Tazemetostat Plus Pembrolizumab Is Tolerable in Advanced Urothelial Carcinoma

Maha H.A. Hussain, MD, FACP, FASCO

Tazemetostat (Tazverik) in combination with pembrolizumab (Keytruda) demonstrated tolerability in patients with advanced urothelial carcinoma who were ineligible for platinum-based chemotherapy or experienced disease progression on or after platinum-based chemotherapy, according to data from the phase 1/2 ETCTN 10183 pilot study (NCT03854474).

Findings presented at the 2024 ASCO Annual Meeting showed that among evaluable patients (n = 25), the overall response rate (ORR) was 21%, which was comprised exclusively of partial responses (PRs). The rates of stable disease (SD) and progressive disease (PD) were 25% and 54%, respectively.

In arm A, patients who had disease progression on or after platinum-based chemotherapy (n = 12) achieved an ORR of 25% with tazemetostat plus pembrolizumab, and 2 of 3 responders had a PR that lasted more than 6 months. The respective SD and PD rates were 25% and 50%. In arm B, patients ineligible for platinum-based chemotherapy (n = 13) experienced an ORR of 17% with SD and PD rates of 25% and 58%, respectively.

“Improvement in efficacy relative to historical data of pembrolizumab alone appears to be modest,” lead study author Maha H.A. Hussain, MD, FACP, FASCO, and colleagues, wrote in a poster presentation of the data. “Response in tumors with COMPASS-related mutations and EZH2 activity will be evaluated.”

Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine; and deputy director and leader of the GU Oncology Program at Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Histone Methyltransferase EZH2 genes such as KDM6A, KMT2D, and KMT2C are overexpressed in approximately 67% of patients with muscle-invasive bladder cancer, and preclinical studies showed treatment with the EZH2 inhibitor tazemetostat led to smaller tumors and enhanced immune response in mice with bladder cancer.

ETCTN 10183 enrolled patients at least 18 years of age with pathologically confirmed, locally advanced or metastatic urothelial carcinoma who were ineligible for platinum-based chemotherapy (arm B) or experienced disease progression within 12 months of platinum-based chemotherapy (arm A). Key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria; an ECOG performance status of 2 or less; and adequate organ and bone marrow function. Prior treatment with a PD-L1 or EZH2 inhibitor was not permitted.

During the safety lead-in phase, patients received oral tazemetostat at 800 mg twice per day in combination with intravenous pembrolizumab at 200 mg once every 3 weeks for up to 2 years. The same regimen was then used during dose expansion. Patients were followed up to 1 year after treatment discontinuation, or until death or disease progression.

Identifying the recommended phase 2 dose during the safety lead-in was the study’s primary end point. Secondary end points included safety, tolerability, ORR, progression-free survival (PFS), and immune-related response.

Among all patients, the median age was 71 years (range, 67-76), 72% of patients were male, 96% of patients were White, and 88% of patients were not Hispanic or Latino. The primary disease site was bladder for most patients (88%), and other primary disease sites included renal pelvis (8%) and ureter (4%). ECOG performance status at baseline included 0 (40%), 1 (48%), and 2 (12%). Disease stage at baseline was comprised of stage II (8%), stage III (20%), or stage IV/IVB (72%). Twenty percent of patients had lymph node lesions with or without other lesions; 16% had liver lesions with or without lung, bone, or lymph node lesions; 52% had lung lesions with or without lymph node or other lesions; and 12% had bone or other lesions.

Additional data showed the median PFS was 3.06 months (95% CI, 1.38-7.75) in arm A and 3.02 months (95% CI, 2.40-5.65) in arm B.

In arm A, the median number of cycles of tazemetostat plus pembrolizumab was 5 (interquartile range [IQR], 3-11; range, 1-35), and the median treatment duration was 15 weeks (IQR, 9-35; range, 3-107). Forty-two percent of patients received at least 9 treatment courses.

In arm B, the median number of treatment cycles was 4 (IQR, 4-7; range, 2-12), and the median treatment duration was 13 weeks (IQR, 11-20; range, 8-37). Twenty-three percent of patients received at least 9 courses of treatment.

Regarding safety, grade 1/2 adverse effects (AEs) attributable to treatment occurred in 12 patients, and 8 patients had grade 3/4 AEs attributable to treatment. The most common AEs attributable to treatment included fatigue (grade 1/2, n = 9; grade 3/4, n = 0), nausea (n = 6; n = 1), hypophosphatemia (n = 6; n = 0), anemia (n = 2; n = 2), lymphopenia (n = 2; n = 2), maculopapular rash (n = 4; n = 0), skin/subcutaneous tissue disorders (n = 3; n = 1), increased creatinine (n = 3; n = 0), diarrhea (n = 3; n = 0), dysgeusia (n = 3; n = 0), hypoalbuminemia (n = 3; n = 0), hypokalemia (n = 3; n = 0), thrombocytopenia (n = 2; n = 1), lung infection (n = 1; n = 1), urinary tract infection (n = 1; n = 1), increased alkaline phosphatase (n = 0; n = 1), sepsis (n = 0; n = 1), and general disorders and administration site condition (n = 0; n = 1).

Reference

Hussain MHA, Kocherginsky M, Singh P, et al. A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183). J Clin Oncol. 2024;42(suppl 16):4574. doi:10.1200/JCO.2024.42.16_suppl.4574