Present and Future Precision Medications Signal Promise for Adults With Glioma

Patrick Wen, MD

Oncologists who treat adults with glioma have systemic options, including chemotherapy and targeted therapy. The targeted agents are active and have improved survival outcomes, as have immunotherapies, according to Patrick Wen, MD.¹

At the Inaugural Miami Cancer Institute Precision Medicine Oncology Symposium, a professor of Neurology at Harvard Medical School and director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, was 1 of 2 presenters in the central nervous system category. Wen discussed precision oncology strategies for glioma.¹

Wen explained that patients with BRAF V600E mutations, IDH 1/2 mutations, or FGFR alterations have good options. For patients with NTRK fusions or AK327 mutations, there are new agents being developed.

The BRAF and MEK combination, dabrafenib (Tafinlar) and trametinib (Mekinist) has shown clinically meaningful activity in patients with IDH and BRAF V600E-mutated high-grade and low-grade glioma. The combination also displayed a safety profile consistent with previous reports, according to results from an open-label, single-arm, phase 2 basket trial (ROAR, NCT02034110). There were 45 patients with high-grade glioma in the study, and the objective response rate (ORR) for this group was 33% (95% CI, 20%-49%) at a median follow-up of 12.7 months (interquartile range [IQR], 5.4-32.3 months). Among the 13 patients with low-grade glioma, the ORR was 69% (95% CI, 39%-91%) at a median follow-up of 32.2 months (IQR, 25.1-47.8 months).²

For patients with IDH-mutated, FGFR-altered recurrent glioma, the FGFR inhibitor, infigratinib (Truseltiq) has demonstrated limited efficacy. In a multicenter, open-label, single-arm phase 2 study (NCT01975701) of 26 patients, durable disease control was achieved with the agent. Moreover, treatment with infigratinib led to a 6-month progression-free survival (PFS) rate of 10.6% (95% CI, 5.0%-32.5%), with a median PFS of 1.7 months (95% CI, 1.1–2.8). The ORR observed with infigratinib was 3.8%, and responses lasted longer than a year.³

In an interview with Targeted Oncology™, Wen discussed his presentation on precision medicine for adult gliomas, including the present and future treatment options.

Targeted Oncology: Can you talk about the different subtypes of adult gliomas and what is known about the molecular biology of these tumors?

Wen: There are 3 types. There are IDH-mutated astrocytoma, IDH-mutated oligodendrogliomas, and then IDH wild-type glioblastoma, which have the worst outcome.

I think a major advance is the understanding of the importance of the idea of mutation. This is an early oncogenic driver that persists throughout the course of the tumor. It's also associated with better outcomes and better response to treatment. I think having this understanding of IDH has allowed these tumors to be classified more accurately, allows more homogeneous populations to enroll into clinical trials, and for us to assign better and more appropriate therapies to them.

There are many unanswered questions about these tumors. Probably the most critical is the issue of tumor heterogeneity, which is present in all grades of tumor, but is worse with glioblastoma. That's a major cause of resistance to treatment. I think glioblastomas also have plasticity between cellular states that adds to the complexity of the heterogeneity, and there's also plasticity allowing tumor cells, potentially to revert to stem cells. A lot of these make it very hard to treat them with targeted therapies.

What are some if the immuno- and targeted therapies showing promise in this space? What ongoing clinical trials are interesting?

I think for a long time, because of the issues of the blood brain barrier, heterogeneity, and redundancy of signaling pathways, there was thought that targeted therapies would never work for glioblastoma. But we have found that these small subsets of patients that do respond. Two percent of patients with glioblastoma that have BRAF V600E mutations have shown responses to the dabrafenib and trametinib, a BRAF and MEK inhibitor combination that's approved for melanoma. The response rate in glioblastoma is about 32%. In low-grade gliomas, it's 69%. Responses in both populations are durable, and it was part of a study with multiple tumors that led to the FDA approval for that combination for all solid tumors in 2022.

There's also evidence that targeted therapies may be helpful for tumors with the very rare TRK fusions. Entrectinib seems to be active for gliomas with NTRK fusion. There's also emerging evidence that erdafitinib, an FGFR inhibitor, has activity in gliomas.

In children, there are even more advances. The low-grade gliomas that have the BRAF V600E mutations respond well to MEK and BRAF combinations, and then the pilocytic astrocytoma and other low-grade gliomas that have the BRAF-KIAA1549 fusions are responding to RAS inhibitors, with response of over 60%, and the responses are durable. I think this is a very exciting area.

Are there any novel targets that should be explored in the future for gliomas?

One biomarker that's been associated with some activity is the AK327 mutation. This is found in diffuse midline gliomas, which are perhaps the worst of all gliomas, including children that diffuse intrinsic pontine glioma, which is deadly and not responsive to anything except radiation. That type of tumor has shown responses to a drug called ONC201, a DRD2 inhibitor and ClpP agonist. The responses are only in the order of 20%-25%, but it's durable, so there's some progress. Lastly, in terms of immunotherapy, the same group of patients are showing responses to GD2 to CAR T cells, and that's a very exciting development.

_REFERENCES:

_{1. Wen PY. Precision oncology approaches in gliomas. Presented at Inaugural Miami Cancer Institute Precision Oncology Symposium; February 3-4, 2022; Coral Gable, FL}

_{2. Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 2022;23(1):53-64. doi:10.1016/S1470-2045(21)00578-7.}

_{3. Lassman AB, Sepulveda-Sanchez JM, Cloughesy TF, et al. Infigratinib in patients with recurrent gliomas and FGFR alterations: a multicenter phase II study. Clin Cancer Res. 2022; 28(11): 2270–2277. doi:10.1158/1078-0432.CCR-21-2664}