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BerGenBio's Anti-AXL/PD-1 Combo Trial Boosts Confidence About Activity in SKT11-Mutated NSCLC

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NEW YORK – BerGenBio has decided to study the activity of its AXL receptor tyrosine kinase inhibitor bemcentinib with Merck's checkpoint inhibitor Keytruda (pembrolizumab) as a first-line treatment for STK11-mutated non-small cell lung cancer patients, after a similarly designed Phase II trial produced encouraging results in the second-line setting.

The Phase II BGBC008 trial, conducted by the Bergen, Norway-based company in partnership with Merck, included 90 evaluable NSCLC patients who'd had at least one prior line of chemotherapy, immunotherapy, or both and whose disease had progressed upon entering the study. The patients received bemcentinib and Keytruda until disease progression.

Median overall survival was 13.0 months, median progression-free survival was 6.2 months, and the overall response rate was 11.1 percent on the combination regimen, with more than half the patients achieving disease control. "It's with great confidence that I can say that it actually does matter to inhibit AXL, specifically, in non-small cell lung cancer," said BerGenBio CEO Martin Olin during a call Thursday morning to discuss the data. "We saw that in terms of very significant clinical benefit for the patients who received the combination of bemcentinib with pembrolizumab, in particular for patients who had an AXL [tumor proportion score] higher than five."

In this study, patients had to provide tumor samples to gauge their AXL kinase expression and PD-L1 expression. Median overall survival and progression-free survival among patients with an AXL expression tumor proportion score of higher than five was 14.8 months and 8.7 months, respectively, compared to 9.9 months and 4.6 months for those with a tumor proportion score of less than five. The median overall survival was similar regardless of PD-L1 expression status, according to the company.

Data from BGBC008 and an investigator-initiated study of bemcentinib with docetaxel in the same setting support the scientific rationale behind AXL inhibition as a therapeutic strategy in NSCLC, according to BerGenBio. Olin said treatment with chemotherapy induces oxidative stress, inflammation, and hypoxia, leading cancer cells to activate AXL, which in turn triggers the epithelial-to-mesenchymal transition and metastasis as well as resistance to DNA damage. Thus, the activation of AXL allows the cells to survive the effects of chemotherapy and also potentially develop resistance to it. And when AXL is activated in immune cells, it creates an immunosuppressive or cold tumor environment where checkpoint inhibition is no longer effective.

Based on this underlying mechanistic understanding, BerGenBio is eager to test its AXL inhibitor in STK11-mutated NSCLC. "The STK11 mutation actually creates a phenotypic environment in which AXL is expressed and activated, which is the setting where inhibition of AXL by bemcentinib has been shown to work in the [BGBC008] trial," said Olin, adding that BerGenBio believes that the mutation creates an immunosuppressive environment leading to AXL expression in around 80 percent of tumors in the first-line setting, compared to only 50 percent in the second-line setting.

According to Olin, marketing bemcentinib as a frontline therapy for STK11-mutated NSCLC patients would be a "significant market opportunity," since there are approximately 30,000 patients with this type of cancer in the US and across five large European countries. STK11 mutations are associated with a poor prognosis in NSCLC and there are currently no molecularly targeted therapies for this subset of patients.

As part of its plan to capture this market, BerGenBio has activated trial sites and begun screening patients for the Phase Ib/IIa BGBC016 trial of bemcentinib plus Keytruda and chemotherapy in the first-line non-squamous NSCLC setting. Newly diagnosed patients with any PDL-1 status are eligible. The Phase Ia portion of the trial is open to all comers, while the Phase IIa portion is enrolling only those with STK11-mutated tumors.

BerGenBio Chief Medical Officer Cristina Oliva said that the Phase IIa expansion in patients with STK11 mutations may begin while the last dose cohort is still underway in Phase Ib. Primary endpoints of the trial will be efficacy and safety, and the company is expecting a data readout in the second half of 2023. Although screening has already begun in this study, "we don't have a patient being treated at this point, but we expect it any day," said Olin.

According to Oliva, BerGenBio doesn't expect to come up against much competition in the STK11-mutated NSCLC setting, since other companies seem largely interested in developing targeted treatments for the much smaller subset of patients with both SKT11 and KRAS G12C mutations in their tumors.

BerGenBio is also studying bemcentinib with Keytruda in a Phase II trial involving previously treated NSCLC patients and single-agent bemcentinib in a Phase Ib/II trial involving patients with acute myeloid leukemia or myelodysplastic syndrome. Outside of cancer, BerGenBio is also investigating bemcentinib as a treatment for hospitalized COVID-19 patients.