Post-Hoc Analysis Shows Adverse Events With First-line Nivolumab Plus Cabozantinib Are Manageable

When comparing nivolumab (Opdivo) plus cabozantinib (Cometriq) vs sunitinib (Sutent) in the first-line setting for patients with advanced renal cell carcinoma (RCC) the safety profile of the combination therapy was manageable and a majority of grade 3 or more adverse events (AEs) were resolved along with stronger efficacy outcomes, according to research presented at the 2021 International Kidney Cancer Symposium (IKCS).¹

In a post-hoc exploratory analysis of the phase 3 open-label CheckMate 9ER (NCT03141177) trial where 651 patients with advanced RCC were randomized to either the combination of nivolumab plus cabozantinib or sunitinib alone, researchers found that 310 patients in the combination arm had any grade treatment-related AE’s compared to 298 patients in the monotherapy arm.

Moreover, 199 patients in the combination arm had grade 3 or higher AEs compared to 199 in the sunitinib arm, but no patients in the combination arm had grade 5 treatment related AEs. However, there was 1 fatal grade 4 treatment related AE in the combination arm due to small-intestine perforation compared to 2 fatal treatment-related AEs for patients on sunitinib due to grade 5 respiratory distress and grade 4 pneumonia.

To manage these AEs, researchers used dose delays and reductions of treatment and the use of corticosteroids and most patients with at least 1 dose delay or reduction continued therapy in both arms. In comparison of the 2 arms, patients on the combination arm had a longer time to dose reduction or delay in comparison to patients on sunitinib.

Overall, patients on the combination of nivolumab and cabozantinib had a median of 4.1 weeks before a delay and 4.9 weeks before the first dose reduction. In comparison, patients on the sunitinib arm had a median of 1.1 weeks to the first dose delay and a median of 4 weeks till the first dose reduction. When looking at the data overall, there was a median time of 3.6 weeks to either dose delay or reduction for patients in the combination vs 1.7 weeks for patients on the monotherapy.

“Frequencies of dose reductions and dose delays were largely balanced between treatment arms among patients with grade ≥ 3 treatment-related AEs, and almost all patients with at least 1 dose delay or reduction were able to subsequently continue therapy in both treatment arms,” the researchers wrote.

Twenty-six percent of patients in the combination arm with grade 3 or greater treatment related AEs received corticosteroids at about 40 mg or more daily. Ten percent of patients who received the corticosteroids continuously for at least 2 weeks and 4.5% of them received corticosteroids for at least 30 days.

The analysis did not look for significance in the differences between onset of AE to its resolution between both treatment populations. In the nivolumab and cabozantinib arm the shortest median time to onset of the AE was the decreased neutrophil count at 2.3 weeks with a median time to resolution of 6.1 weeks, whereas the shortest time to resolution was 3 weeks for patients who experienced diarrhea. In the monotherapy arm these were similar results.

For the patients who with grade 3 or more treatment-related AEs their time to response on the treatment was also shorter and the overall response rate (ORR) was 55.3% in the combination arm compared to 31.5% in the sunitinib arm. The median time to response in the combination arm was 2.8 months compared to 4.3 months in the monotherapy arm.

“Data reported in this post hoc analysis help better inform the timely detection and proactive management of AEs that may occur with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced RCC,” the researchers concluded.

_References

_{Kessler E., Burotto M, Shah A, et al. Outcomes with first-line nivolumab plus cabozantinib versus sunitinibin patients with advanced renal cell carcinoma and treatment-related adverse event timing/management in CheckMate 9ER. Presented at: International Kidney Cancer Symposium, November 5-6, 2021.}