Subcutaneous nivolumab meets coprimary pharmacokinetic end points for ccRCC

Findings from the phase 3 CheckMate 67T trial (NCT04810078) indicate that subcutaneous nivolumab (Opdivo) coformulated with recombinant human hyaluronidase PH20 (rHuPH20) was associated with noninferiority of exposures in terms of time-averaged serum concentration over 28 days (Cavgd28) and trough serum concentration at steady-state (Cminss) vs intravenous (IV) nivolumab in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) that progressed.¹

The results, presented during the 2024 Genitourinary Cancers Symposium in San Francisco, California, met the coprimary pharmacokinetic end points of the study.

Patients in the subcutaneous arm (n = 242) achieved a geometric mean Cavgd28 of 77.373μl/mL (90% CI, 74.555-80.297) compared with 36.875 μl/mL (90% CI, 35.565-38.235) in the IV arm (n = 245), for a geometric mean ratio of 2.098 μl/mL (90% CI, 2.001-2.200). The geometric mean Cminss was 122.227 μl/mL (90% CI, 114.552-130.416) vs 68.901 μl/mL (90% CI, 64.676-73.402), respectively, for a geometric mean ratio of 1.774 μl/mL (90% CI, 1.633-1.927).

Saby George, MD, FACP

“Nivolumab is approved for 22 different indications across multiple malignancies, and evolving treatment paradigms require making treatment burden lower on patients and the subcutaneous delivery of antibodies has proven to be effective and well tolerated by patients,” Saby George, MD, FACP, the director of Network Clinical Trials and a professor of Oncology and Medicine at Roswell Park Comprehensive Cancer Center, as well as an associate professor at the Jacobs School of Medicine and Biomedical Sciences at the University of Buffalo, both in Buffalo, New York, said during the presentation. “Furthermore, subcutaneous administration is typically preferred to IV administration by patients. Subcutaneous dosing was coformulated with rHuPH20, which is a reversible degrader of hyaluronic acid in the extracellular matrix, thus allowing for larger injection volumes.”

CheckMate 67T was an open-label multicenter trial that enrolled patients with locally advanced or metastatic ccRCC that progressed during or after treatment with 1 or 2 previous systemic regimens. Patients were also required to have a Karnofsky performance status of at least 70 and could not have received any prior immuno-oncology therapies. Key stratification factors included baseline weight and IMDC risk group.

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

The coprimary end points were Cavgd28 and Cminss. The key secondary end point was objective response rate (ORR) by blinded independent central review (BICR); other secondary end points included safety, progression-free survival (PFS), and incidence of anti-nivolumab antibodies and neutralizing antibodies.

The baseline patient characteristics were well balanced between the 2 arms; the median age in the subcutaneous arm was 64 years (range, 35-93) compared with 66 years (range, 20-87) in the IV arm. Most patients in both arms were male (66.1% vs 69.2%, respectively), weighed at least 65 kg and less than 90 kg (54.0% vs 56.3%), were from Mexico or South America (64.1% vs 59.9%), had 1 prior line of therapy (89.1% vs 94.7%), had IMDC intermediate-risk disease (63.7% vs 59.5%), underwent a prior nephrectomy (81.9% vs 83.0%), and did not have central nervous system metastasis (86.3% vs 90.7%).

The median weight of patients was 77.8 kg (range, 35.0-152.6) in the subcutaneous arm vs 77.8 kg (range, 47.5-157.4) in the IV arm. Patients had a Karnofsky performance status of 70 (6.9% vs 7.7%), 80 (21.0% vs 19.8%), 90 (31.5% vs 35.6%), or 100 (40.7% vs 36.8%), respectively.

Additional findings from the study demonstrated that the median PFS by BICR in the subcutaneous arm was 7.23 months (95% CI, 5.13-7.49) vs 5.65 months (95% CI, 5.29-7.39) in the IV arm (HR, 1.06; 95% CI, 0.84-1.34). The disease control rate was 62.9% (95% CI, 56.6%-68.9%) vs 62.8% (95% CI, 56.4%-68.8%), respectively (risk ratio, 1.01; 95% CI, 0.88-1.15), and the median time to response was 3.70 months (range, 1.7-11.1) vs 3.68 months (range, 1.6-11.3%), respectively. Best responses in both arms included complete response (2.0% vs 1.6%), partial response (22.2% vs 16.6%), stable disease (38.7% vs 44.5%), and disease progression (25.0% vs 26.7%), respectively. Responses were unable to be determined in 12.1% of patients in the subcutaneous arm and 10.5% of patients in the IV arm.

The key secondary end point, ORR by BICR, met noninferiority. The ORR in the subcutaneous arm was 24.2% (95% CI, 19.0% vs 30.0%) compared with 18.2% (95% CI, 13.6%-23.6%) in the IV arm (relative risk, 1.33; 95% CI, 0.94-1.87).

In terms of nivolumab-related immunogenicity, 5.9% of patients in the subcutaneous arm were anti-drug antibody (ADA) positive at baseline compared with 4.2% in the IV arm. Following treatment, patients in the subcutaneous arm were ADA persistent positive (1.0%), last sample positive (8.4%), other positive (13.4%), neutralizing positive (1.0%), or negative (76.7%). In the IV arm, these rates were 0%, 2.8%, 4.2%, 0%, and 93.0%, respectively. Immunogenicity data were not available for 1 patient in the subcutaneous arm.

The safety profile was consistent between subcutaneous and IV nivolumab. The incidence of any-grade adverse effects (AEs) was 93.1% vs 93.5%, including a grade 3 or 4 AE rate of 35.2% vs 40.8%, respectively. Patients in both arms experienced any-grade treatment-related AEs (TRAEs; 59.1% vs 64.5%), AEs leading to discontinuation (10.1% vs 11.8%), TRAEs leading to discontinuation (4.0% vs 4.9%), serious AEs (SAEs; 27.9% vs 29.0%), and treatment-related SAEs (6.9% vs 6.9%). These events occurred at grade 3 or 4 severity at rates of 9.7% vs 14.7%, 7.3% vs 8.6%, 2.4% vs 3.7%, 21.1% vs 22.9%, and 6.5% vs 6.5%, respectively. Select any grade AEs included hypersensitivity/infusion-related reaction (1.2% vs 3.7%) and local site reactions (8.1% vs 2.0%). There were 3 deaths in the subcutaneous arm compared with 1 in the IV arm.

The median number of doses received was 8.0 (range, 1-25) vs 17.0 (range, 1-52) in the subcutaneous and IV arms, respectively. The median administration time was 5.0 minutes (range, 0-15) vs 30.0 minutes (range, 6-133), respectively. Thirty-six percent of patients in the subcutaneous arm had at least 1 dose delayed vs 54.7% in the IV arm; 1 vs 10 patients, respectively, had at least 1 infusion/injection interrupted.

“The safety profile of subcutaneous nivolumab was consistent with the safety profile of IV nivolumab, with no new safety concerns emerging,” George said in conclusion. “[These data] support the use of subcutaneous nivolumab as a new option to reduce patient treatment burden and improve health care efficiency.”

Reference

1. 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.LBA