New Drug Effective Against Treatment-Resistant Non-Small Cell Lung Cancer (NSCLC)

Posted by Dr. Guneet Walia on November 20th, 2014

Researchers from Japan presented promising new data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain on a new oral drug called ASP8273 that caused significant tumor shrinkage in non small cell lung cancer (NSCLC) patients with activating mutations in the Epidermal Growth Factor Receptor (EGFR) as well as those that had the drug resistant T790M mutant EGFR.

EGFR is a key driver of large percentage of NSCLCs, with 30-35% of Asian NSCLC and 10-15% of Caucasian patients harboring mutations in this gene. Tyrosine kinase inhibitors or TKIs such as erlotinib, gefitinib and afatinib are drugs that target EGFR, and are effective in treating these patients, however, a majority of these cancers develop resistance to therapy over time. Upto 60% of these patients acquire a new mutation in EGFR, the T790M mutation, in their tumors that makes these cancers unresponsive to therapy, necessitating potent new drugs effective against these treatment-resistant tumors.

Second generation EGFR inhibitors target the T790M mutation, however, their clinical efficacy in NSCLC patients with the T790M mutation is limited. These second generation drugs have severe side effects caused by their concomitant inhibition of the normal/non-mutant/wild type EGFR in addition to inhibiting the EGFR mutants.

ASP8273 is a third-generation EGFR inhibitor that overcomes this shortcoming of the second gen drugs. The experimental drug ASP8273 is an orally available (can be taken by mouth), irreversible (designed to block EGFR permanently), EGFR inhibitor that covalently binds to the EGFR mutant protein as well as the T790M drug resistant mutant, preventing their downstream signaling and pro-cancer activity, and has minimal effects on normal/wild type EGFR, thereby minimizing the chances of harmful side effects in patients.

There are currently two other third-gen EGFR inhibitors under development, the experimental AZ9291 and CO-1686 (Roceletinib) compounds that are currently in clinical trials for treating NSCLC patients with drug resistant T790M mutations.

Given its promising preclinical activity, a phase I clinical trial of ASP8273 was launched in January 2014 to evaluate the drug’s efficacy and safety in NSCLC patients whose disease had progressed on prior tyrosine kinase inhibitor therapy, most on whom had the T790M mutation in their tumors. Preliminary results of this phase I clinical trial conducted by researchers in Japan in these patients showed a 78% overall response rate with seven out of nine patients presenting with tumor shrinkage.

The most common adverse reactions to ASP8273 were mild cases of diarrhea (in half of the patients), nausea, and vomiting (in a third of the patients). There were none of the severe respiratory complications, heart problems and high blood sugar levels that have occurred during the clinical trials of the other two drugs, AZ9291 and CO1686.

The phase I efficacy, safety and tolerability study of ASP8273 in NSCLC patients with mutations in EGFR continues to recruit patients and is estimated to end in December 2016.

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