1343 - Treatment-related adverse events and tolerability in patients with advanced renal cell carcinoma treated with first-line combination therapy with checkpoint inhibitors

Background

Inhibition of vascular endothelial growth factor (VEGF) has shown antiangiogenic effects and immunomodulatory effects through enhancing tumor infiltration of immune cells in advanced renal cell carcinoma (RCC). Combination of checkpoint inhibitors with targeted therapy has synergistic antitumor activities and recent studies have demonstrated survival benefits. Yet, there are notable safety concerns. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of treatment-related adverse events (TRAE) and treatment discontinuation due to TRAE.

Methods

PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019 were queried. RCTs utilizing upfront checkpoint inhibitors combination therapy in patients with advanced RCC were incorporated. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI).

Results

4 phase III RCTs including 3758 patients with advanced RCC were eligible. The study arm used nivolumab+ ipilimumab, pembrolizumab+ axitinib, avelumab+ axitinib or atezolizumab+ bevacizumab while control arm utilized sunitinib. The randomization ratio was 1:1 in all studies. The pooled RR of any-grade TRAE was significant at 0.97 (95% CI: 0.95 –0.99, P = 0.007) and RR of high-grade TRAE was 0.88 (95% CI: 0.72 –1.09, P = 0.24). Treatment discontinuation due to TRAE was reported in 314 (16.84%) vs 200 (10.75%) in control group with RR of 1.43 (95% CI: 0.79 –2.57, P = 0.23). Treatment-related deaths were noted in 20 (1.07%) in study arm vs 13 (0.70%) in control arm. The pooled RR was not significant at 1.57 (95% CI: 0.62 –4.01, P = 0.34).

Conclusions

The risk of developing any-grade TRAE was reduced in upfront checkpoint inhibitors combination arm compared to standard sunitinib group, favoring combination therapy. Moreover, no increase in the risk of treatment related deaths as well treatment discontinuation due to TRAE was noted in the study arm.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Kyaw Zin Thein.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.