Ibrutinib Highly Active Against MCL in Pooled Analysis

Simon Rule, MD, PhD

In a pooled analysis of 370 patients, investigators determined that ibrutinib (Imbruvica) induced an objective response rate (ORR) of 66% in patients with mantle cell lymphoma (MCL), according to results published in the British Journal of Haematology.

“These results support the use of ibrutinib earlier in the treatment algorithm, with significant improvements in both progression-free survival (PFS) and overall survival (OS) when used at first relapse rather than later. It also seems that the poor prognostic factors that increase in later lines of therapy not only impact traditional chemotherapy but also ibrutinib outcomes,” first author Simon Rule, MD, Plymouth University Medical School, United Kingdom, and coinvestigators wrote.

“However, ibrutinib also appears to overcome some of the common poor risk factors, such as refractory status and disease stage, and may even provide an important option for patients with blastoid histology, allowing them to bridge to therapies that may lead to better long-term outcomes. Overall, ibrutinib represents a significant advance in the treatment of this challenging lymphoma and further ongoing studies will help define the optimal position in therapy as well as the best combination partner for ibrutinib,” added Rule et al.

Investigators reviewed data from 3 studies—the phase II PCYC-1104 (n = 111) and SPARK (n = 120) trials, and the ibrutinib-only arm of the phase III RAY trial (n = 139)—for this analysis. Based on data from the PCYC-1104 trial, the FDA approved ibrutinib in November 2013 for patients with MCL who have received at least 1 prior therapy.

All patients in Rule et al’s pooled analysis were assigned to 560 mg of daily ibrutinib until progression or unacceptable toxicity. Inclusion and exclusion criteria were similar in all 3 studies; however, SPARK required patients to have received prior rituximab (Rituxan) and bortezomib (Velcade), and RAY required patients to have received prior rituximab.

Median age was 67.5 years for the pooled population and patients received a median of 2 prior lines of therapy. Three-fourths of the patients had intermediate/ high-risk disease according to the simplified MCL international prognostic index (sMIPI), and 49% had bulky disease (longest diameter ≥5 cm). The overall median treatment duration across the 3 studies was 11 months. Median dose intensity was 98.4%, and the median duration of follow-up was 24 months.

At 18 months, 35% of patients were still on therapy. The median PFS in the overall population was 12.8 months (range, 8.5-16.6). Median OS was 25.0 months (range, 21.6 — not evaluable). The median time to first response was 2.07 months (range, 0.53-13.73) and median time to best response was 2.14 months (range, 0.53-24.74).

Investigators said that number of previous lines of therapy was a strong predictor for PFS and OS. Patients who received only 1 prior line of therapy had the longest PFS and OS (median not reached), and 2-year PFS and OS estimates were 57% and 68%, respectively.

ORRs and complete response (CR) rates improved over time. Overall, almost one-third of responders achieved a CR, with an overall CR rate of 20% and partial response rate of 46%.

Number of prior lines of treatment, refractory status, and low sMIPI risk scores were all predictors for response rates. For prior lines of treatment, patients treated with ibrutinib at second-line achieved the highest ORR (73%) and CR rate (27%).

Investigators found that patients who achieved a CR also had the longest PFS and OS. Median PFS and OS in these patients were not reached. At 2 years, PFS was 79% and OS was 92%.

“The pooled analysis confirms that response rates are consistently high across all the different subgroups examined, but PFS and OS are dependent on baseline characteristics,” the investigators wrote. “Both univariate and multivariate Cox regression models show similar and consistent results; together, these analyses indicate that blastoid histology, sMIPI, bulky disease, and ECOG performance status remain prognostic in terms of PFS and OS with ibrutinib.”

Investigators observed treatment-emergent adverse events (AEs) in 364 patients (98.4%). About 71% of patients experienced grade ≥3 AEs.

The most frequently reported all-grade AEs were diarrhea (39.5%), fatigue (34.9%), cough (21.9%), nausea (21.6%), peripheral edema (20.0%), and thrombocytopenia (20.0%). Other grade ≥3 AEs of clinical interest occurred less often, including atrial fibrillation (4.6%) and major bleeding (4.9%).

The incidence of other malignancies was 5.7% in the overall population, most of which (67%) were nonmelanoma skin cancers.

Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies (published online August 18, 2017). Br J Haematol. doi: 10.1111/bjh.14870.