Promote-FL: Pirtobrutinib and mosunetuzumab to enhance treatment efficacy for patients with relapsed/refractory follicular lymphoma

Abstract Background: Bispecific T cell engagers have been approved to treat relapsed/refractory (r/r) follicular lymphoma (FL) after two prior lines of therapy given the promising efficacy. Despite the initial high response rate, remissions following T-cell engager (TCE) therapy are often not durable, and tolerance remains suboptimal. For instance, approximately half of the patients with FL experienced progression at one year of mosunetuzumab (mosun), and close to one fifth suffered grade 2 or higher cytokine release syndrome (CRS) during mosun (Budde et al, 2022, Lancet Oncol). These data revealed a substantial unmet need for more efficacious and better tolerated therapies in FL. Bruton tyrosine kinase inhibitors (BTKi) have shown activities in FL. For instance, zanubrutinib, a newer generation covalent BTK inhibitor (BTKi), showed an improved overall response rate (ORR) in combination with obinutuzumab compared to obinutuzumab alone (69% versus 46%) in the ROSEWOOD trial. Pirtobrutinib (pirto), a non-covalent BTKi, has also demonstrated an ORR of 50% in FL based on the BRUIN trial. Furthermore, emerging preclinical and clinical data have suggested effects of improving T cell fitness from BTKi, which may contribute to increase efficacy of T cell-based immunotherapy, e.g., TCE. Lastly, the anti-inflammatory effect of BTKi may help decrease CRS when BTKi is combined with TCE. Therefore, we aim to examine the safety and efficacy of pirto combined with mosun in this trial and hypothesize that adding pirto helps improve efficacy and decrease CRS of mosun. Study Design and Methods: This is a single-center, single-arm phase II trial, conducted at Fred Hutchinson Cancer Center, in Seattle, WA, and registered on clinicaltrials.gov as NCT06948786. It includes adult patients (≥18 years old) with histologically confirmed FL, grade 1-3A, who have received at least two prior lines of therapy including anti-CD20 agents. Patients should have measurable disease, ECOG performance status 0-1, and adequate organ and bone marrow function. It allows patients previously treated chimeric antigen receptor T cell therapy should they meet the other eligibility criteria. It excludes patients who have received pirto or CD20 × CD3 TCE unless patients had achieved remission for at least 24 months from previous TCE, have BTKi refractory disease, history of bleeding diathesis, other malignancy that interferes the trial therapy, disease involving central nervous system, uncontrolled infection, or clinically significant autoimmune condition. Eligible patients will be started on pirto at 200 mg daily one week prior to the initiation of mosun as a run-in phase and will continue pirto up to 52 weeks. Mosun will be administered per commercial intravenous dosing (C1D1 1 mg, C1D8 2 mg, C1D15 60 mg, C2D1 60 mg, then 30 mg every 21 days). Patients achieving a CR after eight cycles will discontinue mosun, but continue pirto for up to 52 weeks. Those achieving less than a CR but without disease progression at the end of the 8th cycle will continue for a total of 17 cycles of mosun per standard of care along with up to 52 weeks of pirto. Patients will be removed from treatment due to disease progression, unacceptable toxicity, or at the decision of patient/treating physician. The co-primary endpoints are complete response (CR) after 8 cycles of mosun and 1-year progression-free survival (PFS). The secondary endpoints include overall survival, event-free survival, and duration of response, as well as safety with a focus on CRS. We will also explore the impact of adding pirto to mosun on cytokine profile, T cell exhaustion, and microbiome, as well as patient-reported outcomes. We plan to enroll 22 patients and aim to demonstrate a CR rate of 82% and/or 1-year PFS rate of 80%. With the benchmark of CR at 60% and 1-year PFS at 58%, the above rates provide a power of higher than 80% given the one-sided type I error of 0.10. The analyses of the trial results will be primarily descriptive. Potential impact: This trial examines the potential impact of adding pirto to mosun in FL. If successful, it will provide a more efficacious and safer treatment option in heavily treated FL. This approach (adding BTKi) may be applied more broadly in T cell-based immunotherapy in B cell lymphoma.