Pre-clinical

Preclinical study finds Genmab may hold the key to a next-gen triple followup to MEK/BRAF combos

A Genmab-sponsored study touts preclinical evidence that one of its targeted antibody-drug conjugates can be effective against a specific type of melanoma where existing treatment is failing, pointing to a potential new triple combination strategy.

The BRAF gene is a well-studied pathway in melanoma, as a mutation in it causes tumor cells to proliferate. Tailored treatments combining BRAF- and MEK-inhibitors, the current standard, are often effective (Genentech has a combo in the market, while Novartis is hustling ahead with pivotal studies for its combo of Tafinlar and Mekinist). However, as the paper published today by Netherlands Cancer Institute (NKI) in Nature Medicine points out, many tumors develop resistance to them. 

Daniel Peeper

In their previous work, the NKI researchers — led by Daniel Peeper — have discovered these resistant melanomas start producing another protein called AXL. The fact that this protein often sits on the outside of a tumor cell makes them prime targets for the next generation of melanoma drugs.

That’s where Genmab’s AXL-targeting antibody-drug conjugate comes in. Developed with an ADC technology platform licensed from Seattle Genetics, HuMax-AXL-ADC binds to and kills tumor cells expressing the AXL protein. The Danish antibody giant is currently testing it in multiple cancer indications in the clinic.

In melanoma, Peeper’s team found that applying this ADC in mice “effectively eliminated” AXL-high tumors.

The takeaway here isn’t simply that the AXL drug could be an alternative to the BRAF/MEK combo. The researchers are arguing that it is best used in combination with those inhibitors.

Julia Boshuizen

A graduate student in the group observed that most tumors still contained considerable numbers of cells with little or no AXL (not a big surprise; tumors are often made of groups of cancer cells with differential drug sensitivities). On the other hand, BRAF/MEK-inhibitors stimulated the production of AXL in tumor cells.

“The breakthrough here is that we demonstrate that while melanomas that progress on treatment sharply accumulate AXL+ cells, most if not all resistant melanomas remain highly heterogeneous,” Peeper told Endpoints.

The student, Julia Boshuizen, compared the tumor to a bucket of marbles where yellow ones have little AXL and are sensitive to BRAF- and MEK-inhibitors, while red marbles express lots of AXL and don’t respond to BRAF/MEK treatment.

“If you wipe out the yellow marbles only, the red ones remain, and vice versa,” she said. “So, to get rid of both colors, we thought it may be a good strategy to combine BRAF/MEK-inhibitors with HuMax-AXL-ADC.”

If this marble approach goes through to the clinic, according to the researchers, it could signal the next step for personalized cancer medicine.


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