Orelabrutinib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) Who Are Intolerant to Prior Bruton Tyrosine Kinase Inhibitors (BTKi): Updated Results from a Phase 2 Study

Background: BTKi therapy has revolutionized the treatment landscape of several iNHLs, with continuous, long-term administration being the current clinical practice. Despite their general tolerability, BTKis have a unique safety profile, and intolerance is a common reason for clinical discontinuation, potentially leading to early disease progression (PD) and shorter survival. Patients (Pts) who discontinued BTKi due to intolerance, yet with an ongoing therapeutic response, represent an unmet clinical need. Orelabrutinib, a potent second-generation irreversible BTKi, offers improved BTK selectivity and tolerability. A phase 2 study (ChiCTR2400080207) is being conducted to assess the safety and efficacy of orelabrutinib in prior BTKi-intolerant iNHL patients, with updated results being reported here.

Methods: Pts were eligible if they were aged ≥18 years, had histologically confirmed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL), and were intolerant to prior BTKi therapy. Pts received oral orelabrutinib 150 mg/day until PD or intolerant toxicity. The primary endpoint was safety assessed by the recurrence and severity change of adverse events (AEs) and AEs of special interest (AESI). Secondary endpoints included preliminary efficacy with tumor response, progression-free survival (PFS), and overall survival (OS).

Results: As data cutoff (July 9, 2024), 66 pts were enrolled and 64 pts (49 males; 40 CLL, 11 LPL/WM, 7 MZL, 6 MCL) were available for AE and efficacy analysis. Baseline characteristics included a median age of 64.5 years (range, 46-89), 87.5% ECOG PS of≤1, 45.3% two prior lines of therapy and a median BTKi duration of 11.0 months (range, 1.0-60.0). The majority of CLL pts had their disease under control at the time of switching to orelabrutinib: 79.5% with Binet stage A or B and 74.3% with Rai stage 0-II. All LPL/WM pts had median-high risk disease (IWMM standard), and 83.3% MCL/MZL pts were in Ann Arbor stage III-IV. Twenty nine (45.3%) pts were ibrutinib intolerant and 35 (54.7%) were zanubrutinib intolerant.

Sixty-four pts reported 166 intolerant AEs leading to prior BTKi discontinuation (median of 2 per pt; range, 1-4), commonly including anemia (43.7%), hypertension (34.4%), and platelet count decrease (29.7%); 25 (39.1%) pts experiencing ≥grade 3 intolerant events. After switching from prior BTKi to orelabrutinib, 101 (60.8%) intolerant AEs were resolved and 22 (13.2%) relieved. Resolved or relieved AESIs were hypertension (21/22 [95.4%]); cardiac events (12/13 [92.3%]); renal dysfunction (5/10 [50%]); liver dysfunction (2/2 [100%]); infectious events (6/6 [100%]) and bleeding events (4/4 [100%]). Among the 41 unresolved events, 11 (26.8%) showed a trend toward recovery and 25 (61%) remained stable.

After orelabrutinib treatment, 28 (43.7%) pts experienced AEs of any grade (median of 1 per pt; range, 1-2), with 6 (9.4%) pts reporting ≥grade 3 AEs. The most common AEs were hyperuricemia (17.2%), platelet count decreased (15.6%) and neutrophil count decreased (7.8%). Twelve (18.7%) pts reported recurrence of intolerance events, with common recurrences being platelet count decreased (9.4%), neutrophil count decreased (4.7%) and hyperuricemia (4.7%). All 17 recurrent events (100%) were classified as grade 1 or 2. There were no instances of recurrent hypertension, infection, cardiac events, or bleeding events, nor were there any treatment-related serious AEs or deaths.

As of the cutoff date, all (100%) pts had disease control. Among them, 11 (27.5%) CLL, 6 (100%) MCL and 4 (57.1%) MZL pts achieved the best response as complete response (CR); 25 (62.5%) CLL pts achieved partial response (PR) or PR with lymphocytosis (PR-L) and 3 (42.9%) MZL attained PR. At a median follow-up of 6.8 months, the median PFS and OS were not reached. No PFS events or treatment-related deaths occurred, with both PFS and OS rates remained 100%.

Summary/Conclusion: Orelabrutinib improved outcomes of prior BTKi-intolerant AEs, particularly the off-target toxicities. Pts who switched experienced minimal and low levels of intolerance recurrences and all achieved disease control. These updated results show promising efficacy and safety data of orelabrutinib in prior BTKi-intolerant iNHL pts.