Positioning bemcentinib as a potential cornerstone of cancer combination therapy in NSCLC
AXL expression has been established as a negative prognostic factor in a large variety of tumours, with particularly compelling evidence in non-small cell lung cancer (NSCLC).
Lung cancer also represents the largest single unmet medical need: over 230,000 new cases are expected to be recorded in the US in 2018, over 80% of which will be of NSCLC histology.
Major classes of NSCLC therapy are:
- Checkpoint Blockade Inhibition (CBI) e.g. the anti-PD1 antibody therapy KEYTRUDA,
- Targeted therapies, in particular EGFR targeted treatments, e.g. TARCEVA and
- Chemotherapeutics, e.g. paclitaxel and docetaxel.
Each of these treatment modalities is currently used as a first or second line systemic treatment option for a large proportion of NSCLC patients. Furthermore, patients who relapse after receiving CPIs, targeted therapies or paclitaxel, where the treatment was ineffective or the tumour has become resistant, will inevitably receive docetaxel chemotherapy in later lines of treatment.
The orally available, selective AXL inhibitior shows promise enhancing the efficacy of treatments across the NSCLC therapy landscape
Pre-clinical and translational evidence suggest that AXL inhibition may be synergistic with both CPIs, targeted and chemotherapy.
Bemcentinib shows promise in combination with immune checkpoint inhibitors:
The introduction of immune therapeutics means that, for the first time in the history of oncology therapeutics, some patients are able to be fully cured of their cancer. However, although response rates to immune checkpoint inhibitors in NSCLC are relatively high, a large proportion of patients still do not benefit from this revolutionary treatment either because they are not eligible to receive immune checkpoint inhibitors (up to 80% of patients lack sufficient expression of the biomarkers that indicate the treatment) or are resistant to therapy (up to 50% of those receiving the therapy).
There is a strong rationale for AXL inhibition to improve the efficacy of immune checkpoint inhibitor therapy in NSCLC:
- AXL is up-regulated in non-responders to immune therapy
- In preclinical models, bemcentinib increased the efficacy of checkpoint blockade
- Treatment of patient samples and animal models with bemcentinib reverses immunesuppression.
Bemcentinib shows promise in combination with targeted therapies:
EGFR mutation positive NSCLC remains incurable although therapies targeted to the mutated EGF receptor show high initial response rates. Over time, however, virtually all patients develop resistance to the targeted therapy. Resistance is driven either by additional mutations like the T790M mutation or – as in almost half of the patients – bypass mechanisms. AXL and the cellular programme it drives, epithelial-to-mesenchymal transition (EMT), have been implicated in such acquired resistance that is independent of additional mutations. The standard of care for EGFR mutation positive patients who progress on targeted therapy in the absence of an actionable resistance mutation currently is chemotherapy.
There is a strong rationale for AXL inhibition to improve the efficacy of targeted therapy in NSCLC:
- AXL upregulation has been observed in patients who had acquired resistance to EGFR therapy
- In cell lines and in vivo models, AXL has been shown to cause resistance to EGFR targeted therapies
- In preclinical models of NSCLC, treatment with bemcentinib prevented resistance to TARCEVA (erlotinib).
Early clinical data with bemcentinib in NSCLC patients who had progressed on TARCEVA indicated that indeed the selective AXL inhibitor was able to reverse resistance in a subset of patients. Three out of nine patients previously resistant to EGFR directed therapy had their disease stabilised 6 weeks after introduction of bemcentinib in combination with TARCEVA. Two patients saw sustained benefit for a prolonged period of time.
Bemcentinib shows promise in combination with chemotherapy:
The vast majority of NSCLC patients will receive chemotherapy at some stage in their treatment. In a first line setting, patients who are not eligible for immune therapies and for whom no otherwise actionable mutatios can be identified typically receive platinum doublet based therapy. In later lines, patients who have progressed on immune or targeted therapies tend to receive single-agent chemotherapy consisting of docetaxel or pemetrexed. Such therapy is mainly palliative given that the reported response rates to docetaxel in this patient population are in the one- to low two-digit range.
There is a strong rationale for AXL inhibition to improve the efficacy of chemotherapy in NSCLC:
- The tumour microenvironment responds to chemotherapy treatment by activating the AXL pathway
- AXL down-regulation improved NSCLC response to chemotherapeutics
- Treatment with bemcentinib increased the response to docetaxel in animal models of NSCLC.
Early clinical data with bemcentinib in NSCLC patients who had progressed on all therapies available to them (including targeted and immune therapies) indicated that indeed the selective AXL inhibitor bemcentinib was able to reverse resistance in a subset of patients.