Target categories

STX-478 is a wild-type-sparing, CNS-penetrant, oral inhibitor of mutant PI3Kα.

It has been designed to improve outcomes in patients with PI3Kα mutations, which are among the most prevalent drivers of cancer, occurring in over 166,000 patients per year with breast, gynecological and head and neck cancers in the United States alone.

The Phase 1/2 clinical trial will evaluate STX-478 as a monotherapy and in combination with approved agents in patients with HR+/HER2- breast cancer, as well as a monotherapy in advanced solid tumors including gynecological cancers, head and neck squamous cell carcinoma among others.

Currently available treatments for PI3Kα-mutated cancers are limited by their inhibition of the normal, or wild-type, version of PI3Kα in healthy tissues that can lead to significant side effects such as diarrhea and rash, which hinder the ability of patients to tolerate these therapies long-term. Further, these treatments also have little to no CNS penetrance, even though up to 50% of all solid tumor patients develop significant morbidity and mortality from brain metastases.

We have demonstrated excellent in vitro selectivity in multiple preclinical studies and dose-dependent anti-tumor activity in animal models at well-tolerated doses without causing metabolic dysregulation that leads to hyperglycemia — a key challenge associated with targeting this mutation.

STX-721 is designed to selectively target exon 20 insertion mutations in EGFR, a well-known, clinically validated driver oncogene in non-small cell lung cancer (“NSCLC”). 

EGFR exon 20 insertion mutations have been validated as bona fide drivers of cancer development through numerous preclinical studies and clinical trials published by third parties.

While commercially available small molecules have been able to inhibit most EGFR mutations, exon 20 insertion mutations that change the structure of the protein and force it in an activated state are generally resistant to these agents, leaving those patients with a much poorer prognosis. STX-721 exhibits a selectivity profile that could translate into higher response rates and lower toxicities than are associated with other compounds targeting exon 20 insertion mutant EGFR-driven NSCLC.

We have demonstrated superior selectivity in multiple head-to-head preclinical studies versus other agents, and dose-dependent anti-tumor activity in xenograft models at well-tolerated doses.

STX-241 is designed to inhibit EGFR with exon 19 deletion or exon 21 mutations and a co-occurring C797S mutation (“double mutant”) in non-small cell lung cancer (“NSCLC”).

Up to 12.5 percent of NSCLC patients treated with the front-line standard-of-care therapy osimertinib, or approximately 3,000 people each year in the United States, acquire resistance mutations at C797S, for which there are currently no approved therapies.¹

As use of the currently approved therapy in first line EGFR-mutated NSCLC increases, mutations at C797S are expected to increase in parallel, creating a growing need for a fourth-generation EGFR TKI that can be used to treat this patient population. In preclinical studies, STX-241 demonstrated potential best-in-class mutant vs. wild-type selectivity for the EGFR exon 19/C797S and EGFR exon 21/C797S double mutations when compared to key reference benchmarks, which could translate into a wide therapeutic index. In addition, treatment with STX-241 demonstrated tumor regressions in animal models and favorable CNS penetration.

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¹Ramalingam S. (2022, August 6-9). Real-World Landscape of EGFR C797X Mutation as a Resistance Mechanism to Osimertinib in NSCLC. [Oral presentation]. 2022 World Conference on Lung Cancer, Vienna, Austria.

Targets include mutant cancer drivers

Targets are novel synthetic lethal proteins & transcription factors, including those part of our collaboration with AstraZeneca

Targets exploit common loss-of-heterozygosity (LOH) events, amongst other categories