Ibrutinib, a first-in-class oral inhibitor of Bruton’s tyrosine kinase, is the standard-of-care treatment for relapsed/refractory (R/R) mantle-cell lymphoma (MCL). A pooled analysis of ibrutinib-treated patients with R/R MCL enrolled in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) trials, as well as the extension study, CAN3001 (NCT01804686), was conducted. The current report presents updated pooled analysis results, with up to 7.5 years of extended follow-up, as well as a comparison of outcomes with ibrutinib versus the prior regimen.
Patients received ibrutinib 560 mg orally once daily until progressive disease or unacceptable toxicity (SPARK, RAY, PCYC-1104), or until clinical benefit (CAN3001). Time to next treatment (TTNT, defined as date of first dose of prior regimen to date of first dose of ibrutinib) was used as a progression-free survival (PFS) surrogate for the regimen prior to ibrutinib. Progression of disease (POD) on frontline treatment was categorized as early (TTNT <24 months) or late (TTNT ≥24 months).
A total of 370 ibrutinib-treated patients were included in the data analysis (as of April 2019). Patients had received a median of 2 (range, 1-9) prior lines of therapy (LOT), with an exposure of 11.1 (range, 0.03-92.4) months. The 5-year PFS rate was 19% (95% confidence interval [CI], 15-24), and the 5-year overall survival (OS) rate was 41% (95% CI, 35-47). The best outcomes were achieved by patients with 1 prior LOT and those who achieved a complete response (CR); in patients with 1 prior LOT, median PFS was 25.4 (95% CI, 17.5-51.8) and OS was 61.6 (95% CI, 36.0-not estimable [NE]) months, and was 67.7 (95% CI, 51.7-NE) months and not reached (95% CI, NE-NE), respectively, in patients with CR.
In the ibrutinib-treated cohort, median PFS was 12.5 (95% CI, 9.8-16.6) months; median TTNT on the prior regimen was 10.9 (95% CI, 9.1-12.6) months. Compared with benefit with prior regimens, 50% of ibrutinib-treated patients achieved longer PFS, and 27% had ≥12 months of additional benefit.
In second-line treatment, 99 patients received ibrutinib; of these, 43 (43%) had early frontline POD and 56 (57%) had late frontline POD. In patients with early frontline POD, ibrutinib delivered a similar magnitude of PFS benefit in second-line treatment (median PFS, 13.8 [95% CI, 4.3-24.2] vs 14.0 [95% CI, 12.0-16.1] months); median duration of response (DOR) and OS with ibrutinib therapy were 22.1 (95% CI, 10.6-35.6) and 23.5 (95% CI, 10.3-61.6) months, respectively. In patients with late frontline POD, second-line ibrutinib PFS was longer than frontline outcomes (median PFS, 57.5 [95% CI, 31.1-NE] vs median TTNT, 42.2 [95% CI, 35.2-46.5] months); median DOR and OS with ibrutinib therapy were NE (95% CI, 33.1-NE) and NE (95% CI, 51.9-NE), respectively.
With additional follow-up, no notable unexpected toxicities emerged.
Based on results of the pooled analysis of ibrutinib in R/R MCL with up to 7.5 years of extended follow-up, the study investigators concluded that ibrutinib therapy resulted in remissions >5 years when compared with historical controls, with increased likelihood of durable CRs and prolonged PFS when used in second versus later lines.
Rule S, et al. ASH Abstract 1538. Session 623.