PRT811 Showcases Early Signals of Efficacy in IDH-Mutant Glioma and Uveal Melanoma

Phase 1 research indicates that continued investigation with the protein arginine methyltransferase 5 (PRMT5) brain penetrant PRT811 may bolster the uveal melanoma and IDH-mutant high-grade glioma treatment paradigms, addressing unmet needs for these patient populations, according to Varun Monga, MBBS.

At the 2023 ASCO Annual Meeting, Monga presented findings from a phase 1 trial (NCT04089449) investigating PRT811 in these populations. In this trial, 2 patients in the glioma cohort (n = 38) responded to treatment, and both patients had IDH-positive disease. One of these patients achieved a complete response (CR) with a duration of response (DOR) of 31.0 months and was still receiving treatment at the data cutoff date, and the other patient had a CR with a DOR of 7.5 months and subsequently developed progressive disease (PD). In the uveal melanoma cohort (n = 23), 1 patient with splicing mutation–positive disease responded to the agent, achieving a partial response (PR) with a DOR of 10.0 months followed by PD.¹

Previously, in the dose-escalation phase of this trial, patients who received PRT811 at 600 mg daily experienced an 80% mean serum symmetrical demethylated arginine decrease.² Additionally, 1 patient with glioblastoma achieved a PR, and 1 patient with uveal melanoma experienced a 25% reduction in tumor burden per RECIST v1.1 criteria.

“For these 2 disease groups where there are limited treatment options, the PRMT5 inhibitor and brain penetrant, PRT811, certainly offers these patients a treatment option,” Monga said in an interview with OncLive^®.

In the interview, Monga, who is an associate clinical professor of medicine in the School of Medicine at the University of California San Francisco, discussed the mechanism of action of PRT811, key efficacy and safety findings from the phase 1 trial, and potential future directions with this agent.

OncLive: What was the rationale for the phase 1 trial of PRT811 in patients with recurrent high-grade glioma or uveal melanoma?

Monga: PRT811 is a novel compound. It targets PRMT5, which is highly expressed in patients with glioblastoma tumors and high-grade glioma tumors and is also active in patients whose tumors have splicing mutations, as we understand now from this study.

Could you expand on the patient population included this trial?

The dose-escalation phase [included patients with] all solid tumor subtypes. However, this presentation [at ASCO] was about the dose-expansion phase, wherein we [observed patients with] World Health Organization grade III and IV IDH-positive glioma. The uveal melanoma [subgroup] had 2 cohorts [who had] splicing mutation–positive and splicing mutation–negative disease.

What is the mechanism of action of PRT811?

PRT811 is a brain penetrant targeting PRMT5. PRMT5 has an epigenetic regulation. It dimethylates the protein substrates and controls these key cellular processes via epigenetic mechanisms and spliceosome inhibition mechanisms.

What efficacy data were reported with PRT811 in this trial?

We presented the safety and efficacy [data from] the patients who participated in the dose-expansion phase and who received the 600-mg recommended phase 2 dose [of the agent]. We investigated the patients with IDH-positive glioma vs those with IDH-negative glioma and compared [the efficacy and responses in] those 2 patient populations. We divided the uveal melanoma cohort into [those with] splicing mutation–positive and –negative [disease] to see the activity in those [populations].

The overall response rate [ORR] in the IDH-positive glioma subgroup was 12.5%. Additionally, patients in the uveal melanoma splicing mutation–positive subgroup had a 10.0% ORR. However, interestingly, the clinical benefit rate, which was defined as either a CR, PR, or stable disease for more than 6 months, was [31.3% and 30.3% in the IDH-positive glioma and splicing mutation–positive uveal melanoma cohorts, respectively]. There were 2 CRs in the patients with high-grade IDH-positive glioma and 1 PR in the uveal melanoma patient population.

What does the safety profile look like for PRT811?

The adverse effect [AE] profile was what we had anticipated. Constipation, nausea, and fatigue were [some of] the most common AEs. Fall and headache were more common in the patients with glioma compared with those with uveal melanoma. There were also some hematological toxicities, [such as] thrombocytopenia and anemia, [which occurred] in more than 15% of patients.

What are the next steps for this research?

For patients with IDH-mutant glioma, there are not many good treatment options for those who have received several prior lines of treatment. Similarly, for patients with uveal melanoma, there are limited treatment options. This drug certainly offers those patients a treatment option.

By itself, the ORR was at most modest, but there is potential for studying combination treatments [with] therapies like CDK4/6 inhibitors and IDH1 inhibitors that, as we heard in a plenary session [at the 2023 ASCO Annual Meeting], have activity in IDH1-mutant low-grade glioma. Those [agents] could potentially be combined with this drug to see whether there’s more promising data. More studies are to come, and a bigger phase probably needs to be conducted to see what the ultimate outcomes are with this drug.

Disclosures: Dr Monga reports research funding from Amgen (Inst), Astex Pharmaceuticals (Inst), C4 Therapeutics (Inst), Cogent Biosciences (Inst), Hutchison MediPharma (Inst), Oblato (Inst), Pfizer (Inst), and Prelude Therapeutics (Inst); and travel, accommodations, and expenses from Cogent Biosciences.

References

1. Monga V, Johanns TM, Stupp R, et al. A phase 1 study of the protein arginine methyltransferase 5 (PRMT5) brain-penetrant inhibitor PRT811 in patients (pts) with recurrent high-grade glioma or uveal melanoma (UM). J Clin Oncol. 2023;41(suppl 16):3008-3003. doi 10.1200/JCO.2023.41.16_suppl.3008
2. Falchook GS, Glass J, Monga V, et al. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas. Mol Cancer Ther. 2021;20(suppl 12):P044. doi:10.1158/1535-7163.TARG-21-P044