Most Patients With MCL in Study of Pirtobrutinib Show Stable or Improved Physical Symptoms, QOL

More than 70% of patients with mantle cell lymphoma (MCL) who took part in a study that led to accelerated approval of pirtobrutinib (Jaypirca; Eli Lilly) for treatment of relapsed or refractory disease had stable or improved MCL-related symptoms of physical function, fatigue, and global health status (GHS)/quality of life (QOL), according to results published this week.¹

Patient-reported outcomes (PROs) from the phase 1/2 BRUIN study (NCT03740529), which led to FDA’s January 2023 approval of pirtobrutinib for patients with R/R MCL,² appeared in Current Medical Research and Opinion (full approval in R/R MCL came in December 2025). Authors led by Catherine Coombs, MD, of the University of California at Irvine wrote that the findings represented “the final analysis” of PROs from the phase 1/2 BRUIN trial investigating pirtobrutinib monotherapy for the treatment of B-cell malignancies.¹

The authors also published PRO data for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) enrolled in BRUIN, which showed that 80% of these patients retained or improved CLL/SLL-related symptoms for physical function, fatigue, and GHS/QOL.¹

In December 2023, FDA issued an accelerated approval for pirtobrutinib for patients with CLL/SLL in who had received a prior covalent Bruton tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor.³

The final analysis published this week involved 263 patients with CLL/SLL and 124 with non-blastoid MCL who received pirtobrutinib monotherapy after prior BTK inhibitors. Patients with MCL were analyzed through cycle 20 and patients with CLL/SLL were analyzed through cycle 31. Only 39 patients with CLL/SLL were still being treated at the final data cut in January 2025; only 9 patients with MCL were still being treated.¹

Pirtobrutinib is a highly selective, noncovalent (reversible) BTK inhibitor with a different binding mechanism than earlier generation covalent inhibitors, such as ibrutinib or zanubrutinib. The different mechanism allows pirtobrutinib to overcome certain resistance mutations and safely maintain efficacy, even if patients have relapsed on other BTK inhibitors.

The initial phase 3 results for BRUIN showed median progression-free survival (PFS) of 28.4 months, with PFS not reached for CLL (not reached for patients with MCL).^4,5 Confirmatory trials met their end points and more studies are ongoing.¹

“An interim analysis of PROs presented in February 2023 showed that more than 70% of patients with CLL maintained or improved physical function, quality of life, and CLL/SLL-related symptoms over the first 24 cycles of pirtobrutinib treatment,” the authors wrote. “Similarly, interim analyses of those with MCL in the BRUIN trial found that more than75% maintained or improved physical function, quality of life, and MCL-related symptoms during the first 11 cycles of pirtobrutinib treatment.”¹

Two PRO-related secondary end points were included in the BRUIN trial for patients with MCL: these connected clinical tumor response categories with improvements in cancer-related symptoms, as well as links between clinical tumor response categories with improvement in physical functioning. Similar endpoints evaluated these associations as exploratory endpoints for patients with CLL. Exploratory endpoints also included descriptive analyses of change in PROs from baseline, time to worsening (TTW), and longitudinal analyses of PROs throughout the treatment period.

End points were assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ- C30). The questionnaire includes 5 functional assessments, with scales for physical, role, cognitive, emotional, and social functioning, along with 3 symptom scales for fatigue, pain, and nausea and vomiting. Finally, there is a global health status/quality of life (GHS/QOL) scale, and 6 single items assessing other symptoms commonly reported by patients with cancer. The scores are recorded on a scale from 0 to 100, with higher scores indicating better physical functioning and GHS/QOL; this is true for both CLL/SLL and for MCL-related symptoms and fatigue.

Cancer-related symptoms were evaluated with separate MCL-related symptom and CLL/SLL-related symptom scales.

Some notable findings included:

• Among patients with MCL still on study in January 2025, 11.8% reported improved physical function and none reported worsened physical function. Among those with CLL/SLL, 40.0% reported improved physical function and only 12.5% reported worsened physical function.
• Among patients with MCL still on study in January 2025, 35.3% reported improved MCL-related symptoms, while 5.9% reported worsening symptoms. Among those with CLL/SLL, 25.4% reported improved symptoms at data cutoff, while 11.1% reported worsening symptoms.
• Among those with MCL on study at data cutoff, 37.5% reported improvements in global QOL, while 12.5% reported worsening QOL. For the CLL/SLL group at data cutoff, 45.8% saw improvements in global QOL and 9.7% saw worsening of QOL.¹

The small size of the cohorts limited the ability to link PROs with long-term clinical outcomes in the time frame studied. Study authors reported, “There was no clear pattern in the proportion of patients with PRO improvements either at the time of tumor response or throughout the follow-up period by tumor response category.” Also, “Median [time to worsening] was not reached for any of the PRO end points due to the low rate of PRO worsening or death events among patients treated with pirtobrutinib.”

However, the authors noted that the small sample of patients with MCL and the fact that these patients remained stable “remains a favorable outcome, in that very few patients experienced any worsening of PRO during study treatment,” in contrast with the usual trajectory of the disease. By contrast, patients with CLL have a 5-year survival above 85%, which the authors say makes tracking PROs exceedingly important.

“It is likely that the small sample size in the MCL cohort precluded the identification of mean improvements that met a clinically meaningful threshold for longitudinal analyses,” they wrote.

References

1. Coombs CC, Woyach JA, Brown JR, et al. Patient-reported outcomes among patients with mantle cell lymphoma or chronic lymphocytic leukemia receiving pirtobrutinib in the BRUIN phase 1/2 study: final analysis. Curr Med Res Opin. 2026; 1–16. doi:10.1080/03007995.2025.2607542
2. FDA grants accelerated approval to pirtobrutinib in relapsed or refractory mantel cell lymphoma. FDA. January 27, 2023. Accessed January 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma
3. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 27, 2023. Accessed January 31, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic