Bemcentinib-Keytruda Combo Effective in Some Advanced NSCLC Patients with Poor Prognosis

Bemcentinib-Keytruda Combo Effective in Some Advanced NSCLC Patients with Poor Prognosis
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Combining bemcentinib with Keytruda (pembrolizumab) is effective and delays disease progression in people with previously treated advanced non-small cell lung cancer (NSCLC), particularly in those with AXL-positive tumors.

Those updated results from a Phase 2 clinical trial show, to researchers’ surprise, that benefits also were seen in people with low levels of PD-L1 protein in tumor cells. Usually, when cancer cells have a high PD-L1 levels, the patient may benefit more from immune checkpoint inhibitors, such as Keytruda.

“I am impressed by these results that clearly demonstrate the durable clinical benefits in this difficult to treat low PD-L1 patient population,” Hani Gabra, MD, PhD, said in a press release. Gabra is chief medical officer at BerGenBio, developer of bemcentinib.

Results were presented recently in an oral presentation, “A phase II study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC: Updated analysis,” (abstract O26) at the Society for Immunotherapy of Cancer 34th Annual Meeting, held in Maryland.

BerGenBio’s investigational therapy and Keytruda — an immune checkpoint inhibitor marketed by Merck (known as MSD outside the U.S. and Canada) — are designed to boost the body’s anti-tumor response. They target proteins involved in mechanisms used by cancer cells to evade anti-tumor immune responses.

Bemcentinib targets the AXL receptor on cancer cells, which is also involved in tumor’s migration and invasion of other organs. Keytruda targets the PD-1 protein on T-cells (immune cells involved in the fight against cancer), suppressing its interaction with PD-L1 in cancer cells.

Previous studies have suggested that AXL is implicated in resistance to anti-PD-1 therapy, and that bemcentinib may boost the effects of immune checkpoint inhibitors, such as Keytruda.

The open-label, BGBC008 Phase 2 trial (NCT03184571) is evaluating the combination of bemcentinib with Keytruda in previously treated patients with metastatic (stage 4) NSCLC.

The study is comprised of group A with patients whose disease progressed on or after previous treatment (except immunotherapy), and group B, which includes patients showing disease progression on anti-PD(L)-1 therapy.

Both groups follow a two-stage design, in which moving to the second stage (the inclusion of more patients) requires that the first stage has met the primary effectiveness goal.

The trial’s primary goal is to determine whether overall response rate (complete and partial responses in terms of tumor reduction) was higher than the required minimum of 18%.

Secondary goals include the time a patient lived without signs of disease progression — a measure called progression-free survival (PFS) — overall survival, and safety. Responses also will be correlated with levels of AXL and PD-L1.

Participants will be followed for two years. Updated data of BGBC008’s group A were presented at the recent meeting.

At analysis cut-off date — July 2019 — group A had completed enrollment in both stages, corresponding to a total of 50 patients (24 in the first stage and 26 in the second stage).

Participants’ median age was 65 years (range of 39 to 82), and 60% were men. Among the 33 patients with available AXL status 19 (66%) were AXL-positive and 14 were AXL-negative. PD-L1 status was available for 42 patients (90%), revealing that four patients had tumors with more than 50% of cancer cells producing PD-L1, 16 patients had 1% to 49% PD-L1-positive cancer cells, and 22 patients had less than 1% of PD-L1-positive cancer cells.

Results of the 43 patients eligible for analysis (17 AXL-positive, 13 AXL-negative, and 10 AXL-unknwon) showed that the primary goal was met, with an overall response rate of 23% (all partial responses).

Among the 10 treatment responders, six were AXL-positive, two were AXL-negative, and two others were AXL-unknown. Four of them had 50% PD-L1-positive cancer cells (one being AXL-positive), four others had less than 50% of PD-L1-positive cells, and two were PD-L1-unknown (one was AXL-positive and the other was ALX-unknown).

The proportion of patients responding to treatment was higher among AXL-positive patients (35%) than in those without AXL (15%), and AXL-positive patients lived three times longer without disease progression than AXL-negative patients, according to the company.

“Promising clinical activity has been seen, particularly in [patients] with AXL-positive disease and including patients with PD-L-negative tumor,” the researchers wrote.

Overall, the bemcentinib-Keytruda combo was well-tolerated, with the most common adverse events (side effects) being fatigue (54%), increased levels of the liver enzyme transaminase (46%), diarrhea (32%), and decreased appetite (28%). All transaminase-related events were reversible with adequate therapy and discontinuation of the combo therapy.

“Importantly the patients that benefit most match gene signatures that predict poor prognosis and a lack of response to immunotherapy in NSCLC,” Gabra said.

The study, taking place at more than 12 clinical sites across the U.S., U.K., Spain, and Norway, is still recruiting patients for group B; more information on study locations and contacts is available here.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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