Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma

Purpose This study is the first to compare dual inhibition of PI3K/mTOR by apitolisib (GDC-0980) against single inhibition of mTORC1 by everolimus in metastatic renal cell carcinoma (mRCC). Patients and Methods Clear cell mRCC patients who progressed on or after VEGF-targeted therapy were randomized to apitolisib (40 mg QD) or everolimus (10 mg QD). Endpoint included progression-free survival (PFS), safety, overall survival (OS), and objective response rate (ORR). Biomarker assessments were conducted. Results Eighty-five patients were randomized. After 62 events, stratified analysis revealed median PFS was significantly shorter for apitolisib than everolimus (3.7 vs. 6.1 mo: HR 2.04 [95%CI: 1.18-3.54; p<0.01]); apitolisib was not favored in any stratification subgroup. Median OS was not significantly different but trended in favor of everolimus (11.9 vs. 14.6 mo: HR 1.73 [95%CI: 0.87-3.43; p=0.12]). ORR was 7.1% for apitolisib and 11.6% for everolimus. Patients on apitolisib with greater incidences of grade 3-4 adverse events were more likely to discontinue treatment (31% vs. 12% for everolimus). No drug related deaths were observed. Apitolisib in comparison to everolimus was associated with substantially more high-grade hyperglycemia (40% vs. 7%) and rash (24% vs. 5%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High HIF1α protein expression was associated with better outcome in both arms. Conclusion This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than everolimus in mRCC, likely because full blockade of Pi3K/mTOR signaling resulted in multiple on-target adverse events. VHL mutation and HIF1α expression may be predictive of mTOR inhibitor benefit, although prospective validation is required.