SELLAS Life Sciences Group, Inc. (NASDAQ: SLS) (“SELLAS’’ or the “Company”), a late-stage clinical biopharmaceutical company focused on the development of novel therapies for a broad range of cancer indications, announced data from preclinical studies identifying ASXL1 mutation as key predictor of SLS009, a highly selective CDK9 inhibitor, response in solid cancers.
Based on elucidated biology of ASXL1 mutations, results from SELLAS’ clinical trials in acute myeloid leukemia (AML), and reports of common occurrence of ASXL1 mutations in some solid cancers, the Company performed experiments and analyses to explore the following:
The frequency of ASXL1 mutations in certain solid cancers, including colorectal carcinomas (CRC) with high level microsatellite instability (MSI-H) and non-small cell lung cancer (NSCLC)
Whether ASXL1 mutations in solid cancers may predict as high SLS009 efficacy as the efficacy exhibited in AML where ASXL1 and similar mutations demonstrated high response rates in SELLAS’ clinical trials
SELLAS performed experiments in patient derived cell lines (PDCs) exposing them to SLS009 at various concentrations and determining the inhibitory concentration (IC50) for each cell line. All cell lines were analyzed for presence of ASXL1 mutations and other genetic markers. High efficacy was prespecified as IC50 < 100 nM, significantly lower than the standard threshold definition for an effective compound (IC50 < 1,000 nM). This threshold was chosen based on the observed long-lasting concentrations of SLS009 observed in patients, which were ~400 nM.
Negative controls consisted of untreated cell lines, while active negative control varying concentrations of revumenib (drug used in hematologic malignancies). Positive controls involved cell lines treated with staurosporine at different concentrations (staurosporine is a standard control compound for kinase inhibitors due to its high broad-spectrum potency in inhibiting most protein kinases at sub-micromolar concentrations).
The results were as follows:
In CRC MSI-H, ASXL1 mutations were observed in 7/12 (58%) of PDCs, aligning with predicted frequency of ~55%
In NSCLC, ASXL1 mutations occurred in 2/6 (33%) studied cell lines, higher than predicted 2.6%
Overall, in 18 studied solid cancer cell lines, ASXL1 mutations were recorded in 9 cell lines and no ASXL1 mutations were recorded in 9 cell lines which were designated as control
In ASXL1 mutated cell lines, high SLS009 efficacy (IC50 <100 nM) was observed in 6/9 (67%) solid cancer cell lines and in non-ASXL1 mutated cancer high SLS009 efficacy was observed in 0/9 (0%) of studied solid cancer cell lines
In CRC MSI-H, high efficacy (IC50 <100 nM) was observed in 4/7 (57%) of ASXL1 mutated cell lines and in 0/5 (0%) of non-ASXL1 mutated cell lines
In NSCLC, high efficacy (IC50 <100 nM) was observed in 2/2 (100%) of ASXL1 mutated cell lines and in 0/4 (0%) of non-ASXL1 mutated cell lines
No activity was observed in any of the studied cell lines with revumenib (negative control) at any concentration
Staurosporine activity was confirmed, but interestingly and importantly, SLS009 outperformed positive control staurosporine in 5/9 cell lines
“These findings are incredibly encouraging and validate our approach to developing a targeted solid tumor therapy. We are excited that our hypotheses were confirmed, marking, to the best of our knowledge, the first study to advance the identification of ASXL1 mutations as a potential biomarker for a drug response in solid cancers,” said Dr. Dragan Cicic, Senior Vice President, Chief Development Officer at SELLAS. “Our experiments show that SLS009 demonstrates high efficacy with low IC50 values and with 67% of mutated cell lines responding positively, compared to no response in non-mutated cell lines. In addition, SLS009 outperformed positive control in 5 out of 9 cell lines, establishing itself as a highly effective therapeutic candidate. These critical findings are the missing pieces, complementing our existing safety and efficacy data in AML, and positions us strongly with SLS009 in solid cancers.”
SELLAS has filed for provisional patent protection for the use of ASXL1 mutations as predictive diagnostic for selection of cancer patients likely to benefit based on clinical data and biology.
