Key assets, trials and companies targeting brain & spinal tumors, segmented by treatment line

Some thoughts on a difficult space:

• About 25K patients will be diagnosed with brain & other CNS cancers in the US, with ~19K deaths estimated in 2023. Survival rates vary significantly by malignant tumor type, with glioblastoma multiforme (GBM) being the most deadly (and frequent)
• When compared to other areas of oncology, relatively few novel therapeutics have emerged, and standard of care has remained largely the same for over a decade:
• First, debulking surgery to remove as much of the tumor as possible
• Adjuvant: TMZ (chemo) + radiation
• 1L: TMZ +/- Optune
• 2L: Bevacizumab (Avastin) or Optune
• Immunotherapy (i.e. PD-1s) have revolutionized treatment in other indications, but have been largely stonewalled in brain tumors. Similarly, targeted therapies' effectiveness has also been limited
• A few factors converge to make this cancer so difficult to treat:
• The blood-brain barrier (BBB) makes targeted drug delivery & dosing a challenge - systemic therapies (like chemo) also struggle
• Incomplete understanding of underlying biology, resistance mechanisms & TME
• Immense heterogeneity of brain tumors
• Surgery is tricky - the margin for error is much smaller than with other tumors
• Brain tumors are rare - less than 1% of the population will be impacted in their lifetime; this has unfortunate downstream R&D allocation consequences
• Against this backdrop, a few encouraging options have begun to emerge
• Day One Biopharma's tovorafenib demonstrated strong efficacy in r/r BRAF+ pediatric low grade glioma, which has essentially no effective treatments. Early data also showed activity in adult tumors. A rolling NDA has been initiated, with estimated completion in Oct'23
• Other targeted treatments have emerged, including Servier's vorasidenib (IDH1/2), Black Diamond Therapeutics' BDTX-1535 (EGFR) and SpringWorks Therapeutics' mirdametinib (MEK1/2). Other companies are testing combos, most commonly with Merck's pembrolizumab or current SoC
• Given the significant unmet need, particularly for recurrent disease, the near-term focus for this space will be on better understanding the underlying mutation drivers, identifying novel agents that can cross the BBB and testing combos that can hit multiple targets