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Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up

T he long-term outcome for patients with mantle cell lym- phoma (MCL) has been improving; however, historical evidence indicates that progression-free survival (PFS) declines and high-risk factors accumulate with each successive line of chemoimmunotherapy (CIT). 1,2 Median PFS with CIT declined by 70% from first-line (1L) (47.4 mo) to second-line (14.0 mo) and by 86% after third-line therapy (6.5 mo), 1 empha-sizing a need for therapies that will reverse or mitigate these trends. Ibrutinib is a once-daily, oral inhibitor of Bruton’s tyrosine kinase, established as a standard-of-care for patients with relapsed/refractory (R/R) MCL. 3–6 A previously published pooled analysis of 370 ibrutinib-treated patients with R/R MCL from 3 studies with up to 6.5 years’ follow-up (phase 2 PCYC-1104 [NCT01236391] and SPARK [NCT01599949], phase 3 RAY [NCT01646021]) showed that outcomes improved with earlier use of ibrutinib, with rapid and durable responses and median PFS >2 years when used at second line. 7 Here, we pres-ent updated efficacy and safety outcomes of these

T he long-term outcome for patients with mantle cell lymphoma (MCL) has been improving; however, historical evidence indicates that progression-free survival (PFS) declines and high-risk factors accumulate with each successive line of chemoimmunotherapy (CIT). 1,2 Median PFS with CIT declined by 70% from first-line (1L) (47.4 mo) to second-line (14.0 mo) and by 86% after third-line therapy (6.5 mo), 1 emphasizing a need for therapies that will reverse or mitigate these trends.
Ibrutinib is a once-daily, oral inhibitor of Bruton's tyrosine kinase, established as a standard-of-care for patients with relapsed/refractory (R/R) MCL. [3][4][5][6] A previously published pooled analysis of 370 ibrutinib-treated patients with R/R MCL from 3 studies with up to 6.5 years' follow-up (phase 2 PCYC-1104 [NCT01236391] and SPARK [NCT01599949], phase 3 RAY [NCT01646021]) showed that outcomes improved with earlier use of ibrutinib, with rapid and durable responses and median PFS >2 years when used at second line. 7 Here, we present updated efficacy and safety outcomes of these patients with up to 9.7 years of follow-up, and explore whether ibrutinib treatment changes the trend of declining PFS reported with CIT retreatment.
Among the 370 enrolled patients, 87 patients who were benefiting from ibrutinib treatment at the end of the 3 studies were rolled-over to the open-label long-term extension study CAN3001 (NCT01804686). As previously described, 7 disease evaluations were conducted per routine clinical practice and patients could continue treatment if they derived benefit, as assessed by the attending physicians. Positron emission tomography scans were not routine but were required to confirm complete response (CR). Only grade ≥3 adverse events (AEs) of special interest (major hemorrhage), and serious AEs (SAEs) were collected in CAN3001. PFS, duration of response (DOR), and overall survival (OS) were analyzed by number of prior lines of therapy (LOT; 1 and >1) and best overall response rate (ORR, CR, and partial response). The PFS for the regimen used before ibrutinib (denoted throughout as "estimated prior-line PFS") was calculated as time from the first dose of the prior regimen to the first dose of ibrutinib, which was likely to overestimate rather than underestimate the true PFS. Progression of disease (POD) on frontline treatment was categorized as occurring within 24 months (POD24) or later (POD ≥24).
Best outcomes with ibrutinib were noted in patients with 1 prior LOT and those achieving a CR (Table 1; Figure 1A). In ibrutinib-treated patients with 1 prior LOT (N = 99), median PFS was 25.4 months and median OS was 61.6 months ( Figure 1B,C); ORR was 77.8%, with a CR rate of 37.4% and a median DOR of 35.6 months. Median PFS with 2L ibrutinib was even longer (57.5 mo) in patients who experienced extended response to frontline CIT (POD ≥24, Figure 1D); median DOR was not reached (NR). In patients who achieved a CR (N = 102), median PFS and DOR were 68.5 and 66.4 months, respectively, and median OS was NR with a 5-year OS rate of 83%. The durability of response in patients who achieved a CR was similar regardless of number of prior LOT.
There was no late unexpected toxicity with ibrutinib during extended follow-up. The incidence of grade ≥3 treatment-emergent AEs (TEAEs) and SAEs was highest during the first year of treatment and generally decreased over time (Suppl. Table  S2). With up to 9.7 years of follow-up, the most frequent grade ≥3 TEAEs (in ≥5% of patients) included neutropenia (17.0%), pneumonia (13.5%), thrombocytopenia (12.4%), anemia (10.5%), atrial fibrillation (6.8%), and hypertension (5.1%). During the 2 additional years of follow-up since the last reported 2019 data cut, 9 the overall AE profile remained largely unchanged, indicating that long-term use of ibrutinib may not lead to cumulative toxicities. Among hematologic TEAEs, there were no new onsets of grade ≥3 or serious neutropenia, anemia, or thrombocytopenia. No new grade ≥3 or serious TEAEs of atrial fibrillation were reported. The rate of secondary malignancies was 11.9% (44/370) versus 11.6% (43/370) reported in 2019. 9 The most common type of secondary malignancy was nonmelanoma skin cancer. Since the 2019 report, 1 additional patient experienced a grade 5 TEAE of prostate cancer, which was considered unrelated to ibrutinib by the investigator.
This pooled analysis of ibrutinib treatment in R/R MCL with extended follow-up of nearly 10 years indicates that a notable number of patients had durable disease control for >5 years. Patients with only 1 prior LOT and those achieving a CR continued to have the best outcomes with ibrutinib. There was no emerging toxicity with additional follow-up.
A novel and interesting finding of this analysis is that treatment with single-agent ibrutinib in R/R MCL appears to have mitigated the historical trend of successive declines in median PFS with each line of CIT, 1 regardless of age and prior LOT. Among the 370 ibrutinib-treated patients, median PFS with ibrutinib was slightly longer versus the prior regimen (12.5   POD status following frontline therapy was previously shown to be predictive of poor survival with CIT-based salvage therapies. [10][11][12] In this analysis, outcomes with 2L ibrutinib were also impacted by frontline POD status, likely reflecting disease biology. Despite a much shorter PFS in ibrutinib-treated patients with frontline POD24 (median 13.8 mo) versus frontline POD ≥24 (median 57.5 mo), ibrutinib appeared to perform better in patients with POD24 than 2L CIT, based on historical reports (range, 5.5-9.7 mo). 1,12 This finding is consistent with data from the MANTLE-FIRST study, in which 2L ibrutinib was associated with significantly improved PFS and OS versus CIT (including BR or R-BAC) in younger patients with frontline POD24. 12 In the current pooled analysis, median PFS with ibrutinib was >4 years in patients with POD ≥24, which translated to a 15-month improvement versus frontline PFS. In this patient subgroup, ibrutinib reversed the trend of PFS decline reported with CIT retreatment. 1 The recent introduction of CAR-T therapy adds an additional sequencing option for patients who progress after 2L ibrutinib. In the phase 2 ZUMA-2 study, all patients were previously treated with BTKi (85% with ibrutinib, 24% with acalabrutinib, 9% with both). The median PFS with KTE-X19 in patients with POD24 versus POD ≥24 was 11.3 versus 29.3 months, respectively. 13 Interestingly, the CAR-T cell expansion peak was higher in patients who received prior ibrutinib versus acalabrutinib alone, indicating the unique property of ibrutinib to enhance CAR-T cell expansion. 14 The sequencing of ibrutinib and CAR-T in R/R MCL has potential to further improve the overall outcome in R/R MCL, regardless of POD status.
Taken together, these findings support the long-term efficacy and safety of single-agent ibrutinib in R/R MCL. Ibrutinib represents a significant advancement in treating MCL and should be considered a standard-of-care 2L treatment option, regardless of a patient's initial response to frontline therapy.