Authors: Jin-Ji Yang, Liu Yang, Andrew Farnsworth, Amir Handzel, Tanya Coleman, Shethah Morgan, Yi-Long Wu
Background: Savolitinib (AZD6094, volitinib, HMPL-504) is a potent & selective small molecule MET inhibitor. In preclinical models the combination of savolitinib & gefitnib was more effective than either compound alone (D’Cruz et al, 2014; Zhou et al, 2013). EGFR TKI failure is frequently attributable to MET amplification.
Methods: The intent of the study is to test that NSCLC pts who progressed on previous EGFR-TKI treatment, can receive treatment with gefitinib & savolitinib and potentially demonstrate an improved clinical response. This study (NCT02374645) has 2 phases: safety run-in phase (n~12) & expansion phase (n~20). Eligibility requires advanced EGFRm+ NSCLC, measurable disease, adequate PS (0-1) & organ function, progression on any prior EGFR-TKI. MET status is not required for the safety run-in but MET amplification by tumor biopsy confirmation is mandatory in the expansion phase. Data from the safety run-in phase presented here are unvalidated & preliminary.
Results: As of 17 January 2016, 13pts have completed the DLT assessment with fixed dose of gefintinib 250 mg QD in combination with savolitinib at 600 mg QD (n = 6) & 800 mg QD (n = 7). No DLT in the 600mg QD cohort & a potential DLT of G3 febrile neutropenia in the 800 mg QD cohort. 11pts are evaluable for response & 12pts are evaluable for safety analysis at the data cut off. Drug-related (either gefitinib or savolitinib) adverse events most common across both dose levels were nausea (40% – G1), blood bilirubin increased (30% – G1/2), vomiting (30% – G1). Two confirmed partial responses (pts METamp neg) were reported at 12wks so far with this combination, at 18wks 1pt had PD & 1pt is ongoing. Exposure & PK parameters for gefitinib & savolitinib lie within range& align well with historical data.
Conclusions: The toxicity & PK profile of savolitinib makes rational combination with gefitinib feasible in EGFRm+ NSCLC pts who failed EGFR TKI. The expansion phase in pts with MET amplification will evaluate anti-tumor activity.
Reference: D’Cruz, C et al Cancer Res 2014;74(19 Suppl):Abstract nr 3114. Zhou, F et al Cancer Res 2013;73(8 Suppl):Abstract nr 971. Clinical trial information: NCT02374645