A Phase Ib Dose-Escalation Study of the Hsp90 Inhibitor Snx-5422 and Erlotinib in Patients with Egfr-Mutant Lung Cancer and Acquired Resistance to Egfr Tyrosine Kinase Inhibitors

Abstract

ABSTRACT Aim: SNX-5422 is a pro-drug of SNX-2112, a highly potent, non-geldanamycin analogue, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumour models including models of acquired resistance (AR) in EGFR-mutant lung cancer. To prevent disease flare after stopping EGFR tyrosine kinase inhibitors (TKIs) in patients (pts) with EGFR mutant lung cancer, erlotinib (E) is often continued with subsequent lines of treatment for AR. This phase IB study will determine the maximally tolerated dose (MTD) of SNX-5422 and E for pts with mutated EGFR and RECIST progression on EGFR TKIs. Methods: All pts had EGFR mutant lung cancer, with development of AR (per Jackman, JCO 2010) after treatment with an EGFR TKI. Pts underwent repeat tumour biopsies after development of AR and prior to study entry. Pts received SNX-5422 qod, 3 wks on/1 wk off, and E 150mg daily P.O. in 28-day cycles, with dose escalation using a standard 3 + 3 design. Safety and tolerability were evaluated also to determine the MTD and blood samples were obtained for pharmacokinetics. Results: Since May 2013, 17 pts were enrolled. No dose-limiting toxicities (DLTs) were reported in the first cohort (SNX-5422 50 mg/m2 + E), but DLTs (diarrhoea) were reported by 2 pts in the second cohort (SNX-5422 75 mg/m2 + E). Adverse events possibly related to the combination in ≥ 4 of 17 pts in were diarrhoea, nausea, fatigue, dry eyes, paronychia, and rash, all graded 1 or 2; except for 2 cases of grade 3 diarrhoea. No cardiovascular, renal or hepatic toxicities have been observed. 1 Pt reported mild, reversible nictalopia at the DLT level of SNX-5422 75 mg/m2 + E. Pts received a median of two cycles (range 1-6), and 3 remain on study. No partial responses have been seen in 15 evaluable pts; 1 ongoing pt had an 18% decrease from baseline in target lesions in Cycle 4. Stable disease was the best response in 4 pts at 8 wks, 3 pts at 16 weeks and 1 pt at 24 weeks. Conclusions: SNX-5422 and E is a well-tolerated combination at dose levels up to SNX-5422 50 mg/m2 qod + E 150 mg. The MTD was declared SNX-5422 50 mg/m2 + E. Disclosure: J. Hinson: I am employed by Esanex, Inc who is marketing and developing the drug in this study; E. Orlemons: I am employed by Esanex Inc who is developing the agent studied in this trial. I have financial interests including stock ownership. All other authors have declared no conflicts of interest.