Tesaro didn't supply any real data at submission time. I'm sure it'll be updated.
TSR-011: A potent inhibitor of ALK with activity in crizotinib-resistant tumor models in phase 1-2 development for ALK+ NSCLC
G. Weiss(1), J.C. Sachdev(1), J.R. Infante(2), M. Mita(3), K.M. Wilcoxen(4), V. Kansra(5), D.G. Brooks(5), R.E. Martell(5), S.P. Anthony(6)
(1)Scottsdale Healthcare, Virginia Piper Cancer Center, Scottsdale AZ, USA
(2)Sarah Cannon Research Institute, Phase 1, Nashville TN, USA
(3)Cedars-Sinai Medical Center, Oncology, Los Angeles CA, USA
(4)TESARO Inc, Scientific Affairs, Waltham MA, USA
(5)TESARO Inc, Medical Research, Waltham MA, USA
(6)Evergreen Hematology & Oncology, Spokane WA, USA
Background: Significant progress has been made in treatment of the subset of non-small cell lung cancer (NSCLC) driven by the echinoderm microtubule associated protein like 4 (EML4) anaplastic lymphoma kinase (ALK) gene and other fusions. Despite approval of crizotinib for ALK+ NSCLC there are still significant challenges. In order to address limitations of crizotinib, such as resistance mutations in ALK, TSR-011, a potent, small molecule, second generation ALK inhibitor is undergoing clinical evaluation. TSR-011 was specifically designed using X-ray structure based drug design, and hence has very high affinity for the ALK kinase domain (Kd = 0.36 nanomolar, [nM]). TSR-011 inhibits wild type, recombinant ALK kinase activity with an IC50 value of 0.7nM and exhibits sustained potent inhibition of ALK-dependent tumor growth in mice. ALK amplification and mutations that are important drivers of NSCLC cell growth or crizotinib resistance are inhibited by TSR-011 at low nM (IC50 values of 0.1 to 2.2nM) concentrations. The (sub)nanomolar potency and activity against clinically observed ALK mutations of make TSR-011 a promising 2nd generation ALK inhibitor.
Methods: A Phase 1–2a dose escalation and cohort expansion study sponsored by TESARO is underway to evaluate safety, tolerability, PK, and efficacy of TSR-011. Phase 1 is evaluating patients with advanced solid tumors and lymphomas of any ALK status. The maximum tolerated or recommended Phase 2 dose will be evaluated in Phase 2a in patients required to have ALK+ tumors (defined by immunohistochemistry and fluorescent in-situ hybridization) including those with NSCLC progressing on, or naive to, ALK inhibitor therapy, as well as, non-lung malignancies. This study was approved by Institutional Review Boards of all participating institutions.
Results: As of April 2013, patients have been enrolled at doses between 30 and 480mg orally. Tumor types include ALK+ and negative NSCLC, papillary thyroid cancer and neuroendocrine tumors. Once daily dosing resulted in dose responsive pharmacokinetic parameters and human drug exposures in excess of that associated with efficacy in murine models. No DLTs or visual changes have been reported.
Conclusions: Based on tight binding to ALK, potency at inhibiting ALK enzymatic activity, activity in crizotinib resistant cellular models and early clinical data TSR-011 is a promising agent for ALK-dependent malignancies.
Conflict of interest: Ownership: TESARO, Inc. Other substantive relationships: stock ownership, employment
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