Brain metastasis from melanoma is particularly deadly and options are limited due to the difficulty of breaching the brain-blood barrier.
Recent research illustrated the potent and prolonged antitumor activity of a BRAF inhibitor, C1a, that can cross the blood-brain barrier to attack brain metastases from malignant melanoma.
Brain metastasis is found in between 7%-20% of patients at diagnosis, and in up to around 70% at later stages of disease, with frequent relapse occurring primarily at the brain metastatic site.
Brain metastatic lesions do not respond well to current treatment options, partly because pharmacological compounds cannot reach the brain since they do not cross the blood-brain barrier.
Currently approved therapies include immune checkpoint inhibitors (ICIs), and combinations of BRAF and MEK inhibitors (BRAFi/MEKi), such as dabrafenib and encorafenib, and binimetinib and trametinib, respectively. But not all patients respond to ICIs, and resistance to BRAFi/MEKi occurs.
In the current study, investigators assessed C1a in patient-derived preclinical models of mutant-BRAF-driven melanoma brain metastases, even upon relapse on approved BRAF and BRAFi/MEK inhibitors.
The brain-penetrant BRAFi C1a was developed to have optimized brain permeability, avoid the paradoxical activation (paradox breaker) of the MAPK signaling pathway, and selectively target BRAF V600E/K tumors.
C1a triggered robust responses in BRAF V600E patient-derived models, showing permeability, activity, and potency as a paradox breaker.
The investigators then performed a head-to-head comparison of dabrafenib with C1a, and results showed that C1a outperformed dabrafenib that was administered at a 10-times higher dose.
It increased survival by more than 3-fold compared with those treated with or relapsing on combinations of BRAF and MEK inhibitors. In addition, treatment at a maximized dose of C1a led to disease remission in tumors progressing upon treatment of these approved inhibitors.
The researchers also unveiled mechanisms of resistance and discovered that combinatory treatment with immunotherapy prevents resistance and tumor relapse.
A clinical trial is now open to test its efficacy in melanoma brain metastasis.
The researchers also studied mechanisms of resistance to help prevent tumor escape from C1a, and sought to identify a potential combinatorial treatment strategy to further prolong antitumor responses.
The ex vivo analysis of tumors manifesting relapse on C1a demonstrated that MAPK-reactivation occurs as the main resistance mechanism in both peripheral and brain metastatic setting, with BRAF kinase domain duplication as the dominant driver of resistance.
Transcriptomic analysis of the resistant tumors showed an inflammatory phenotype indicating a clear implication of the immune system. Considering that ICIs are used to treat melanoma, the investigators explored a combinatorial approach with C1a and anti-PD1 antibody. Results showed that C1a also promotes potent anti-tumor responses when combined with anti-PD1 and dramatically reduces the onset of relapse when compared to C1a monotherapy.