Mantle cell lymphoma (MCL) is a rare, incurable form of non-Hodgkin lymphoma (NHL) with a heterogenous clinical presentation and course. While treatment options are numerous for patients with newly diagnosed disease, they are limited for those with relapsed/refractory (R/R) disease. Recent studies have demonstrated that the timing of relapse impacts long-term outcomes in this patient population, reporting poor outcomes among those who experience relapse within 24 months of initial definitive therapy.1 Covalent, permanent-binding Bruton tyrosine kinase inhibitors (cBTKi) are a well-established treatment in the second-line setting and appear to confer a substantial benefit even in cases of early relapse after initial therapy.2-5 However, when disease progresses despite cBTKi treatment, survival rates among patients with MCL are dismal. Although two second-generation agents have been developed, the major difference between these covalent drugs is increased fidelity to BTK, and progression on one BTKi translates to progression on them all. In this post-BTKi setting, other drugs with activity in MCL have yielded a limited duration of response, including lenalidomide (median progression free survival [PFS] not reported; duration of response [DOR]: 20 weeks) and venetoclax (median PFS: 3.2 months; DOR: 8.1 months).6-7 Thus, identifying new agents or novel combinations that can induce durable responses in cases of post-BTKi progression remains essential.2
In their recent study, Dr. Michael Wang and colleagues8 evaluated the safety and efficacy of a non-covalent BTKi, pirtobrutinib, in 164 patients with R/R MCL. The efficacy cohort included 90 patients with prior cBTKi treatment and 14 BTKi-naïve patients. The study’s notable findings include an improved safety profile relative to that of cBTKi treatment, with only 9.1% of patients discontinuing treatment due to adverse events. In the efficacy analysis, the authors observed an overall response rate (ORR) of 57.8% and a complete response (CR) rate of 20%, with a median DOR of 21.6 months and median PFS of 7.4 months. While no major differences in ORR were noted between patients who discontinued cBTKI treatment due to disease progression (ORR: 50%) and the overall population, the CR rate for the former group (7%) was approximately half that observed in the overall population. Additionally, the median DOR for pirtobrutinib after failure of cBTKi as the most recent line of therapy was 14.8 months, with a PFS of 5.5 months. This stands in stark contrast to the findings observed in patients who had previously discontinued cBTKi treatment due to intolerance, among whom the ORR was 92% and median DOR/PFS were not reached.
In Brief
Based on these results, pirtobrutinib has been granted accelerated approval for patients with R/R MCL who experience disease progression on a cBTKi. The major question raised here is whether this agent is currently positioned best to serve our patients with R/R MCL. This point is raised mainly based on the fact that the mechanisms explaining the efficacy of pirtobrutinib in patients with cBTKi-resistant MCL remain unclear: Could pirtobrutinib target something beyond BTK in this patient population? Despite these unanswered questions, the data clearly demonstrate significant differences in ORR and DOR between those who have experienced disease progression on a cBTKi and those who have discontinued cBTKi treatment due to toxicity. For those with MCL progression on a cBTKi, the PFS rate was comparable with that observed for venetoclax monotherapy, which is currently viewed as a suboptimal treatment option in this patient population. To support the current FDA indication, clear evidence concerning outcomes in patients who initiated pirtobrutinib therapy immediately after experiencing MCL progression on a cBTKi is necessary. In the end, pirtobrutinib may represent a small step forward for those with cBTKi-resistant R/R MCL, serving as a bridge to another, more effective therapy (e.g., CAR T-cell therapy, bispecific T-cell engagers9-11 ); however, based on its safety profile, it may represent a generational leap forward for BTKi-naïve patients. The current phase III trial of pirtobrutinib versus the approved cBTKi and the expected “real-world” utilization of pirtobrutinib in those with progression on a cBTKi should aid in answering these questions.
Competing Interests
Drs. Phillips and Herrera indicated no relevant conflicts of interest.
