AXL inhibitor bemcentinib deserves further attention in advanced NSCLC
medwireNews: The oral selective AXL inhibitor bemcentinib is well-tolerated and clinically active when combined with pembrolizumab to treat immunotherapy-naïve or refractory advanced non-small-cell lung cancer (NSCLC), phase 2 study data show.
The findings, presented at the IASLC 2020 World Conference on Lung Cancer, “support further development of AXL inhibition with bemcentinib to extend the efficacy of immunotherapy in biomarker-selected refractory NSCLC,” said study investigator Matthew Krebs, from The University of Manchester in the UK.
He explained that “AXL is a mediator of resistance to immunotherapy and a negative prognostic factor for NSCLC.” In mouse models, bemcentinib has been shown to reverse tumor epithelial–mesenchymal transition, repolarize tumor-associated macrophages, and enhance checkpoint inhibitor (CPI) efficacy.
The BGBC008 study investigated treatment with bemcentinib 200 mg/day plus pembrolizumab 200 mg every 3 weeks in 48 CPI-naïve patients who had previously received platinum-containing chemotherapy (cohort A) and in 29 patients who had progressed after at least 12 weeks of clinical benefit on PD-L1 or PD-1 inhibitor monotherapy (cohort B).
Krebs reported that across both cohorts the treatment combination was “well tolerated,” and showed a favorable toxicity profile when compared with historic data for docetaxel.
The most common adverse events were increased alanine aminotransferase (33% overall, 12% ≥grade 3) and increased aspartate aminotransferase (32% overall, 8% ≥grade 3), which were both reversible, and diarrhea (32% overall, 1% ≥grade 3).
In cohort A, 15 patients were positive for composite AXL on immunohistochemistry analysis of tumor biopsies, which Krebs explained was defined as AXL expression being present in the tumor cells and/or the stroma.
The objective response rate (ORR) in these patients was 33% and the clinical benefit rate (CBR) was 73%. By comparison, the ORR was 7% and the CBR was 40% among the 15 cAXL-negative patients, indicating that cAXL-positive patients “seem to be more likely to benefit from this combination of treatment,” Krebs remarked.
In cohort B, which contained individuals resistant to prior immunotherapy, the ORR was 14% and the CBR was 86% in the cAXL-positive patients (n=7), with corresponding rates of 0% and 29% among the cAXL-negative patients (n=7).
Krebs suggested that cAXL positivity may therefore “be a predictive biomarker” for patients most likely to respond to this type of treatment.
He concluded that “bemcentinib may reverse acquired resistance to checkpoint inhibition by targeting AXL-positive and TREM2 macrophages and regulatory dendritic cells.”
He added that recruitment for the study is ongoing in the immunotherapy-refractory population and in a third cohort of patients refractory to chemoimmunotherapy.
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