BPI20-012: Relative Risk of Various Endocrinopathies Associated With the Use of Immune Checkpoint Inhibitors in the First-Line Treatment of Advanced Renal Cell Carcinoma: a Systematic Review and Meta-Analysis

Background: While immune checkpoint inhibitors (ICI) are an important addition to the armamentarium in the fight against advanced renal cell carcinoma (aRCC), ICIs are associated with significant endocrine toxicities. We conducted a meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the risk of various endocrinopathies associated with first-line use of ICI-based regimens for the treatment of aRCC. Methods: We conducted a systematic search of PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until May 2019. We included phase 3 RCTs using ICIs 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: Four phase 3 RCTs — CheckMate 214, IMmotion151, JAVELIN Renal 101 and KEYNOTE-426 — were identified. Some studies did not report number of events for all five endocrinopathies of our interest. For hypothyroidism, all four RCTs including 3706 patients were analyzed. For hyperthyroidism and adrenal insufficiency, CheckMate 214, IMmotion151, and KEYNOTE-426 including 2833 patients were analyzed. For hypophysitis and diabetes, CheckMate 214 and KEYNOTE-426 including 1936 patients were analyzed. ICI regimens used in the study arms are — CheckMate 214: nivolumab + ipilimumab; IMmotion151: atezolizumab + bevacizumab; JAVELIN Renal 101: axitinib + avelumab; and KEYNOTE-426: axitinib + pembrolizumab. The control arms used sunitinib. The pooled RR of any grade endocrinopathies are as follows — hypothyroidism: 1.01 (95% CI: 0.68-1.50, P= 0.96, I2=91%); hyperthyroidism: 3.28 (95% CI: 2.26-4.75, P<0.00001, I2=19%); adrenal insufficiency: 19.52 (95% CI: 4.70-81.07, P<0.0001, I2=0%); hypophysitis: 22.40 (95% CI:3.00-167.45, P=0.002, I2=0%); and diabetes: 6.64(95% CI: 0.78-56.31, P=0.08, I2=0%). Conclusions: The relative risk of hyperthyroidism, adrenal insufficiency and hypophysitis were significantly higher with ICI-based regimens compared to sunitinib. Although hypothyroidism was the most commonly reported endocrinopathy in all these trials, the relative risk of hypothyroidism was not significantly higher in ICI arms compared to sunitinib arms. A careful monitoring of the endocrine functions and initiation of appropriate treatment is crucial to reduce endocrine related morbidity and mortality in these patients.

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Corresponding Author: Nusrat Jahan, MD
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