Subcutaneous nivolumab under review in EU for solid tumors

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of a subcutaneous formulation of nivolumab (Opdivo), co-formulated with recombinant human hyaluronidase (rHuPH20; Enhanze), across multiple previously approved solid tumor indications.^1,2

Subcutaneous nivolumab was approved by the FDA in December 2024.

This includes nivolumab as a monotherapy, monotherapy maintenance following completion of nivolumab plus ipilimumab (Yervoy) combination therapy, or in combination with chemotherapy or cabozantinib (Cabometyx). Nivolumab is currently approved across several indications in renal cell carcinoma (RCC) and urothelial carcinoma.

The application will now be reviewed by the European Commission, who must issue a decision on or by June 2, 2025. If approved, the decision would be applicable in all EU member states plus Iceland, Norway, and Liechtenstein.

“The positive CHMP opinion is an important step forward in the evolution of immuno-oncology and in the potential of subcutaneous nivolumab to help transform the lives of people living with cancer,” said Dana Walker, MD, MSCE, Opdivo global program lead at Bristol Myers Squibb, in the company’s news release.¹ “We look forward to bringing the same high-quality care that transformed cancer treatment with an administration method that has the potential to improve the patient experience and efficiency of health care systems in Europe."

The positive opinion is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab with rHuPH20 met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time-averaged nivolumab serum concentration over 28 days (C_avgd28; geometric mean ratio [GMR}, 2.10; 90% CI, 2.00-2.20) and minimum serum concentration at a steady state (C_minss; GMR, 1.77; 90% CI, 1.63-1.93) in patients with advanced or metastatic clear cell RCC (ccRCC).³

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California, also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, patients in 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) among patients in the IV arm.

Additionally, the median progression-free survival per BICR was 7.23 months (95% CI, 5.13-7.49) in the subcutaneous arm vs 5.65 months (95% CI, 5.29-7.39) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Serious adverse events (AEs) were reported in 28% of patients in the subcutaneous arm, which included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%).

Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. AEs led to treatment discontinuation in 10% of patients.

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 prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus hyaluronidase-nvhy 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, completion of 2 years of treatment, 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.

Subcutaneous nivolumab, co-formulated with rHuPH20, was approved by the FDA in December 2024 based on findings from this trial.

REFERENCES

1. Bristol Myers Squibb receives positive CHMP opinion for the subcutaneous formulation of opdivo (nivolumab) across multiple solid tumor indications. News release. Bristol Myers Squibb. March 28, 2025. Accessed March 31, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-the-Subcutaneous-Formulation-of-Opdivo-nivolumab-Across-Multiple-Solid-Tumor-Indications/default.aspx

2. Halozyme announces Bristol Myers Squibb received positive CHMP opinion for the subcutaneous formulation of Opdivo (nivolumab) with ENHANZE across multiple solid tumor indications. News release. Halozyme Therapeutics, Inc. Published online and accessed March 31, 2025. https://ir.halozyme.com/news/news-details/2025/Halozyme-Announces-Bristol-Myers-Squibb-Received-Positive-CHMP-Opinion-for-the-Subcutaneous-Formulation-of-Opdivo-nivolumab-with-ENHANZE-Across-Multiple-Solid-Tumor-Indications/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