A recent phase III clinical trial has demonstrated that subcutaneous administration of nivolumab is noninferior to intravenous administration in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC). The study, known as CheckMate 67T (NCT04810078), was an open-label, multicenter, randomized noninferiority trial funded by Bristol Myers Squibb. The results were published in the Annals of Oncology on September 15, 2024.
The primary objective of the study was to assess the noninferiority of subcutaneous nivolumab compared to intravenous nivolumab based on pharmacokinetic parameters and objective response rate (ORR). The trial enrolled 495 patients with advanced or metastatic ccRCC who had received one or two prior systemic therapies but no prior immune checkpoint inhibitor therapy. Patients were randomized 1:1 to receive either subcutaneous nivolumab (1200 mg every 4 weeks, coformulated with recombinant human hyaluronidase PH20) or intravenous nivolumab (3 mg/kg every 2 weeks).
Eligible patients were aged 18 years or older with histologically confirmed ccRCC, a Karnofsky performance status of 70 or higher, and evidence of disease progression on or after prior treatment within 6 months of randomization. The study population was diverse, with a median age of 64-66 years and inclusion of patients from 17 countries, with a large proportion of Latin American participants.
The coprimary endpoints were time-averaged serum concentration over the first 28 days (Cavgd28) and minimum steady-state serum concentration (Cminss). The key secondary endpoint was ORR as assessed by blinded independent central review (BICR). The study met its primary objective, demonstrating noninferiority of subcutaneous nivolumab to intravenous nivolumab for both pharmacokinetic endpoints. The geometric mean ratios (subcutaneous vs. intravenous) for Cavgd28 and Cminss were 2.098 (90% CI: 2.001-2.200) and 1.774 (90% CI: 1.633-1.927), respectively, both exceeding the prespecified noninferiority threshold of 0.8 for the lower boundary of the 90% confidence interval.
After a minimum follow-up of 8 months, the ORR was 24.2% (95% CI: 19.0%-30.0%) in the subcutaneous arm compared to 18.2% (95% CI: 13.6%-23.6%) in the intravenous arm, with a relative risk of 1.33 (95% CI: 0.94-1.87). This met the prespecified noninferiority threshold for ORR. At the secondary database lock, with a minimum follow-up of 15 months, the ORR increased to 26.6% for subcutaneous nivolumab and 20.6% for intravenous nivolumab.
Secondary efficacy endpoints, including disease control rate, time to objective response, progression-free survival, and overall survival, were numerically similar between the two arms. The safety profile of subcutaneous nivolumab was consistent with that of intravenous nivolumab, with no new safety signals identified. The incidence of treatment-related adverse events was comparable between the two arms, with 61.5% in the subcutaneous arm and 65.7% in the intravenous arm experiencing any-grade treatment-related adverse events.
One notable difference was the higher incidence of anti-nivolumab antibodies in the subcutaneous arm compared to the intravenous arm. However, further assessments did not identify any apparent clinically meaningful impact of these antibodies on nivolumab pharmacokinetics, efficacy, or safety.
Patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) and the EuroQol 5 dimensions, 5 levels (EQ-5D-5L), showed that health-related quality of life was stable over time and comparable between the two administration routes.
The study had some limitations, including the open-label design and the relatively short follow-up period for assessing long-term outcomes. Additionally, the study population was limited to patients with ccRCC, and further research may be needed to confirm these findings in other tumor types.
The authors concluded that subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR, with a consistent safety profile. They suggest that these findings support the potential use of subcutaneous nivolumab as a new option to reduce patient treatment burden and improve healthcare efficiency across solid tumors.
The potential clinical impact of this study is significant. Subcutaneous administration of nivolumab could offer several advantages over intravenous administration, including shorter preparation and chair occupancy times, potentially improved healthcare resource utilization, and reduced administrative workload. Patients may prefer subcutaneous administration due to its convenience and shorter administration time, which could potentially improve treatment adherence and quality of life. Additionally, the option for subcutaneous administration could allow for treatment closer to patients' homes, further reducing the burden of cancer care.
As the field of oncology continues to evolve, the availability of subcutaneous formulations of immune checkpoint inhibitors like nivolumab could represent an important step forward in optimizing cancer treatment delivery and patient care. However, further studies may be needed to assess the long-term efficacy and safety of subcutaneous nivolumab across various tumor types and in combination with other therapies.
References
Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol. 2025;36(1):99-107. doi:10.1016/j.annonc.2024.09.002
