Combination therapy could treat tumors resistant to MAPK pathway inhibitors

In a study published in Nature Medicine, Genmab A/S (CSE:GEN; Pink:GMXAY) and academic researchers identified a combination therapy approach that could combat drug resistance in heterogeneous tumors.

Melanoma tumors with BRAF mutations that are -- or become -- resistant to BRAF and MEK inhibitor therapies often express AXL receptor tyrosine kinase (AXL;UFO), while tumors with low AXL expression are generally sensitive to the drugs. In this study, researchers used Genmab's antibody-drug conjugate (ADC), called HuMax-AXL-ADC, to target AXL-positive cancer cells as monotherapy and in combination with BRAF and MEK inhibitors.

In mice injected with patient-derived melanoma cells resistant to BRAF and/or MEK inhibitors, HuMax-AXL-ADC decreased tumor growth compared with a combination of BRAF and MEK inhibitors. In the mice that received the MAPK inhibitor combination, adding HuMax-AXL-ADC as a third treatment increased survival compared with the MAPK inhibitors or HuMax-AXL-ADC alone. Similarly, the triple combination decreased tumor growth while increasing survival in mice with treatment-naïve patient-derived melanoma.

The researchers found the BRAF and MEK inhibitor combination upregulated AXL in patient-derived melanoma cell lines, suggesting the treatment made the remaining resistant cells susceptible to HuMax-AXL-ADC.

HuMax-AXL-ADC as monotherapy also decreased tumor growth in 18 of 25 patient-derived xenograft mouse models of primary cancers, with a correlation between high AXL tumor expression in tumors and response. Models included lung, ovarian, pancreatic, esophageal, thyroid and cervical cancers and epidermoid carcinoma and sarcoma.

HuMax-AXL-ADC contains a human anti-AXL antibody linked to monomethyl auristatin E (MMAE). Genmab has the ADC in a Phase I/II basket trial as monotherapy to treat solid tumors and melanoma.

BioAtla LLC (San Diego, Calif.) has CAB-AXL-ADC, an ADC containing a conditionally active biologic (CAB) and targeting AXL, in preclinical development for solid tumors. As of December 2016, there were at least eight other compounds in clinical or preclinical development that target AXL or its ligand, growth arrest-specific 6 (GAS6). At least two additional AXL-targeting compounds have entered preclinical development since then -- anti-Axl kinase mAb BGB149 from BerGenBio ASA (OSE:BGBIO) and CT413 from HEC Pharm Group (Dongguan, China), a dual inhibitor of AXL and c-Mer proto-oncogene tyrosine kinase (MERTK) (see BioCentury Innovations, Dec. 15, 2016).