Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.

Abstract

e19005 Background: Ultimately, the majority of anaplastic lymphoma kinase (ALK) rearranged (+) non-small cell lung cancers (NSCLC) are either unresponsive to crizotinib or develop resistance mutations. Similarly, gene rearrangements in NTRK1 have been identified as a potentially actionable oncogenic aberration. TSR-011 inhibits ALK and tropomyosin-related kinase (TRK) A, B, and C receptor activity with IC50 values < 3 nM and exhibits inhibition of oncogenic echinoderm microtubule associated protein like 4 (EML4)-ALK and tropomyosin (TPM)-TRKA dependent tumor growth in mice. Methods: A Ph 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Ph 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Ph 2 dose will be evaluated in Ph 2a in patients with ALK+ or TRK ligand/receptor + tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy. Results: Twenty-three patients with advanced cancer have been enrolled at oral total daily doses between 30 and 480 mg, including NSCLC (n=10, including 5 ALK+), pancreatic (3), ovarian (2), salivary gland (2) and 1 each with papillary thyroid, cholangiocarcinoma, bladder, carcinoid, colon & leiomyosarcoma. Bi-exponential PK was observed, with dose proportional Cmax and AUC and t1/2 of 12-24 h. Dose-limiting toxicities included dysaesthesia and QTc prolongation; MTD has been defined. PK modeling revealed that a fractionated dose of 60 mg daily (dose expansion cohort) minimizes peak exposure and achieves sustained trough concentrations well above the IC50 for ALK inhibition. Of 5 patients with ALK+ NSCLC, 3 (all crizotinib-resistant) achieved PR (1 met RECIST criteria and 2 had non-measurable disease, so not formally RECIST-classified) 1 is early (not imaged yet), and 1 discontinued for DLT. Stable disease was observed in ALK- papillary thyroid, pancreatic and colorectal patients. Conclusions: TSR-011 is a well-tolerated promising second-generation agent for ALK-dependent and crizotinib resistant NSCLC, and is being explored in ALK+ and TRK+ tumors. Clinical trial information: NCT02048488.