AP32788 is an experimental drug for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer and one that accounts for about 85 percent of all  cases diagnosed in the U.S. The treatment, being developed by Ariad Pharmaceuticals, is a tyrosine kinase inhibitor (TKI) for NSCLC patients with specific mutations in the EGFR or HER2 genes.

Mutations in the EGFR gene are estimated to be present in up to half of all lung cancers. The EGFR gene provides information on how to make a protein within the cell membrane, information that aids in cell division and growth. A mutation in this gene can result in protein production that is consistently activated or “turned on” so that cells are continuously being encouraged to proliferate — or divide and grow beyond what is healthy — leading to a tumor. About 15% of NSCLC patients in the U.S. have EGFR mutations.

The HER2 gene (also known as ERBB2 gene) encodes a member of the epidermal growth factor receptor family of receptor tyrosine kinases. Mutations in this gene are more frequently observed in younger patients with NSCLC lung cancer with no history of smoking.

How AP32788 works

AP32788 works by targeting NSCLC caused by mutations in the EGFR or HER2 gene, and was designed to selectively stop kinases (enzymes that modify other proteins) with mutations in a region of the gene called exon 20. Exon 20 mutations in the EGFR gene are found in 4% to 9% of people with NSCLC, while HER2 mutations account for 2% percent of NSCLC lung cancers, and most of these are exon 20 insertion mutations. Currently, these patients have few treatment options.

AP32788 research

A Phase 1/2 study (NCT0271611) is currently recruiting NSCLC patients to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral AP32788. This study is being conducted in two parts: a dose escalation phase followed by an expansion phase. The objective of the dose escalation phase is to determine the safety profile of AP32788, including the maximum tolerated dose, dose limiting toxicities, a recommended dose for Phase 2, and the drug’s pharmacokinetic profile (how a drug is absorbed, distributed and metabolized in the body). Once a Phase 2 dose is determined, the expansion phase will begin, and evaluate the anti-tumor activity of AP32788 in four groups of people with NSCLC:

• People with NSCLC and EGFR exon 20 activating insertions with no active, measurable central nervous system (CNS) metastases
• People with NSCLC with HER2 exon 20 activating insertions or point mutations with no active, measurable CNS metastases
• People with NSCLC with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases
• NSCLC with other targets against which AP32788 has shown preclinical activity, and other uncommon EGFR activating mutations with or without active, measurable CNS metastases

The trial is expected to finish in October 2019. The expansion phase has set overall response rate, at 24 months after first treatment, as its primary goal. The trial is taking place at seven sites across the U.S. and all are currently enrolling patients.

Preclinical study results in engineered cell lines showed that AP32788 inhibited all EGFR and HER2 mutations, including exon 20 insertion mutations. AP32788 also induced tumor regressions in a mouse model of NSCLC with EGFR exon 20 mutations at doses that were well-tolerated.

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