Bemcentinib-Keytruda Combo Provides Durable Response in Advanced NSCLC, Phase 2 Trial Shows

Combining bemcentinib with Keytruda (pembrolizumab) has shown efficacy and led to longer survival than previous second-line treatments in patients with advanced non-small cell lung cancer (NSCLC), according to updated results of a Phase 2 trial.

The research, “A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy,” was presented at the recent 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Treatment options for NSCLC cancer patients that have not responded to anti-PD-1 therapies such as Keytruda represent a significant unmet medical need,” Enriqueta Filip, the study’s principal investigator from Hospital Vall d’Hebron in Barcelona, said in a press release. “These data, which suggest that combination therapy with bemcentinib has the potential to enhance patient responses … is a very significant and encouraging development.”

BerGenBio’s bemcentinib is an investigational small molecule inhibitor of AXL, an enzyme with a relevant role in tumor capacity to migrate and invade other organs, and also a key suppressor of anti-tumor immune responses, helping cancer cells survive.

Merck‘s Keytruda is a type of therapy called an immune checkpoint inhibitor, which targets the PD-1 protein on immune T-cells to prevent their binding to PD-L1 on cancer cells. This PD-1/PD-L1 interaction is used by tumors to evade immune attack.

The open-label BGBC008 trial (NCT03184571) is testing the combination of bemcentinib with Keytruda in previously treated patients with advanced (stage 4) lung adenocarcinoma, which represents most NSCLCs. The study is being conducted in the U.S., U.K., Spain, and Norway. Patients are still being enrolled; more information on study locations and contacts is available here.

Participants receive 400 mg of bemcentinib orally in the first three days, tapered to 200 mg daily thereafter. Keytruda is given at a 200 mg dose every three weeks.

The trial’s goal is to determine anti-tumor activity. Responses will be correlated with biomarker status, including levels of AXL and PD-L1. Higher levels of PD-L1 have been previously associated with better treatment response.

Patients eligible for inclusion in group A must have experienced cancer worsening on or after prior treatment excluding immunotherapy, whereas group B includes patients actively progressing on treatment containing an anti-PD(L)-1 medicine.

Both groups follow a two-stage design. While group A has already successfully advanced into the second stage after meeting the main efficacy goal, the advancement of group B will be evaluated after analyzing the response of 13 patients.

At the analysis cut-off date, 35 of 46 patients were eligible for analysis; 58% were AXL-positive, 53% PD-L1-negative, and another 39% were PD-L1-positive. The AXL-positive patients showed a 40% objective response rate — the proportion of patients with reduced tumor size —regardless of their PD-L1 score. The overall response rate — including both complete (total cancer disappearance) and partial responses — was 29%.

Median survival rate was 12.2 months, which significantly outperforms prior studies of second-line treatment of NSCLC with a stand-alone PD-1 inhibitor.

As for safety, the combo approach was generally well-tolerated. The most frequent adverse events were increased levels of the liver enzyme transaminase (35%), fatigue (30%), and diarrhea (26%). All adverse events were reversible. No deaths occurred.

“Overall, bemcentinib in combination with pembrolizumab (Keytruda) was well tolerated and promising clinical activity was seen, particularly in [patients] with AXL positive disease,” the team wrote.

“The clinical activity … surpasses what has been shown historically in previously-treated, PD-L1 low patients on PD-1 inhibitor monotherapy, and supports the hypothesis that AXL is implicated in the failure of anti-PD-L1 therapies.” said Richard Godfrey, BerGenBio’s CEO.

Godfrey added that further investigation is warranted and that the company looks forward to sharing updates this year.