- Germline hypermutator glioblastomas (HmGB) may have a durable response to immune-oncology (IO).
Why this matters
- Glioblastoma is a cold tumour, only 11% have detected lymphocytes.
- Phase 3 trial on recurrent glioblastomas with nivolumab failed to extend survival.
- Independent, retrospective analysis of patients between 2012 through 2018 at a single centre (MD Anderson).
- 312 gliomas analysed with next-generation sequencing were identified.
- HmGB was defined as tumour mutational burden of 30 or more mutations per megabase, or mutations in mismatch repair (MMR) or DNA-polymerase genes.
- IO seems to be ineffective in HmGB with somatic mutations regardless of the onset of diagnosis or phenotype. However, germline HmGB may have durable responses to IO.
- 30 (9.6%) patients had HmGB. Of those, 9 (30%) received IO.
- HmGB was found as initial diagnosis in 5 (56%) cases, the rest after temozolomide (TMZ) treatment.
- Only 1 patient had germline MMR mutation (Lynch Syndrome).
- 8 HmGB patients received either checkpoint inhibitors (CPI) or cellular therapy (T-cells or NK cells) after TMZ, only 1 patient received CPI at initial diagnosis.
- In HmGB with somatic mutations, OS from initial diagnosis was 39 months. PFS was 72 days.
- PFS after TMZ, CPI, and cell therapies was 51, 41, and 175 days, respectively, whereas the PFS in newly diagnosed HmGB was 96 days.
- Median cumulative dose of pembrolizumab: 720 mg per patient.
- The patient with germline HmGB is still on pembrolizumab and is the only one with stable disease for more than 16 months.
- Funding: none.
- Single centre study; small sample.