Dose Reductions With Cabozantinib Associated With Improved Efficacy Outcomes

A surrogate for toxicity and drug exposure, cabozantinib dose reductions were tied to longer durations of time to treatment failure and overall survival for patients with metastatic renal cell carcinoma.

Results presented at the 2022 Genitourinary Cancers Symposium indicated that better time to treatment failure (TTF) and overall survival (OS) outcomes in patients with metastatic renal cell carcinoma (mRCC) were linked with dose reductions of cabozantinib.

Data collected from the Canadian Kidney Cancer Information System database were presented at the by Jeffrey Graham, MD, professor, Department of Internal Medicine, section of Hematology/Oncology University of Manitoba, Canada, and suggest that toxicity could serve as an indicator of sufficient drug exposure.

In 260 patients, 103 (39.6%) needed cabozantinib dose reduction (DR), defined as less than the starting dose at the time of treatment discontinuation. Investigators divided the patients into 2 cohorts: a DR group and a no-DR group across lines of treatment.

When stratified by DR status, overall median TTF for the DR group was 13.3 months (95% CI, 10.5-20.0) vs 7.4 months (95% CI, 5.7-9.4) in the no-DR group (P = .1976). Overall median OS for the DR group was 27.4 months (95% CI, 19.0-29.7) compared with 15.2 months (95% CI, 10.4-21.1; P = .003) for the no-DR group. Objective response rates (ORR) were 19.6% and 18.9% for the DR and no-DR groups, respectively.

Researchers compared DR status through TTF, OS, ORR, and reported outcomes by line of therapy and throughout the whole patient population.

Median OS for each treatment line also favored the DR groups. The second line showed a median OS of 45.1 months (95% CI, 13.3-51.4), the third line had 22.1 months (95% CI, 13.6-29.7), the fourth line had 27.9 months (95% CI 11.2-42.6), and the fifth line had 26.2 months (95% CI, 9.7-54.4). Among the no-DR groups, the median TTF was 9.9 months (95% CI, 5.4-17.2) in the second line, 15.2 months (95% CI, 8.2-22.6) in the third line, 20.8 months (95% CI, 10.8-not reached [NR]) in the fourth line, and 18.8 months (95% CI, .062-27.4) in the fifth line.

Within each treatment line, the median TTFs for the second line was 12.5 months (95% CI, 7.9-32.2) vs 6.2 months (95% CI, 3.4-30.1) for the DR and no-DR groups, respectively. In the third line, the DR group had a TTF of 11.6 months (95% CI, 6.5-16.9) compared with 6.4 months (95% CI, 5.5-11.0) in the no-DR group. The TTF in the fourth line was 17.7 months (95% CI, 5.8-27.2) vs 9.4 months (95% CI, 6.2- NR) for the no-DR group, and the fifth line had a median TTF was 20.0 months (95% CI, 5.6-53.4) vs 4.5 months (95% CI, .03-NR) for the DR and no-DR groups, respectively.

Patients were 76.2% male, and 71.2% were 65 years or younger. For each line of treatment with cabozantinib, 59 patients (22.7%) received it in the second line, 116 (44.6%) received it in the third line, 58 (22.3%) received it in the fourth line, and 28 (10.8%) received it in the fifth line. According to International Metastatic RCC Database Consortium risk group criteria, 27 patients (10.4%) were favorable risk, 138 patients (53.5%) were intermediate risk, and 58 patients (22.3%) were poor risk.

Regarding RCC histology, the majority of patients had clear cell (70.8%), papillary (8.5%), and unclassified RCC (7.3%) malignancies.

DR vs no-DR OS by multivariable analysis had an overall hazard ratio (HR) of 0.68 (95% CI, 0.448-.97; P = 0.0338). DR vs no-DR TTF by multivariable analysis had an overall HR of 0.78 (95% CI, 0.56-1.09; P = 0.1396).

Investigators concluded toxicity driven and individualized dosing strategies for cabozantinib as monotherapy and in combination with immunotherapy in patients with mRCC warrant further investigation.

Reference

Graham J, Basappa N, Ghosh S, et al. Association of cabozantinib dose reductions for toxicity with clinical effectiveness in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis). Poster presented at the 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, CA. Accessed February 19, 2022. doi: 10.1200/JCO.2022.40.6_suppl.316