Treatment-free survival outcomes of nivolumab and salvage nivolumab plus ipilimumab in advanced clear cell renal cell carcinoma

Nivolumab monotherapy with salvage nivolumab plus ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with advanced clear cell renal cell carcinoma and results in substantial treatment-free survival (TFS) and toxicity-free TFS. In the HCRN GU16 260 trial, TFS was particularly noted in patients with IMDC favourable-risk disease, further supporting the use of an immunotherapy-only regimen in this population.

Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Unfortunately, toxicity from therapy can also persist after cessation. Treatment-free survival (TFS) with and without toxicity can characterise survival time. Significant TFS was reported for the CheckMate-067 trial in patients with metastatic melanoma and the CheckMate-214 trial for patients with advanced renal cell carcinoma (aRCC), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. Therefore, Atkins et al. sought to assess TFS in the phase II HCRN GU16 260 trial, which was designed to reduce toxicity by limiting CTLA4 blockade and capping immunotherapy duration at 96 weeks.

Study design

In part A, patients received nivolumab monotherapy for up to 96 weeks of total treatment. If patients experienced disease progression (PD) at any time or had a best response of stable disease (SD) at 48 weeks of treatment (prolonged SD), they were potentially eligible for part B, which involved the combination of nivolumab/ipilimumab (NIVO/IPI) for 12 weeks followed by nivolumab monotherapy for up to 48 weeks. Data were analysed from 128 patients with clear-cell aRCC. TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, both estimated from 36-month mean times. The time on or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured.

Results

At 36 months from enrolment, 68.3% of patients were alive: 96.8% of IMDC favourable-risk (FAV) patients and 56.6% of those with intermediate/poor-risk (I/P), respectively. The objective response rates were 58%, 26%, and 33% for patients with IMDC favourable, intermediate, and poor risk categories, respectively. The 36-month mean time on protocol therapy was 11.5 months (16.0 months for FAV patients and 9.6 months for I/P patients). The 36-month mean TFS for the whole population was 9.4 months. For favourable risk patients the mean TFS was 12.9 months, of which TFS with grade 3+ TRAEs was 1.5 months. For intermediate/poor risk patients, the mean TFS was 8.0 months, of which TFS with grade 3+ TRAEs was 1.0 months. At 36 months, 65.6% of favourable risk patients and 27.1% of intermediate/poor risk patients were alive and second-line treatment-free.

Conclusion

Nivolumab monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve patients with aRCC and results in substantial TFS and TRAE-free TFS. TFS was particularly noted in patients with favourable risk disease, further supporting the use of an immunotherapy-only regimen in this population. TFS was increased by, and sustained following, elective treatment cessation at 96-108 weeks. TFS captures valuable information not contained in traditional trial endpoints.

Reference

Atkins M, et al. Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A). Presented at ASCO GU 2023; Abstract 604.