Subcutaneous noninferior to intravenous nivolumab for clear cell renal cell carcinoma

Subcutaneous nivolumab is good enough for patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC) when compared with intravenous nivolumab, with no significant differences in the pharmacokinetic, efficacy, and safety endpoints, according to data from the open-label, phase III CheckMate 67T study.

The study met the noninferiority criteria for the coprimary pharmacokinetic endpoints of time-averaged serum concentration over 28 days (C_avgd28) and minimum serum concentration at steady state (C_minns). The geometric mean C_avgd28 was 77.373 μg/mL with subcutaneous nivolumab and 36.875 μg/mL with intravenous nivolumab (geometric mean ratio, 2.098, 90 percent confidence interval [CI], 2.001–2.200), and the geometric mean C_minss was 122.227 μg/mL and 68.901 μg/mL, respectively (geometric mean ratio, 1.774, 90 percent CI, 1.633–1.927). [ASCO GU 2024, abstract LBA360]

The lower bound of the 90 percent CI for both Cavgd28 and Cminss exceeded the noninferiority margin of 0.8, reported lead investigator Dr Saby George of the Roswell Park Comprehensive Cancer Center in Buffalo, New York, US.

Likewise, subcutaneous nivolumab showed noninferiority to the intravenous formulation in terms of the powered secondary endpoint of blinded independent central review (BICR)-assessed objective response rate (ORR). ORR rates were 60 percent in the subcutaneous arm and 45 percent in the intravenous arm (relative risk, 1.33, 95 percent CI, 0.94–1.87), with the lower bound of the 95 percent CI above the noninferiority threshold of 0.6, George said.

Results for the additional secondary endpoints were comparable between the subcutaneous and intravenous arms. George noted that there were 2.0 percent and 1.6 percent of patients in the respective arms who achieved complete response. Disease control rates were 62.9 percent and 62.8 percent (risk ratio, 1.01, 95 percent CI, 0.88–1.15), median time to response was 3.70 and 3.68 months, and median progression-free survival by BICR was 7.23 and 5.65 months (hazard ratio, 1.06, 95 percent CI, 0.84–1.34), respectively.

No new safety concerns

Finally, the safety profile of subcutaneous nivolumab was consistent with that of the intravenous formulation, George pointed out. Rates were similar or lower in the subcutaneous versus the intravenous arm for the following: any-grade adverse events (AEs; 93.1 percent vs 93.5 percent), grade 3/4 treatment-related AEs (TRAEs; 9.7 percent vs 14.7 percent), grade 3/4 AEs leading to treatment discontinuation (7.3 percent vs 8.6 percent), grade 3/4 serious AEs  (21.1 percent vs 22.9 percent), and treatment-related serious AEs (grade 3/4: 6.5 percent in both arms). Arthralgia, fatigue, diarrhoea, and hyperglycaemia were the most common AEs.

“Toxicity led to three deaths in the subcutaneous arm and one death in the intravenous arm. Local site reactions in the subcutaneous arm were of low grade and transient [and] resolved without intervention,” George said.

Positivity for antidrug antibodies (ADAs) was documented in 22.8 percent of patients receiving subcutaneous nivolumab versus 7.0 percent of patients receiving intravenous nivolumab. But this, according to George, did not have any clinically meaningful impact on pharmacokinetics, efficacy, or safety.

The study included 495 patients with advanced or metastatic ccRCC who had received one or two prior systemic regimens. These patients were randomly assigned to treatment with subcutaneous nivolumab at 1,200 mg plus recombinant hyaluronidase every 4 weeks (n=248) or intravenous nivolumab at 3 mg/kg every 2 weeks (n=247).

Clinical equipoise

“These data indicate that subcutaneous nivolumab provides clinical equipoise to standard intravenous nivolumab dosing, supporting the use of [the subcutaneous dosing] as a new option to reduce patients’ treatment burden and improve healthcare efficiency,” George said.

“Having the option to administer immunotherapy subcutaneously could undoubtedly reduce the treatment burden that [patients with cancer] currently face, as well as help maximize efficiencies within healthcare systems by freeing up infusion chairs, so we get more patients the medicine they need quickly,” he added.

Study discussant Dr Ulka Vaishampayan of the University of Michigan in Ann Arbor, Michigan, US, maintained that it is “reasonable” to substitute subcutaneous nivolumab where intravenous single-agent nivolumab is used, given the pharmacokinetic comparability seen in the study.

Subcutaneous nivolumab has several merits, including easier clinic administration and reduced risk of hypersensitivity reactions, Vaishampayan added.

However, the discussant acknowledged that the questions of whether nivolumab could be safely combined with other agents used as standard frontline therapy for RCC and its effect on pharmacokinetics remain to be addressed.