SELLAS Reveals ASXL1 Mutations Predict Response to SLS009 in Solid Cancers

On November 27, 2024, SELLAS Life Sciences Group, Inc. (NASDAQ: SLS), a late-stage clinical biopharmaceutical company devoted to pioneering novel cancer therapies, unveiled data from preclinical studies that spotlight ASXL1 mutation as a significant predictor of the response to SLS009, a highly selective CDK9 inhibitor, in solid cancers.

This announcement is built upon the biological understanding of ASXL1 mutations, clinical trial outcomes in acute myeloid leukemia (AML), and the documented prevalence of ASXL1 mutations in some solid tumors. SELLAS embarked on experiments to investigate:

1. The prevalence of ASXL1 mutations in specific solid cancers, such as colorectal carcinomas (CRC) with high microsatellite instability (MSI-H) and non-small cell lung cancer (NSCLC).
2. Whether ASXL1 mutations in solid cancers could forecast a high efficacy of SLS009, similar to results observed in AML clinical trials where ASXL1 mutations showed significant response rates.

To conduct these investigations, SELLAS utilized patient-derived cell lines (PDCs) and exposed them to various concentrations of SLS009, determining the inhibitory concentration (IC50) for each line. The presence of ASXL1 mutations and other genetic markers were analyzed. High efficacy was defined as IC50 values below 100 nanomolar.

Control experiments included untreated cell lines and varied concentrations of revumenib, a drug used in hematologic malignancies, as an active negative control. Staurosporine, known for its broad-spectrum kinase inhibition, served as a positive control.

The experimental findings were notable:
- In CRC MSI-H, ASXL1 mutations were detected in 7 out of 12 (58%) PDCs, consistent with the predicted ~55% frequency.
- In NSCLC, ASXL1 mutations were found in 2 out of 6 (33%) cell lines, surpassing the predicted 2.6%.
- Across 18 solid cancer cell lines, ASXL1 mutations were present in 9 cell lines, while the other 9 cell lines without these mutations were used as controls.
- High SLS009 efficacy (IC50 < 100 nanomolar) was observed in ASXL1 mutated cell lines, specifically 67% in CRC MSI-H and NSCLC, compared to no activity in non-mutated lines.

Revumenib showed no activity in any studied cell lines, regardless of concentration. Staurosporine's activity was confirmed, yet SLS009 exceeded staurosporine's efficacy in 5 out of 9 cell lines tested.

Dr. Dragan Cicic, Senior Vice President and Chief Development Officer at SELLAS, expressed enthusiasm over these findings, stating, “These results are extremely promising and affirm our strategy to develop targeted solid tumor therapies. The confirmation of our hypotheses represents the initial study advancing ASXL1 mutations as a potential biomarker for drug response in solid cancers."

The study demonstrated that SLS009 has high efficacy with low IC50 values, with 67% of ASXL1 mutated cell lines responding positively, compared to no response in non-mutated cell lines. SLS009 also outperformed the positive control in 5 of 9 cell lines, solidifying its status as a potent therapeutic candidate. These outcomes, combined with existing safety and efficacy data in AML, position SELLAS favorably with SLS009 in treating solid cancers.

SELLAS has filed for provisional patent protection for using ASXL1 mutations as a predictive diagnostic tool to identify cancer patients likely to benefit from SLS009, based on clinical data and biological insights.

SELLAS is advancing its lead product, GPS, licensed from Memorial Sloan Kettering Cancer Center, targeting the WT1 protein found in various tumor types. GPS holds potential as a monotherapy and in combination with other treatments for a wide range of hematologic and solid tumors. The company is also developing SLS009, a small molecule CDK9 inhibitor with reduced toxicity and enhanced potency compared to other CDK9 inhibitors, showing high response rates in AML patients with poor prognostic factors like ASXL1 mutations.