PRMT5 Inhibitor Exhibits Efficacy and Tolerability in NHL, Advanced Solid Tumors

Ulrik N. Lassen, MD

GSK3326595, a PRMT5 inhibitor, displayed modest efficacy and safety signals that were consistent with those that were previously reported with the agent among patients with advanced solid tumors, according to results from the phase 1 METEOR-1 trial (NCT02783300) presented at the 2022 ESMO Congress.

There were 3 confirmed partial responses in patients with solid tumors; 2 in the cohort of patients with adenoid cystic carcinoma (n = 50; ACC) and 1 among patients with estrogen receptor (ER)–positive breast cancer (n = 47). One of the patients with ACC was previously treated and had a duration of response (DOR) of 9.3 months and the other patient with ACC, who was treatment naïve, experience a DOR of 1.9 months. The patient with ER-positive breast cancer had a median DOR of 3.7 months.

Additionally, patients with non-Hodgkin lymphoma (n = 29; NHL) experienced an overall response rate of 10%. Two of these patients, 1 with follicular lymphoma and 1 with diffuse large B-cell lymphoma (DLBCL), experienced a complete response.

The DOR for the patient with follicular lymphoma was 32.4 months and follow-up is ongoing. The DOR was 3.4 months for the patient with DLBCL. Another patient with follicular lymphoma had a partial response with a DOR of 2.7 months.

“The investor-based waterfall plot shows some regression among different tumor types,” Ulrik N. Lassen, MD, a clinical professor in the Department of Clinical Medicine at the University of Copenhagen in Denmark, said in an invited discussion of the findings. “That was especially [true] in cystic carcinomas and NHL. The study drug was well tolerated, and the actual data corresponds to what was seen in the dose-escalation part [of the study].”

The open-label METEOR-1 trial is the first-in-human study of GSK3326595 in adult patients with advanced metastatic solid tumors or NHL. Eligible patients had relapsed/refractory disease or disease with no standard of care. Patients also needed to have adequate organ function and an ECOG performance status of 1 or less.

In the part 1 dose-escalation portion, the recommended phase 2 dose of GSK3326595 was determined to be 400 mg every day. However, the does was subsequently changed to 300 mg once daily after an ongoing assessment of safety and tolerability. The NSCLC and ACC cohorts were initiated after the dose change and all patients received 300 mg GSK3326595

The objectives of part 2, which was the focus of the presentation, were clinical efficacy by ORR in disease-specific expansion cohorts. Duration of response, safety, and 6-month progression-free survival (PFS) in theglioblastoma multiforme (n = 29; GBM) subgroup were also explored.

Patients with triple-negative breast cancer (n = 22; TNBC), metastatic transitional cell carcinoma of the urinary system (n = 16; mTCC), human papillomavirus–positive solid tumors (n = 28), and non–small cell lung cancer (n = 7; NSCLC) made up the rest of the patients with solid tumors. Patients with NHL either had a TP53 mutation (n = 8), TP53 wild-type disease (n = 10), or unknown TP53 status (n = 11).

Additional data from the trial showed that patients in the TNBC, mTCC, ER-positive breast cancer, human papillomavirus–positive solid tumors, and NSCLC subgroups experienced stable disease at a rate of 9%, 44%, 35%, 32%, and 43%, respectively. Patients remained on treatment for a median of 1.4 months (range, 0.2-10.3), 3.1 months (range, 0.5-30.4), 1.6 months (range, 0.1-14.5), 2.5 months (range, 0-12.7), and 1.7 months (range, 1.1-18.1), respectively. Patients with GBM were treated for a median of 1.4 months (range, 0-7.1).

Twenty-four patients experienced stable disease among previously treated patients with ACC (n = 34). Patients with ACC who were treatment naïve (n = 16) achieved stable disease at a rate of 56%. The median time on treatment was 5.2 months (range, 0.5-24.1) and 4.2 months (range, 0.7-17.8) for the previously treated and treatment-naïve patients, respectively.

Two patients with TP53-mutant NHL experienced stable disease, 3 patients with TP53 wild-type NHL had stable disease, and 2 patients with NHL with an unknown TP53 status had stable disease following treatment with GSK3326595. The median time on treatment was 1.9 months (range, 1.4-37.3), 2.6 months (range, 0.6-7.3), and 1.8 months (range, 0.5-6.2), respectively.

Regarding safety, treatment-related adverse effects (TRAEs) of any grade were reported in 95% of the 218-patient safety population. Grade 3 TRAEs occurred at a rate of 46%, grade 4 TEAEs were present in 7% of patients, and no grade 5 events related to study treatment were observed.

Common any-grade TRAEs included fatigue (45%), anemia (41%), nausea (39%), and alopecia (31%). Grade 3 TRAEs were reported for anemia (24%), fatigue (8%), and thrombocytopenia (7%). There were 5 instances of grade 4 thrombocytopenia, 4 instances of grade 4 decreased platelet count, and 1 occurrence of grade 4 anemia.

Any grade serious TRAEs were seen in 19% of patients. Dose reduction due to any AE, treatment interruption or delay due to any AE, and treatment discontinuation due to any AE occurred at a rate of 56%, 70%, and 12%, respectively.

Reference

Postel-Vinay S. METEOR-1: A phase 1 study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors. Presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France. Abstract 456MO.