Limitations
tumors
TUMORS
Inherent to small phase I/II studies, the main limitations of this clinical trial include small number of patients, single-arm design with no comparator treatment arm, and absence of randomization. Another limitation is the heterogeneity of the patients included in this study. Because of demonstrated activity of cabozantinib in both ccRCC and nccRCC, we included patients with both histologic subtypes. This may have diluted out the true ORR of this combination in ccRCC tumors alone. However, although numbers of patients with nccRCC were small and no formal conclusions can be made, a response rate of 50% (3/6) gave us insight into potential activity of this CPI-TKI combination in nccRCC. These results are consistent with those of the phase II KEYNOTE-B61 study of 147 untreated patients with metastatic nccRCC which showed promising results of ORR 47.6%, DCR 79.3%, 6-month PFS 72.3%, 6-month OS 87.8% (Our study was initially designed with historical comparisons with single-agent cabozantinib. As cabozantinib monotherapy has approval in both 1 L and ≥2 L settings for mRCC, we also included patients regardless of line of therapy. As ORR is expected to be highest with 1 L and lower with 2 L therapies, combining these cohorts could have overestimated the response in the 2 L setting and underestimated the response in the 1 L setting. What we observed was ORR of 65.8% in all response-evaluable patients, ORR 73.3% (11/15 patients) in 1 L and ORR 56% (14/25 patients) in the 2 L setting, which is similar to the reported ORR with other combinations in 1 L or 2 L settings, and higher when compared with cabozantinib alone in these settings.