Bemcentinib/Pembrolizumab Shows Clinical Activity, Tolerability in Advanced NSCLC

Patients with checkpoint inhibitor (CPI)-naïve and CPI-refractory composite AXL (cAXL)-positive non—small cell lung cancer (NSCLC), responded to treatmen with the first-in-class oral kinase inhibitor bemcentinib (BGB324) in combination with pembrolizumab (Keytuda), and the compound was well-tolerated, according to updated results from the phase 2 BGBC008 clinical trial (NCT03185471) presented as part of the 2020 World Conference on Lung Cancer (WCLC) Singapore

AXL is a mediator of resistance to immunotherapy and a negative prognostic factor for NSCLC. Results from this ongoing study support the continued development of AXL inhibition with bemcentinib in order to extend the efficacy of immunotherapy in biomarker-selected refractory NSCLC, according to Matthew G. Krebs, MB ChB, FRCP, PhD, of the University of Manchester and the Christie NHS Foundation Trust UK.

“Bemcentinib may reverse acquired resistance to checkpoint inhibition by targeting AXL-positive TREM2 macrophages and regulatory dendritic cells,” Krebs explained during an oral presentation of the data.

In this single-arm, 2-stage study, patients were treated with bemcentinib at a dose of 200mg per day and pembrolizumab at a dose of 200 mg every 3 weeks. The study includes 3 patient cohorts; cohort A consists of chemotherapy-failed IO-naïve patients (post-Chemo), cohort B includes patients progressing on prior CPI therapy (post-CPI monotherapy), and cohort C is made up of patients treated with platinum-doublet chemotherapy in combination with pembrolizumab (post-Chemo-CPI).

As of August 2020, enrollment in cohort A and stage 1 of cohort B had been completed. Stage 2 of cohort B and stage 1 of cohort C continue to recruit. Currently, 48 patients have been enrolled in cohort A, 29 have been enrolled in cohort B, and 29 have been enrolled in cohort C. Notably, each patient has the potential for at least 24 weeks of follow-up.

The study’s primary end point is overall response rate (ORR) per RECIST1.1 with pre-defined criteria to proceed from the first to second stage in each cohort. Secondary end points include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Moreover, exploratory end points include biomarker analysis and correlation with clinical endpoints, including composite cAXL score, PD-L1 tumor proportion score (TPS), and genome-wide mutational and transcriptome analyses.

In cohort A, radiologically evaluable patients who were cAXL positive (n = 15) demonstrated an ORR of 33% and a clinical benefit rate (CBR) of 73%. Evaluable patients who were cAXL negative (n = 15) demonstrated an ORR of 7% and a CBR of 40%.

Similarly, in cohort B, radiologically evaluable patients who were cAXL positive (n = 7) demonstrated an ORR of 14% and a CBR of 84%. Evaluable patients who were cAXL negative (n = 7) demonstrated an ORR of 0% and a CBR of 29%.

RNAseq analysis of patients in stage 1 of cohort B who benefitted from combination treatment with bemcentinib and pembrolizumab identified the following gene signatures:

• Increased AXL expression
• Genes associated with tumor cell EMT
• Presence of TREM2-positive tumor associated macrophages
• Presence of CCR7-positive m-regulatory dendritic cells

“Interestingly, there are some common gene signatures we saw in cohort A that which later on presented here in [cohort] B, suggesting a common mechanism of immune suppression in both intrinsic and acquired resistance to checkpoint inhibitors,” Krebs noted.

Regarding safety, the treatment combination was well tolerated, with a safety profile consistent with that of individual drugs. Moreover, when compared with docetaxel, the toxicity profile of the combination was considered favorable.

Treatment related adverse events (TRAEs) were found to be generally mild and reversible. The most frequently observed TRAEs (≥10% dosed patients) occurring in 75 patients included increased alanine aminotransferase (ALT; 33%), increased aspartate aminotransferase (AST; 32%), diarrhea (32%), asthenia (19%), pruritus (16%), nausea (15%), increased blood creatinine (13%), prolonged electrocardiogram QT (13%), fatigue (13%), anemia (12%), and decreased appetite (11%). Importantly, all cases of treatment-related ALT and AST increase were reversible and managed with concomitant administration of steroids and treatment interruption.

Overall, only 3 patients (4%) reported grade 4 TRAEs and no patients reported any grade 5.

Given these results, the investigators indicated that moving forward the focus will be on the predictive value of cAXL in patients on second-line therapy following either CPI monotherapy or chemo-CPI relapse, together with transcriptional analysis to identify gene based predictive signatures.

_Reference:

_{Krebs MG, Helland Å, Carcereny Costa E, et al. A phase II study of the oral selective AXL inhibitor bemcentinib with pembrolizumab in patients with advanced NSCLC. Presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer Singapore; January 28–31, 2021; Virtual. Abstract OA01.07}