A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Activating epidermal growth factor receptor (EGFR) mutations drive lung cancer, targeted by tyrosine kinase inhibitors (TKIs).
• Acquired resistance to TKIs like osimertinib often involves secondary mutations and bypass signaling through receptors such as AXL receptor tyrosine kinase.
• Overcoming AXL-mediated resistance is crucial for durable responses in EGFR-mutated lung cancer.

Purpose of the Study:

• To compare the efficacy of two anti-AXL drugs (mAb654 and bemcentinib) in combination with osimertinib to overcome drug resistance.
• To evaluate the potential of a bispecific antibody targeting both AXL and EGFR in combination with osimertinib for sustained tumor inhibition.

Main Methods:

• Preclinical models of EGFR-mutated lung cancer resistant to osimertinib were treated with combinations of osimertinib, anti-AXL agents (mAb654, bemcentinib), and anti-EGFR antibody (cetuximab).
• A novel bispecific antibody targeting both AXL and EGFR was developed and tested in combination with osimertinib.
• Tumor response and relapse dynamics were monitored over time.

Main Results:

• Neither osimertinib plus an anti-AXL drug alone prevented tumor relapses.
• Triplets combining osimertinib, cetuximab, and an anti-AXL drug showed initial efficacy, with the mAb654-containing triplet demonstrating superior long-term control.
• The bispecific antibody targeting AXL and EGFR, when combined with osimertinib, consistently inhibited tumor relapses in preclinical models.

Conclusions:

• AXL inhibition is necessary but insufficient to prevent osimertinib resistance alone.
• Combination strategies involving EGFR and AXL inhibition, particularly with a bispecific antibody, offer a promising approach to prevent tumor relapse in EGFR-mutated lung cancer.
• The developed bispecific antibody warrants further clinical investigation for treating resistant lung cancer.