Ariad Pharmaceuticals Inc fka ARIA

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FYI: AP26113 presentation at World Conference on Lung Cancer


Session Info: Mini Oral Session, [MO11] Preclinical Models II
Day/Date: Tuesday, July 5, 2011
Session Time: 10:30 AM - 12:00 PM
Room: G106
[11:34 AM] MO11.12 | AP26113, a potent ALK inhibitor, is also active against EGFR T790M in mouse models of NSCLC
J.J. Miret, F. Wang, R. Anjum, S. Zhang, J. Keats, M. Cookson, Y. Ning, S. Wardwell, L. Moran, Q. Mohemmad, Y. Wang, J. Qi, R. Squillace, N. Narasimhan, D. Dalgarno, T. Clackson, W. Shakespeare, V. Rivera
ARIAD Pharmaceuticals/UNITED STATES OF AMERICA
Background:

Activating mutations in EGFR and anaplastic lymphoma kinase (ALK) are drivers in ~20% of all NSCLCs. First generation EGFR and ALK inhibitors are clinically efficacious, but are susceptible to mutation-based resistance creating a medical need for second-generation agents. For EGFR inhibitors, the T790M gatekeeper mutation accounts for ~50% of resistance. Potent irreversible T790M inhibitors are in development but can exhibit toxicity due to co-inhibition of native (endogenous) EGFR, suggesting that T790M-selective agents will be required. For the ALK inhibitor crizotinib, clinical resistance has been linked to the L1196M gatekeeper mutation. Previously, we have identified AP26113 as a potent ALK inhibitor that overcomes this and other mutations. A broad kinase screen revealed that AP26113 also reversibly inhibits EGFR harboring activating and T790M mutations.
Methods:

The activity of AP26113 against native, activated (L858R or delE746_A750 [DEL]), and T790M mutant (L858R/T790M or DEL/T790M) forms of EGFR was examined in NSCLC as well as engineered Ba/F3 and 3T3 cell lines. EGFR signaling was assessed by measuring levels of phosphorylated EGFR (Y1068), in vitro proliferation measured by MTS assay, and in vivo tumor growth measured in mouse xenografts following daily oral dosing.

Results:

AP26113 was essentially inactive against native EGFR, inhibiting signaling with IC50s >1000 nM in a NSCLC cell line (H358) and native EGFR-transduced Ba/F3 and 3T3 cells. In contrast, potent activity was demonstrated against activated forms of EGFR. EGFR signaling was inhibited with IC50s of 10-50 nM in HCC827 (DEL), DEL Ba/F3 and L858R 3T3 cells. In HCC827 cells, proliferation was inhibited with an IC50 of 105 nM. In an HCC827 xenograft model, doses of 25 mg/kg or greater induced tumor regression (>33%) and >90% and >60% inhibition of EGFR signaling 10 and 24 hours after dosing. Significantly, AP26113 also demonstrated potent activity against T790M mutant forms of EGFR. EGFR signaling was inhibited with IC50s of 10-63 nM in H1975 (L858R/T790M), and DEL/T790M and L858R/T790M Ba/F3 and 3T3 cells. In H1975 and DEL/T790M Ba/F3 cells proliferation was inhibited with IC50s of 85-350 nM. In an H1975 xenograft model, doses of 50 and 75 mg/kg led to significant tumor growth inhibition (=45%). In a DEL/T790M Ba/F3 xenograft model, doses of 50 and 75 mg/kg led to tumor stasis and 50% tumor regression. In both models, substantial prolonged inhibition of EGFR signaling was observed.
Conclusion:

AP26113 is a novel reversible inhibitor of activated and resistant mutants of EGFR, and does not inhibit the native enzyme. Importantly, oral doses that are efficacious in mice against activated and T790M mutant EGFR are similar to those active against native- and crizotinib-resistant ALK variants, suggesting that AP26113 is a dual ALK/mutant EGFR inhibitor. These data support clinical evaluation of AP26113 in patients with resistant EGFR-driven tumors.

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