From Infusion Chair to Clinic Visit: How Subcutaneous Nivolumab May Simplify RCC Care

As the treatment landscape for clear cell renal cell carcinoma (ccRCC) continues to evolve, emphasis is increasingly placed on reducing barriers and complications to care, optimizing healthcare resources, and prioritizing patient-centered approaches—all without compromising efficacy or safety.

To help bring this patient-centered approach into practice, a recent study published in the Annals of Oncology evaluated a novel subcutaneous (SC) formulation of the PD-1 immune checkpoint inhibitor nivolumab with hyaluronidase versus traditional intravenous (IV) delivery in previously treated patients with advanced or metastatic ccRCC.

The Study Design

CheckMate 67T was a multicenter, open-label, phase III trial that enrolled 495 patients from 73 sites in 17 countries. Participants were randomized 1:1 to receive either SC nivolumab (1,200 mg every 4 weeks) or IV nivolumab (3 mg/kg every 2 weeks).

The study's co-primary pharmacokinetic (PK) endpoints were:

• The average serum concentration over 28 days (C_avgd28)
• The trough concentration at steady state (Css_min)

Noninferiority was defined as a geometric mean ratio (GMR) of ≥0.80 for each.

Secondary endpoints included both additional PK and pharmacodynamic (PD) assessments. Secondary PK measures included:

• The minimum concentration on day 28 (C_mind28)
• The maximum after the first dose(C_max1)
• The time-averaged (Css_avg)
• The maximum (Css_max) concentration at steady state
• The trough concentration (C_trough) at week 17

The PD and efficacy endpoints were objective response rate (ORR), best overall response (BOR), complete response, partial response, stable disease, progressive disease, progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and time to objective response (TTR).

Regarding safety, the endpoints included the incidence of adverse events (AEs), treatment-related AEs (TRAEs), serious AEs (SAEs), treatment-related SAEs (TRSAEs), and AEs leading to treatment discontinuation.

Lastly, immunogenicity was also assessed by monitoring the presence of anti-nivolumab antibodies and neutralizing antibodies throughout the study.

Patient Population

After randomizing the 495 enrolled, baseline characteristics were well balanced between the two treatment arms. Approximately 92 percent of all patients had received one prior systemic therapy: 88.7 percent in the SC arm and 94.7 percent in the IV arm, with 11.3 percent and 5.3 percent receiving two, respectively.

Most patients had intermediate or poor IMDC risk scores, and the majority had undergone prior nephrectomy: 81.9 percent and 83.0 percent for the two arms, respectively.

Results for the Pharmacokinetic Endpoints

Results of the primary pharmacokinetic endpoints after a minimum of eight months of follow-up are:

• C_avgd28: The geometric mean C_avgd28  for the SC arm (n = 242) was 77.373 ug/mL and in the IV arm (n = 245), it was 36.875 ug/mL. The GMR of C_avgd28 for the SC arm compared to the IV arm was 2.098.
• Css_min: The geometric mean Css_min for the SC arm was 122.227 ug/mL and 68.901 ug/mL in the IV arm. The SC:IV GMR of Css_min was 1.774.

Collectively, these results indicate that the study met both pharmacokinetic endpoints. Researchers confirm that SC nivolumab was noninferior to IV administered nivolumab, as the GMR exceeded the threshold (≥0.8). Secondary endpoints also indicate higher exposure after SC administration versus IV.

Results for the Secondary Efficacy, Safety, and Tolerability Endpoints

After a minimum of 15 months of follow-up, the results of the secondary endpoints were:

• ORR was 26.6 percent in the SC arm and 20.6 percent in the IV arm, with a risk ratio of 1.28, meeting the predefined noninferiority criteria.
• No significant differences between the arms were observed for BOR, DCR, TTR, and PFS, although OS was not reached in either arm by study cutoff.

The safety profile of SC nivolumab was also consistent with the IV formulation. Similar or lower rates were observed in the SC compared to IV at any grade for all-cause AEs, TRAE, and discontinuation associated all-cause AEs and TRAES.

The three most common AEs reported were anemia, pruritus, and arthralgia. The most common nonendocrine immune-mediate AEs reported were rash in the SC arm and hepatitis in the IV arm. Injection-site reactions were reported but were mild and resolved on their own. Study-related deaths included three in the SC arm—all of which were attributed to drug toxicity—and two in the IV arm: one due to immune-mediated infection with disease progression, and the other due to vanishing bile duct syndrome.

Anti-nivolumab antibodies were higher in the SC arm (24 percent) than the IV arm (6.9 percent) but were consistent with previously reported IV exposures. Neutralizing antibodies were present in a minority of ADA-positive cases, and no impact on efficacy, pharmacokinetics, or safety was identified.

Clinical Implications

Based on these results, the CheckMate 67T trial demonstrates that SC nivolumab was noninferior pharmacokinetically and clinically comparable to IV treatment in this population.

But even looking beyond its comparable efficacy and safety, the SC formulation could offer meaningful advantages for patients, including shorter administration times, fewer clinic visits, and reduced burden on infusion resources, all of which could help improve accessibility and convenience without compromising outcomes.

Reference
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