Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study

Abstract

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS_2-3 ). Key secondary endpoints included overall survival from second line (OS₂ ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS_2-3 and OS₂ , NC sequence was superior to CN (PFS_2-3 : HR = 0.58 [0.34-0.98], P = .043; OS₂ : 0.66 [0.42-1.05], P = .080). Superior PFS_2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFS_L3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.

Keywords: cabozantinib; immunotherapy; matching-adjusted study; nivolumab; renal cell carcinoma; tyrosine kinase inhibitor.

FIGURE 1

Progression‐free survival from L2 to L3 (PFS2‐3) in matched (1:1) population. Kaplan‐Meier curve of progression‐free‐survival from second line to third line in matched (1:1) population (n = 38). The red curve represents the cabozantinib‐nivolumab (CN) sequence and the blue curve represents the nivolumab‐cabozantinib (NC) sequence [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Forest plot of sequence effect (PFS2‐3 and OS2) in different models. Forest plot representing the effect of cabozantinib‐nivolumab (CN) and nivolumab‐cabozantinib (NC) sequences on progression‐free‐survival from line 2 to line 3 (PFS_2‐3) and on overall survival from line 2 (OS₂), according to the following models: all patients (n = 139), all patient with adjustment on propensity score (PrS, n = 139), 1:1 matched population (n = 38), 1:2 matched population (n = 76). Hazard ratio below 1 favors the NC sequence [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Progression‐free survival (PFS) in second and third lines. Kaplan‐Meier curves of progression‐free‐survival (PFS) in second (A) and third line (B). The red curve represents the cabozantinib‐nivolumab (CN) sequence and the blue curve represents the nivolumab‐cabozantinib (NC) sequence [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Objective response rate (ORR) during second and third lines. Histogram representing the objective response rate (RECIST 1.1) with cabozantinib and nivolumab in second (left) and third line (right) in matched (1:1) population (n = 38). Green bars represent responders (complete and partial), dark blue bars represent nonresponders (progression and stable disease) and light blue bars represent nonevaluable patients. CN, cabozantinib‐nivolumab; NC, nivolumab‐cabozantinib [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

Forest plot of sequence effect (PFS2‐3) by subgroups. Forest plot representing the effect of cabozantinib‐nivolumab (CN) and nivolumab‐cabozantinib (NC) sequences on progression‐free‐survival (PFS) from line 2 to line 3, according to frontline VEGFR‐TKI duration (<6 months, 6‐18 months and >18 months) in the following models: all patients, 1:1 matched population, 1:2 matched population. Hazard ratio below 1 favors the NC sequence [Color figure can be viewed at wileyonlinelibrary.com]