Background: Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma (NHL) with an aggressive disease course in the majority of cases. While BTK inhibitors (BTKis) have markedly improved the outcomes in relapsed or refractory (R/R) MCL, a significant proportion of patients develop resistance to BTKis. CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) has shown remarkable activity in patients with R/R MCL, including in those progressing on BTKis. However, not everyone is eligible for CAR-T due to medical comorbidities, toxicity concerns (CRS and ICANS), or logistical challenges. Furthermore, the outcomes of patients with MCL who progress on CAR-T are poor. Hence, it is essential to identify small molecule inhibitors that are effective in R/R MCL for patients who are ineligible for CAR-T, as a bridge to CAR-T (for CAR-T eligible patients), and for those who progress following CAR-T.

Marginal zone lymphoma (MZL) is the third most commonly diagnosed B-cell lymphoma and accounts for ~7% of all newly diagnosed non-Hodgkin lymphoma (NHL) (Teral LR, et al. CA Cancer J 2016). The disease is heterogeneous with a relapsing and remitting course. BTKis are effective in R/R MZL with ORR ranging between 48-68%. However, responses are not deep (CR rates range between 3-25%) or durable. Additionally, patients who progress on BTKi, especially primary progressors, have poor outcomes (Epperla N, et al. Blood Adv 2023). Thus, there is an unmet need for novel therapies in patients with R/R MZL.

Given the increased expression of FGFR1 in MZL and preclinical data demonstrating FGFR1 as a candidate target for therapy in MCL (Sircar A, et al. Leukemia 2023), we hypothesize that the inhibition of FGFR1 signaling with pemigatinib will result in high response rates and durable remissions in patients with R/R MCL and MZL.

Study Design and Methods: PERFORM is a phase 2, multicenter, single arm, open-label, nonrandomized study (NCT06300528). Eligible patients are 18 years of age or older with histologically confirmed MCL or MZL and have received at least two prior lines of systemic therapy. Patients must have adequate end-organ function including ANC ≥1000 cells/mm3 independent of G-CSF support, platelet count ≥75,000 cells/mm3 independent of transfusion support, and hemoglobin ≥8 g/dL independent of transfusion support. These thresholds are lower in the event of documented bone marrow involvement. Patients with CNS involvement are excluded.

Treatment will be delivered in 28-day cycles. Pemigatinib will be administered orally once daily (13.5 mg). The duration of treatment will depend on treatment response. Subjects who achieve a partial response or better will continue study treatment until progression.

The primary endpoint is ORR at cycle 7 (C7) and key secondary endpoints include CR rate at C7, duration of response, progression-free survival, and overall survival in R/R MCL and R/R MZL cohorts, respectively.

Sample sizes for the R/R MCL and MZL cohorts were determined using Simon's two-stage minimax design. For both cohorts, the design aims to provide at least 80% power with a one-sided type I error rate of 5%, testing the null hypothesis of a historical ORR against a clinically meaningful alternative. For the R/R MCL cohort, the null hypothesis assumes an ORR ≤15%, with an alternative hypothesis of ORR ≥45%. A total of 14 participants are required. The null hypothesis will be rejected if 5 or more responses are observed among the 14 participants. For the R/R MZL cohort, the null hypothesis assumes an ORR ≤20%, with an alternative hypothesis of ORR ≥55%. A total of 11 participants are required. The null hypothesis will be rejected if 5 or more responses are observed among the 11 participants.

Diagnostic tissue, peripheral blood, and bone marrow aspirate from different timepoints are being banked for planned exploratory analysis to evaluate predictive factors of response to pemigatinib and identify mechanism of resistance to therapy. Whole exome and RNA sequencing analysis will also be performed.

This independent research (investigator-initiated trial) was supported by Incyte Corporation (Wilmington, DE, USA) through the supply of funding and drug (pemigatinib) free-of-charge.

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2025
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