BPI20-013: A Systematic Review and Meta-Analysis on Mucocutaneous Toxicities Associated With Upfront Use of Immune Checkpoint Inhibitor and Anti-Angiogenic Tyrosine Kinase Inhibitor Combinations for Advanced Renal Cell Carcinoma

Background: In recent clinical trials, immune checkpoint inhibitor (ICI) and anti-angiogenic tyrosine kinase inhibitor (VEGFi) combinations have shown superior outcomes compared to the previous standard of care sunitinib as the first-line treatment for advanced renal cell carcinoma (aRCC). When used individually, both ICIs and VEGFis have significant mucocutaneous toxicities. We performed a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of different mucocutaneous toxicities associated with ICI and VEGFi combinations in first-line treatment of aRCC. Methods: We conducted a systematic search in PUBMED, MEDLINE, EMBASE, and meeting Abstracts as per PRISMA guidelines from inception until May 2019. We included phase 3 RCTs using ICI and VEGFi combinations in the intervention arm for the first-line treatment of aRCC. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2-value. Results: Two RCTs, JAVELIN Renal 101 and KEYNOTE-426, randomizing 1727 patients (863 in the intervention arms and 864 in the control arms) were included in the final analysis. JAVELIN Renal 101 used avelumab and axitinib and KEYNOTE-426 used pembrolizumab and axitinib combination in the intervention arms, while sunitinib was used in the control arms for both studies. The randomization was 1:1 in both studies. The pooled RR of any-grade mucocutaneous toxicities are as follows — palmar-plantar erythrodysesthesia (PPE): 0.83 (95% CI: 0.59-1.17, P = 0.29, I2 = 85%); rash: 1.28 (95% CI: 1.00-1.65, P = 0.05, I2 = 0%); pruritus: 2.68 (95% CI: 1.94-3.70, P < 0.00001, I2 = 0%); and stomatitis: 0.87 (95% CI: 0.65-1.17, P = 0.36, I2 = 58%). The pooled RR of grade 3 and higher mucocutaneous toxicities are as follows — PPE: 1.35 (95% CI: 0.88-2.06, P = 0.17, I2 = 0% ); rash: 0.76 (95% CI: 0.17-3.46, P = 0.72, I2 = 0%); stomatitis: 0.83 (95% CI: 0.14-4.93, P = 0.84, I2 = 75%). Conclusions: ICI and VEGFi combinations are associated with increased risk of any-grade pruritus and rash compared to sunitinib. However, two more serious mucocutaneous toxicities, PPE and stomatitis, were not significantly different between ICI and VEGFi combination arms and sunitinib arms.

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Corresponding Author: Nusrat Jahan, MD
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