Tirabrutinib Generates Sustained Efficacy in Relapsed/Refractory PCNSL

Treatment with the second-generation BTK inhibitor tirabrutinib continued to elicit durable responses in patients with relapsed/refractory primary central nervous system lymphoma (PCNSL), according to findings from the final 3-year analysis of a phase 1/2 trial (jRCT2080223590), which were presented at the 2023 ASCO Annual Meeting.¹

At a median follow-up of 37.1 months and a data cutoff date of April 27, 2022, tirabrutinib generated an overall response rate (ORR) of 63.6% (n = 28; 95% CI, 47.8%-77.6%) in the entire study population, including an ORR of 52.9% (n = 9; 95% CI, 27.8%-77.0%) in patients who received the agent at 480 mg once daily while fasting, which is the approved dose of the agent in Japan. Additionally, the ORR was 60.0% (n = 12; 95% CI, 36.1%-80.9%) in patients who received the agent at 320 mg once daily and 100.0% (n = 7; 95% CI, 59.0%-100.0%) in those who received the agent at 480 mg once daily.

“PCNSL has aggressive symptoms, [and patients have] a poor prognosis,” lead study author Katsunori Asai, MD, PhD, of Osaka International Cancer Institute in Japan, said in an interview with OncLive®.

In 2020, tirabrutinib was approved in Japan for patients with relapsed/refractory PCNSL.² The approval was supported by findings from the phase 1/2 trial. Furthermore, on March 23, 2023, the FDA granted orphan drug designation to tirabrutinib for patients with PCNSL.³

This multicenter, open-label, single-arm trial enrolled 44 patients at least 20 years of age with a Karnofsky performance status of at least 70 and relapsed or refractory PCNSL who had received at least 1 prior therapy.¹

The primary end point of this trial was ORR by independent review committee. Secondary end points included investigator-assessed ORR, best overall response, duration of response (DOR), disease-free survival, time to response, progression-free survival (PFS), overall survival (OS), and safety.

Patients received tirabrutinib in 1 of 3 arms and continued treatment until disease progression or clinically unacceptable toxicity for the duration of 1, 28-day cycle. Cohort 1 (n = 20) received tirabrutinib at 320 mg once daily, cohort 2 (n = 7) received the agent at 480 mg once daily, and cohort 3 (n = 17) received the agent at 480 mg once daily while fasting.

In the overall population, patients had a median age of 60.0 years (range, 29-86) and a median Karnofsky performance status of 80.0 (range, 70-100). Patients had a median of 2.0 prior lines of therapy (range, 1-14).

At the data cutoff date, 5 patients were still receiving tirabrutinib, 4 of whom were in cohort 3 and 1 of whom was in cohort 1. Of those 5 patients, 4 achieved a best overall response of complete response (CR) or unconfirmed CR (CRu).

At a median follow-up of 37.1 months (range, 1.4-52.2), in the entire population, the median duration of treatment was 2.7 months (range, 0.8-46.9). Reasons for treatment discontinuation included disease progression (70.5%), adverse effects ([AEs] 9.1%), and other reasons (9.1%). In cohort 1, at a median follow-up of 37.9 months (range, 4.8-52.2), patients had remained on treatment for a median of 2.3 months (range, 0.9-46.9), and reasons for treatment discontinuation included disease progression (70.0%), AEs (10.0%), and other reasons (15.0%). In cohort 2, at a median follow-up of 48.6 months (range, 1.4-50.2), the median duration of treatment was 11.1 months (range, 0.8-29.6), and patients discontinued treatment because of disease progression (71.4%) and AEs (28.6%). In cohort 3, at a median follow-up of 36.8 months (range, 2.9-40.1), patients had remained on treatment for a median of 7.4 months (range, 0.9-39.6), and reasons for treatment discontinuation included disease progression (70.6%) and other reasons (5.9%).

In the overall population, 20.5% (n = 9), 15.9% (n = 7), 27.3% (n = 12), 15.9% (n = 7), and 20.5% (n = 9) of patients achieved best overall responses of CR, CRu, partial response (PR), stable disease (SD), and progressive disease (PD), respectively, and the median time to response was 0.9 months (range, 0.3-1.2). In cohort 1, 15.0% (n = 3), 10.0% (n = 2), 35.0% (n = 7), 20.0% (n = 4), and 20.0% (n = 4) of patients achieved best overall responses of CR, CRu, PR, SD, and PD, respectively, and the median time to response was 0.9 months (range, 0.9-1.2). In cohort 2, 14.3% (n = 1), 42.9% (n = 3), and 42.9% (n = 3), of patients achieved best overall responses of CR, CRu, and PR, respectively, and the median time to response was 0.9 months (range, 0.3-1.0). In cohort 3, 29.4% (n = 5), 11.8% (n = 2), 11.8% (n = 2), 17.6% (n = 3), and 29.4% (n = 5) of patients achieved best overall responses of CR, CRu, PR, SD, and PD, respectively, and the median time to response was 0.9 months (range, 0.8-1.0).

In all patients, the median DOR was 9.2 months (range, 0.6-45.9), the 12-month DOR rate was 46.4% (95% CI, 27.6%-63.3%), and the 36-month DOR rate was 19.8% (95% CI, 7.4%-36.5%). In cohort 1, the median DOR was 3.7 months (range, 0.6-45.9), and the 12- and 36-month DOR rates were 41.7% (95% CI, 15.2%-66.5%) and 20.8% (95% CI, 3.5%-47.9%), respectively. In cohort 2, the median DOR was 10.2 months (range, 0.6-28.7), the 12-month DOR rate was 42.9% (95% CI, 9.8%-73.4%), and the 36-month DOR rate was 0% (95% CI, not available [NA]-NA). In cohort 3, the median DOR was 12.1 months (range, 0.9-38.7), and the 12- and 36-month DOR rates were 55.6% (95% CI, 20.4%-80.5%) and 33.3% (95% CI, 7.8%-62.3%), respectively.

In the entire trial population, the median PFS was 2.9 months (95% CI, 1.8-11.1), the 12-month PFS rate was 32.5% (95% CI, 18.9%-46.9%), and the 36-month PFS rate was 13.9% (95% CI, 5.2%-26.7%). In cohort 1, the median PFS was 2.1 months (95% CI, 1.8-18.2), and the 12- and 36-month PFS rates were 29.4% (95% CI, 11.0%-50.7%) and 14.7% (95% CI, 2.7%-36.2%), respectively. In cohort 2, the median PFS was 11.1 months (95% CI, 1.4-22.0), the 12-month PFS rate was 42.9% (95% CI, 9.8%-73.4%), and the 36-month PFS rate was 0% (95% CI, NA-NA). In cohort 3, the median PFS was 5.8 months (95% CI, 1.0-13.0), and the 12- and 36-month PFS rates were 31.7% (95% CI, 11.6%-54.1%) and 19.0% (95% CI, 4.7%-40.6%), respectively.

Overall, the median OS was not reached (NR; 95% CI, 21.0-NA), the 12-month OS rate was 72.7% (95% CI, 57.0%-83.5%), and the 36-month OS rate was 56.7% (95% CI, 40.9%-69.8%). In cohort 1, the median OS was 37.9 months (95% CI, 11.2-NA), and the 12- and 36-month OS rates were 75.0% (95% CI, 50.0%-88.7%) and 55.0% (95% CI, 31.3%-73.5%), respectively. In cohort 2, the median OS was NR (95% CI, 1.4-NA), the 12-month OS rate was 85.7% (95% CI, 33.4%-97.9%), and the 36-month OS rate was 71.4% (95% CI, 25.8%-92.0%). In cohort 3, the median OS was NR (95% CI, 5.5-NA), and the 12- and 36-month OS rates were 64.7% (95% CI, 37.7%-82.3%) and 52.9% (95% CI, 27.6%-73.0%), respectively.

Of the entire trial population, 20 patients were treated for at least 6 months, and 6 patients received treatment for 3 years.

Across all treated patients, AEs of any grade occurred in 86.4% (n = 38), and AEs of grade 3 or higher occurred in 52.3% (n = 23). The most common AEs included rash (any-grade, 36.4%; grade ≥ 3, 2.3%), erythema multiforme (11.4%; 6.8%), drug eruption (9.1%; 4.5%), neutropenia (27.3%; 9.1%), leukopenia (25.0%; 9.1%), lymphopenia (18.2%; 6.8%), thrombocytopenia (11.4%; 0%), anemia (9.1%; 0%), increased blood bilirubin (9.1%; 2.3%), constipation (13.6%; 0%), stomatitis (11.4%; 0%), nausea (11.4%; 2.3%), vomiting (9.1%; 0%), epipharyngitis (11.4%; 0%), headache (11.4%; 0%), pyrexia (9.1%; 0%), hypokalemia (9.1%; 4.5%), and decreased appetite (9.1%; 2.3%).

In cohort 1, AEs of any grade occurred in 80.0% (n = 16) of patients, and AEs of grade 3 or higher occurred in 35.0% (n = 7) of patients. The most common AEs of grade 3 or higher were neutropenia (10.0%), leukopenia (10.0%), erythema multiforme (5.0%), drug eruption (5.0%), increased blood bilirubin (5.0%), and decreased appetite (5.0%).

In cohort 2, AEs of any grade occurred in 100% (n = 7) of patients, and AEs of grade 3 or higher occurred in 71.4% (n = 5) of patients. The most common AEs of grade 3 or higher were erythema multiforme (28.6%), lymphopenia (28.6%), drug eruption (14.3%), and hypokalemia (14.3%). One patient in cohort 2 experienced grade 5 pneumocystis jirovecii pneumonia and interstitial lung disease 32 days after tirabrutinib treatment initiation.

In cohort 3, AEs of any grade occurred in 88.2% (n = 15) of patients, and AEs of grade 3 or higher occurred in 64.7% (n = 11) of patients. The most common AEs of grade 3 or higher were neutropenia (11.8%), leukopenia (11.8%), lymphopenia (5.9%), nausea (5.9%), hypokalemia (5.9%), and rash (5.9%).

“Atrial fibrillation of any grade was not detected,” Asai said in the interview.

Most patients experienced their first treatment-related AE within 6 months of initiating tirabrutinib.

“Tirabrutinib showed durable responses and long-lasting efficacy in patients with relapsed/refractory PCNSL,” Asai said to OncLive®.

Disclosures: Dr Asai reports institutional research funding from Ono Pharmaceuticals.

References

1. Asai K, Narita Y, Nagane M, et al. Final three-year follow-up analysis of phase I/II study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma. J Clin Oncol. 2023;41(suppl 16):7548. doi:10.1200/JCO.2023.41.16_suppl.7548
2. ONO receives a manufacturing and marketing approval for Velexbru tablet 80mg, a BTK inhibitor, for treatment of recurrent or refractory primary central nervous system lymphoma in Japan. Ono Pharmaceutical Co., Ltd. News Release. March 25, 2020. Accessed August 10, 2023. https://www.ono-pharma.com/sites/default/files/en/news/press/sm_cn200325.pdf
3. ONO PHARMA USA's tirabrutinib receives orphan drug designation from the FDA for the treatment of primary central nervous system lymphoma. ONO PHARMA USA. News Release. March 23, 2023. Accessed August 10, 2023. https://www.prnewswire.com/news-releases/ono-pharma-usas-tirabrutinib-receives-orphan-drug-designation-from-the-fda-for-the-treatment-of-primary-central-nervous-system-lymphoma-301779681.html