal cell carcinoma (ccRCC) who had received no more than 2 prior lines of systemic therapy. Patients who were treated with subcutaneous nivolumab coformulated with recombinant human hyaluronidase PH20 (rHuPH20; n = 242) demonstrated a time-averaged serum concentration over 28 days (Cavgd28) of 77.373 μl/mL (90% CI, 74.555-80.297) compared with 36.875 μl/mL (90% CI, 35.565-38.235) in patients treated with IV nivolumab (n = 245); the geometric mean ratio was 2.098 μl/mL (90% CI, 2.001-2.200). Additionally, the geometric mean trough serum concentration at steady-state (Cminss) was 122.227 μl/mL (90% CI, 114.552-130.416) and 68.901 μl/mL (90% CI, 64.676-73.402) in the subcutaneous and IV arms, respectively, creating a geometric mean ratio of 1.774 μl/mL (90% CI, 1.633-1.927). These data were shared at the 2024 ASCO Genitourinary Cancers Symposium(2024 GU Symposium).^1,2

“Subcutaneous nivolumab has the potential to change the way patients living with cancer receive nivolumab 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 nivolumab 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,” Susan Parker, vice president, global program lead, Product Design and Development, Bristol Myers Squibb, stated 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 nivolumab.”

CheckMate-67T enrolled patients with locally advanced or metastatic ccRCC that had progressed during or after 1 to 2 prior lines of systemic therapy. Patients were required to have a Karnofsky performance status of at least 70 and could not have received prior immuno-oncology therapies.

Upon determination of eligibility, patients were randomly assigned 1:1 to either subcutaneous nivolumab 1200 mg coformulated with rHuPH20 every 4 weeks or IV nivolumab 3 mg/kg every 2 weeks. Treatment in both groups continued until disease progression, unacceptable toxicity, withdrawal, completion of 2 years of treatment, or death.

The coprimary end points of the trial were Cavgd28 and Cminss of subcutaneous nivolumab vs IV nivolumab and a key secondary end point included objective response rate (ORR).¹

The key secondary end point of ORR as assessed by blinded independent central review (BICR) vs IV nivolumab was also met. In the subcutaneous arm, the ORR was 24.2% (95% CI, 19.0%-30.0%) vs 18.2% (95% CI, 13.6%-23.6%) in the IV arm (relative risk, 1.33; 95% CI, 0.94-1.87).²

Notably, in May 2024, the FDA accepted a biologics license application (BLA)seeking the approval of the subcutaneous formulation in this patient population, with an FDA assigned Prescription Drug User Fee Act goal date of February 28, 2025. The BLA is based on these same data from CheckMate-67T.³

The safety profile of subcutaneous nivolumab was consistent with that of the IV formulation, according to data shared at the 2024 GU Symposium. Additional safety outcomes and patient-reported outcomes were also presented at the 2024 ASCO Annual Meeting, supporting these previous findings.¹

References

1. European Medicines Agency validates Bristol Myers Squibb’s application for subcutaneous nivolumab. News release. Bristol Myers Squibb. June 21, 2024. 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. George S, Bourlon MT, 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. 2024;42(suppl 4):LBA360. doi:10.1200/JCO.2024.42.4_suppl.LBA360
3. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News Release. Bristol Myers Squibb. May 6, 2024. Accessed June 21, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx