Immunotherapy rechallenge in metastatic renal cell carcinoma: a meta-analysis of randomized clinical trials.

[INTRODUCTION] The rapid integration of immune checkpoint inhibitor (ICI) based combination therapies in first-line treatment of metastatic renal cell carcinoma (mRCC) is raising questions about next-line treatments and outcomes of ICI rechallenge.

[METHODS] We performed a meta-analysis using the results from the phase-III RCTs, CONTACT-03 and TiNivo-2, to evaluate the effect of adding a PD-1/PD-L1 inhibitor rechallenge to a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) vs a VEGF TKI alone in patients with mRCC who had progressed on ICI based combination therapy or ICI monotherapy.

[RESULTS] A total of 865 patients with mRCC were included in this meta-analysis. The meta-analysis showed no difference in progression free survival between ICI plus VEFG TKI combination and TKI monotherapy groups (HR = 0.96, 95% CI, 0.76-1.21; P = .75) in patients previously progressing on ICI. Furthermore, adding ICI to anti-VEGF TKI therapy was not associated with improve overall survival (HR = 1.06, 95% CI, 0.89-1.25; P = .52).

[CONCLUSION] In summary, PD-1/PD-L1 inhibitor rechallenge with a VEGF TKI in mRCC does not improve survival outcomes and should not be used in patients with prior progression to ICI. Understanding both intrinsic and acquired resistance mechanisms to ICI therapy is crucial for developing effective initial and sequential immunotherapy strategies in RCC.