Could VAL-083 Address Modest Treatment Efficacy in Glioblastoma?

Patrick Y. Wen, MD

Glioblastoma (GBM) remains a difficult malignancy to treat, despite countless clinical trials that have introduced new therapies for patients with the disease, according to John de Groot, MD and Patrick Y. Wen, MD. However, targeting a novel mechanism of action could be the answer to improving the survival rates for these patients.^1,2

The treatment modalities being used for GBM include maximum safe resection, chemotherapy, chemoradiotherapy, immunotherapy, and Tumor Treating Fields (TTF). The alkylating chemotherapy agents appear to have the most efficacy, explained Groot, professor, Departments of Neurology and Neurosurgery, The University of California in San Diego, California during a virtual event held by Kintara Therapeutics, Inc.¹

“Targeted therapy and immunotherapy, which has been really successful in other diseases, has been very challenging to demonstrate any sort of benefit in these patients. Alkylating agents like VAL-083, remain the most effective therapies for glioblastoma,” Groot said, during his presentation.

Groot’s statement on the standard of care (SoC) was supported by data from multiple clinical trials.

Historic Evidence

Back in 2013, radiotherapy with concomitant and adjuvant temozolomide was the SoC therapy, but a phase 3 study (NCT00304031) aimed to show that dose dense (DD) temozolomide could improve overall survival (OS) and methylguanine-DNA methyltransferase (MGMT) status.³

Brain matter | Image Credit: © lukszczepanski - www.stock.adobe.com

The study included 833 patients with GBM who were randomized 1:1 to receive with DD temozolomide of SoC. The median OS shown in the study was 16.6 months with DD temozolomide vs 14.9 months with SoC, not reaching the threshold for statistically significant (HR, 1.03; P = .63). The median progression-free survival (PFS) observed with DD temozolomide was 55.5 months v 6.7 months with SoC (HR, 0.87; P =.06). Moreover, there was no difference in methylation status between the treatment arms.

A year later, in the AVAGLIO study (NCT00943826), the hypothesized OS improvement from adding an anti-VEGF therapy to radiotherapy and temozolomide was not shown. The study of 921 patients with GBM randomized the patient to receive bevacizumab (Avastin) with radiotherapy and temozolomide vs placebo plus radiotherapy and temozolomide.⁴

The median OS shown with the experimental combination in AVAGLIO was 16.8 months compared with 16.7 months in the placebo arm (HR, 0.88; 95% CI, 0.76-1.02; P =.10). the median PFS shown was 10.6 months with added bevacizumab vs 6.2 months without (HR, 0.64 95% CI, 0.55-0.74; P < .001). Although there was a PFS benefit shown by adding bevacizumab, continued use of the combination was prohibited by the higher rate of toxicity compared with the placebo arm.⁴

More recently, trials of immune checkpoint inhibitors (ICIs) vs temozolomide in patients with GBM have also been negative.

In the phase 3 CheckMate 498 study (NCT02617589)5, which investigated radiotherapy in combination with nivolumab (Opdivo) in patients with newly diagnosed disease, the primary end point of improvement in PS was not met. Of the 560 patients treated with either radiotherapy and nivolumab (n = 280) or radiotherapy plus temozolomide (n = 280), the median PS was 13.4 months vs 14.9 months, respectively (HR, 1.31; 95% CI, 1.09-1.58; P =.0037). Further, the median PFS was 6.0 month with radiotherapy and nivolumab compared with 6.2 months with radiotherapy and temozolomide (HR, 1.38; 95% CI, 1.15-1.65), however, the experimental treatment appeared not be well-tolerated in patients.

In another trial (CheckMate 548; NCT02667587), the use of temozolomide plus nivolumab in the newly-diagnosed GBM with methylated MGMT promoter population, no survival advantage was shown compared with radiotherapy and temozolomide alone.⁶

A total of 716 patients in CheckMate 548 were randomized 1:1 to receive radiotherapy and temozolomide plus nivolumab or radiotherapy and temozolomide alone. The median PFS in the experimental arm was 10.6 months vs 10.3 months with the control, and the median OS was 28.9 months vs 32.1 months.No new safety signals were observed with added nivolumab.

“If you look back to the early-mid 1970s all the way 2015, for the average patient who is 65 years old or higher, there has been no difference in the 5-year overall survival rate. In the most recent time frame, the rate is under 5%,” explained Groot.

To date, temozolomide remains a SoC therapy for patients with newly-diagnosed GBM. Moreover, the recent introduction of targeted therapies has not offered much benefit, said Groot.

Modern Management

According to Wen, director, Center for Neuro-Oncology, and institute physician at Dana-Farber Cancer Institute, and professor of Neurology at Harvard Medical School, the use of concomitant and adjuvant of temozolomide with radiotherapy increases median survival by only 2.5 months, and the addition of TTF can add another 4-month increase in survival. “So, the benefit of standard therapy remains very modest,” he explained.

There is an unmet need for patients with GBM, according to Wen, and the introduction of VAL-083, an alkylating agent, could be beneficial.

Early research

In a phase 3 study, SoC is being assessed against VAL-083 and other investigational therapies in attempt to improve patient outcomes. GBM AGILE (NCT03970447) will include 1030 patients with either newly diagnosed or recurrent GBM.⁷

Wen explained, however, that a different approach may need to be taken for patients with MGMT unmethylated GBM, for example, following standard chemoradiotherapy with temozolomide or immediately after radiotherapy, but omitting temozolomide. A future indication for VAL-083 will be dependent on the amount of benefit demonstrated in GBM AGILE.

GBM AGILE is investigating the primary end point of OS along with the secondary end points, which include PFS, tumor response, and duration of response. Those treated in the VAL-083 arm will receive the standard 40-mg/m2 dose of the agent on day 1, 2, and 3 of a 21-day cycle.

Wen also explained that there are many other potential indications for VAL-083 aside from GBM being researched.

_REFERENCES:

_{1. Groot, J. Glioblastoma: The unmet medical need. Presented at: Kintara Therapeutics KOL Event on VAL-083: A Potential First-in-Class Small Molecule Chemotherapeutic for Glioblastoma; August 21, 2023; virtual.}

_{2. Wen PY. Treatment landscape and where VAL-083 could fit in, if approved. Presented at: Kintara Therapeutics KOL Event on VAL-083: A Potential First-in-Class Small Molecule Chemotherapeutic for Glioblastoma; August 21, 2023; virtual.}

_{3. Gilbert MR, Wang M, Aldape KD,e t ak. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32): 4085-91. doi: 10.1200/JCO.2013.49.6968.}

_{4. Chinot OL, Wolfgang W, Mason W, et al. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370:709-722. doi: 10.1056/NEJMoa1308345}

_{5. Omuro A, Brandes AA, Carpentier AF, et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial. Neuro Oncol. 2023;25(1):123-134. doi: 10.1093/neuonc/noac099.}

_{6. Lim M, Weller M, Adbaih A, et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol. 2022;24(11):1935-1949. doi: 10.1093/neuonc/noac116.}

_{7. A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). ClinicalTrials.gov. Updated August 22, 2023. Accessed August 22, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03970447}