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A randomized phase II study of GDC-0980 versus everolimus in metastatic renal cell carcinoma (mRCC) patients (pts) after VEGF-targeted therapy (VEGF-TT).
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: GDC-0980 (G) is a potent oral dual pan-PI3K and mTOR (TORC1/2) inhibitor that has been evaluated in multiple solid tumors in Phase I and II. Everolimus (E) inhibits TORC1 and is active in mRCC post VEGF-TT. This study is the first to dirctly test if a PI3K/mTOR inhibitor may improve efficacy over a TORC1 inhibitor. Methods: Clear cell mRCC pts who progressed on or after VEGF-TT were randomized (1:1) to G (40 mg QD) or E (10 mg QD), stratified by MSKCC score and time to progression on first VEGF-TT (≤ or > 6 months). The primary endpoint was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), objective response rate (ORR); and pharmacokinetic (PK) and biomarker correlation with safety and efficacy were exploratory. Results: Eighty-five pts were randomized (G 42:E 43). After 62 events (G 32:E 30), stratified analysis revealed the median PFS was significantly shorter for G than E (3.7 vs. 6.1 mo: HR 2.04 [95%CI: 1.18-3.54; p<0.01]) and did not favor G for any stratification subgroup. Median OS was not significantly different but trended in favor of E (11.9 vs. 14.6 mo: HR 1.73 [95%CI: 0.87-3.43; p=0.12]). ORR was 7.1% for G and 11.6% for E. Patients treated with G had greater incidence of Grade 3-4 adverse events (AEs) and were more likely to discontinue treatment because of an AE (G 31%:E 12%). G was associated with substantially more high-grade hyperglycemia (G 40%:E 7%) and rash (G 24%:E 5%). PK analyses of G suggest a relationship between exposure and safety (rash and hyperglycemia), but no clear exposure-efficacy relationship. Retrospective biomarker analyses from archived tissue revealed a relationship between VHL mutation status (by NGS) and outcome with E but not G. High HIF1A protein expression was associated with better outcome in both arms. Conclusions: This study was unable to demonstrate that inhibition of PI3K/TORC1/TORC2 with GDC-0980 provides any benefit over inhibition of TORC1 alone with everolimus. This may be due to the high rate of AEs associated with potent pathway inhibition. VHL mutation and HIF1A expression may be predictive of mTOR inhibitor benefit, though future prospective validation is required. Clinical trial information: NCT01442090.
Abstracts by Thomas Powles:
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