Matthew Krebs, MBChB, PhD
The first-in-class AXL inhibitor bemcentinib (BGB324) demonstrated activity in combination with the PD-1 inhibitor pembrolizumab (Keytruda) in patients with advanced non–small cell lung cancer (NSCLC) who had no prior exposure to immunotherapy, according to results of a phase II study that were presented at the 2019 World Conference on Lung Cancer.
Results showed that, with the combination, the objective response rate (ORR), confirmed by tissue analysis, was 40%, and the median overall survival (OS) was 12.2 months. The most commonly reported treatment-related adverse event (TRAE) was increased transaminase, which was reversible in all cases.
“Response rates to the combination of bemcentinib and pembrolizumab are encouraging in the immuno-oncology–naïve population,” presenting author Matthew Krebs, MBChB, PhD, of the University of Manchester in England, and colleagues stated in a poster presentation during the conference. “The combination treatment of bemcentinib and pembrolizumab was well tolerated.”
The initial results involved patients with chemotherapy-refractory disease, and recruitment is ongoing in a second cohort for an evaluation of the combination in PD-1/PD-L1–refractory NSCLC.
The rationale for the investigation came from recognition that single-agent pembrolizumab or in combination with chemotherapy represents a standard first-line therapy for patients with metastatic NSCLC. However, new therapeutic strategies are needed to improve the efficacy of second-line therapy while limiting toxicity.
The AXL receptor tyrosine kinase is expressed by tumor and suppressive immune cells and is a key driver of immune escape, treatment resistance, and metastasis. The AXL kinase mediates intrinsic resistance to both natural killer cell and cytotoxic T-lymphocyte–mediated killing of lung cancer cells but can be reversed by AXL signaling inhibition.
Bemcentinib is a highly selective, oral AXL kinase inhibitor in clinical development as a therapy for patients with solid tumors and myeloid malignancies. Studies of bemcentinib include as monotherapy and in combinations with immunotherapy, targeted agents, and chemotherapy for NSCLC, acute myeloid leukemia/myelodysplastic syndromes, and melanoma.
The phase II trial (NCT03184571) of patients with NSCLC comprises two types of investigation. During the initial component of the study, investigators enrolled patients with platinum-refractory NSCLC and no prior exposure to a PD-1/PD-L1 inhibitor (n = 48). The second part of the trial will evaluate bemcentinib and pembrolizumab in patients with PD-1/PD-L1 inhibitor–refractory NSCLC with an expected enrollment of 58 patients.
Eligible patients have histologically or cytologically confirmed stage IV adenocarcinoma and adequate fresh tumor tissue for assessment of PD-L1 and AXL expression, although expression status is not an inclusion criterion. Patients could also not have EGFR
rearrangements. Treatment consists of pembrolizumab at 200 mg and a 400-mg loading dose of bemcentinib, followed by 200 mg once daily.
The primary endpoint of the trial is ORR. Secondary endpoints include disease control rate, duration of response, progression-free survival, 12-month OS rate, and response by biomarker status.
A biomarker analysis, which is ongoing, will include an immunohistochemistry test of AXL and PD-L1 expression, comprehensive liquid biopsy analysis, as well as other assays.
Of the 48 patients enrolled in the first part of the trial, 58% had AXL
-positive tumors and 53% had PD-L1–negative tumors.
Regarding safety, the combination was well tolerated in the chemotherapy-refractory patient population, Krebs and colleagues reported. The most common all-grade AEs were asthenia/fatigue (48%), increased transaminases (43%), and diarrhea (33%). All of the treatment-related transaminase increases were reversible and manageable with concomitant administration of systemic corticosteroids and/or interruption of study treatment. The safety of the combination will also be evaluated in the population of patients who are refractory to PD-1/PD-L1 inhibitors.
Krebs MG, Brunsvig P, Helland Å, et al. A phase II study of selective AXL inhibitor bemcentinib and pembrolizumab in patients with NSCLC refractory to Anti-PD(L)1. Presented at: International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer; September 7 to 10, 2019; Barcelona, Spain. Abstract P1.01-72.
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