Subcutaneous nivolumab non-inferior to intravenous nivolumab in previously treated clear cell renal cell carcinoma

In previously treated patients with advanced or metastatic clear cell renal cell carcinoma, a subcutaneous formulation of nivolumab was found to be non-inferior to the intravenous formulation, which is standard of care for nivolumab in renal cell carcinoma and other cancers. According to the results of the randomised, open-label, phase III CheckMate 67T trial, subcutaneous nivolumab demonstrated non-inferiority for the two co-primary pharmacokinetic endpoints and for secondary efficacy endpoints, including overall response rate, with a safety profile that was generally similar to that of intravenous nivolumab.

Intravenous (IV) nivolumab has improved outcomes in various cancer types, including clear cell renal cell carcinoma (ccRCC). However, improved administration options are needed to decrease treatment burden and improve the efficiency of healthcare systems. For various cancer indications, subcutaneous (SC) injection of antibodies has proved to be effective and well-tolerated. Furthermore, SC administration decreases preparation and chair occupancy times and reduces the administrative burden. Nivolumab SC is co-formulated with recombinant human hyaluronidase PH20, which reversibly degrades hyaluronan in the extracellular matrix around the injection site and enables the administration of large drug volumes. Previously, in the dose-finding phase I/II CheckMate 8KX study, various doses of nivolumab SC were evaluated in patients with metastatic or unresectable solid tumours. In the phase III CheckMate 67T study, the efficacy and safety of nivolumab SC was compared with nivolumab IV in patients with previously treated ccRCC.

Methods

CheckMate 67T is a multicentre, randomised, open-label, phase III study that enrolled patients with previously treated locally advanced or metastatic ccRCC. Eligible patients had measurable disease that progressed during or after 1 or 2 prior systemic regimens, no prior immuno-chemotherapy, and a Karnofsky performance score ≥70. Participants were randomised 1:1 to receive nivolumab (1,200 mg SC) plus recombinant human hyaluronidase PH20 once every 4 weeks or nivolumab (3 mg/kg IV) once every 2 weeks until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years of treatment, or death. Co-primary pharmacokinetic endpoints for non-inferiority testing were time-averaged serum concentration over the first 28 days (C_avgd28) and minimum serum concentration at steady state (C_minss). The objective response rate (ORR) by blinded independent central review was the key powered secondary endpoint for non-inferiority testing. Other secondary endpoints were progression-free survival (PFS), nivolumab-related immunogenicity, and safety.

Results

In total, 495 patients were randomised to receive nivolumab SC (n=248) or nivolumab IV (n=247). The average administration time with nivolumab SC was ≤5 minutes. Most patients received all doses of the study drug without an infusion or injection interruption or dose delay. The most common reason for dose delays was adverse events (AEs). Non-inferiority for the co-primary pharmacokinetic endpoints was met. The geometric mean C_avgd28 was 77.4 µg/ml in the SC group versus 36.9 µg/ml in the IV group (geometric mean ratio [90% CI]: 2.10 [2.00-2.20]). The geometric mean C_minss was 122.2 and 68.9 µg/ml in the SC and IV group, respectively (geometric mean ratio [90% CI]: 1.77 [1.63-1.93]). Non-inferiority for the ORR was also met (24.2% vs. 18.2%; RR [95% CI]: 1.33 [0.94-1.87]). No significant difference in PFS was found between treatment groups (median 7.23 vs. 5.65 months; HR [95% CI]: 1.06 [0.84-1.34]). Anti-drug antibody positivity was 22.8% in the SC group, compared with 7.0% in the IV group. Rates of grade 3 or 4 AEs (35.2% vs. 40.8%), treatment-related AEs (9.7% vs. 14.7%), serious AEs (21.1% vs. 22.9%), and treatment-related serious AEs (6.5% vs. 6.5%) for the SC group were similar to or lower than the rates for the IV group. Local site reactions in the SC group were low grade, transient and most resolved without treatment. No anaphylactic reactions were observed in either arm. Study drug toxicity led to three deaths in the SC group and one death in the IV group.

Conclusions

In the phase III CheckMate 67T study, the co-primary pharmacokinetic endpoints and key powered secondary endpoint were met. Nivolumab SC demonstrated non-inferiority of exposures (C_avgd28 and C_minss) and efficacy (ORR) versus nivolumab IV. Moreover, the safety profile of nivolumab SC was similar to that of nivolumab IV. According to the researchers, these results support the use of nivolumab SC as a new treatment option for patients with previously treated locally advanced or metastatic ccRCC.

Reference

George S, 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. Presented at ASCO GU 2024; Abstract LBA360.