Ibrutinib/Rituximab Combo Induces 3-Year OS of 69% in Relapsed/Refractory MCL

Michael Wang, MD

Michael Wang, MD

The combination of ibrutinib (Imbruvica) and rituximab (Rituxan) produced durable remissions in patients with relapsed/refractory mantle cell lymphoma (MCL), according to 4-year follow-up results from a single-arm phase II clinical trial.¹

At a median follow-up of 47 months (range, 1-52), 58% (29 of 50) of patients had achieved complete remission. The median progression-free survival (PFS) was 43 months (range, 1-48) and 3-year PFS was 54%. The median overall survival (OS) was not reached and 3-year OS was 69%.

The median duration of response (DOR) was 46 months (range, 1-48) and 68% of patients had a response lasting &ge;24 months. Ninety percent (n = 10) of patients who had DOR <24 months had an intermediate- or high-risk MIPI score

The overall response rate (ORR) was 88% and 58% of patients had complete remission (CR). Fifteen (30%) had partial remission (PR). Three (6%) patients had stable disease and 3 experienced disease progression.

Twelve patients remain on study, all of whom had CR.

&ldquo;[The] combination is safe and efficacious in patients with RR-MCL, significantly prolonged survival in a subset of patients with RR-MCL, and has a favorable impact on long-term outcome in RR-MCL when compared to data from other non-transplant modalities,&rdquo; corresponding author Michael Wang, MD, professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, and colleagues wrote.

&ldquo;Unfortunately, this is not a curative regimen, and specific subsets of MCL, such as blastoid morphology, high-risk MIPI and high Ki67 (&ge;50%), continue to pose a therapeutic challenge. Further studies are needed to understand the pathobiology of these subsets of MCL.&rdquo;

In results of an open-label, single institution trial of 50 patients with relapsed/refractory MCL published in theLancetin 2016, the median PFS and OS were not reached at a median follow-up of 16.5 months (IQR, 12.09-19.28). At 15 months, OS was 83% (95% CI, 72-94.5) and PFS was 69% (95% CI, 57-84).²

Patients were assigned to 560 mg of continuous daily oral ibrutinib until progression or unacceptable toxicity and 375 mg/m²of weekly rituximab for 4 weeks during cycle 1, on day 1 of cycles 3 through 8, and then once every other cycle up for to 2 years.

Forty-four (88%) patients had ORR in the 2016 data (95% CI, 75.7-95.5), including 22 CRs (44%, 95% CI, 30.0-58.7) and 22 PRs (44%; 95% CI, 30.0-58.7). The median DOR, PFS, and OS were not reached.

Enrollment was open from July 2013 through June 2014 and patients were followed until January 2018.

Seven patients improved from PR to CR from 2016 to 2018.

The median patient age was 67 years (range, 45-86), and 16 (32%) were aged >70 years. Seventy-six percent were men and all had an ECOG performance status of 0 to 1. Fourteen percent had blastoid morphology. Half of patients had intermediate-risk disease by MIPI score, 36% were high risk, and 14% were low risk.

Seventy-seven percent were Ki67-low (<50%) while 22% were Ki67-high (&ge;50%). Fifty-three percent had Ki67 &ge;30%.

Patients in the Ki67-low group enjoyed a significant survival advantage over the Ki67-high group. The median PFS was not reached for Ki67-low patients compared with 8 months for Ki67-high (P<.0001). The 3-year PFS similarly favored Ki67-low, 68% versus 1%. Three-year OS in the Ki67-low group was 67% compared with 27% for Ki67-high (P<.0001).

Lead study author Preetesh Jain, MBBS, MD, DM, PhD, et al also found that patients with nonblastoid morphology had a better median PFS than those with blastoid (48 vs 21 months;P= .16). Similarly, nonblastoid morphology (P= .15) was associated with superior OS.

Those with the MIPI low- or intermediate-risk those in the high-risk MIPI had a poorer median PFS. Three-year OS was 98% in the low-risk MIPI group and 75% in intermediate-risk compared with 44% for high-risk.

&ldquo;These outcomes are significant in the RR-MCL setting where most of the nontransplant treatment modalities do not induce durable responses,&rdquo; Jain et al wrote.

The median event-free survival was 16 months. Twenty (40%) patients received &ge;24 cycles of treatment and the median number of cycles was 17 (range, 1-56).

Eighteen (36%) patients died on study, primarily (78%) due to progression. There were no treatment-related deaths recorded. Thirty-eight (76%) patients discontinued treatment, including 14 (28%) who discontinued for disease progression. Nine (18%) discontinued due to toxicity. Eighteen patients required dose reductions of ibrutinib.

Compared with the 2016 findings, there was 1 additional incidence each of grade 3 anemia, diarrhea, pleural effusion, and hyperuricemia, as well as incidents of grade 3 pneumonia, sinusitis, and enterocolitis that were not seen in the previous data. There were no new cases of grade 3/4 atrial fibrillation or bleeding.

As with the earlier results, there was 1 incidence of grade 4 diarrhea and 1 incidence of grade 4 neutropenia.

&ldquo;There were no emergent unexpected serious toxicities,&rdquo; Jain et al wrote.

There are a number of ongoing trials exploring BTK inhibitors for MCL. Investigators are conducting a phase I/II study (NCT02558816) of ibrutinib in combination with obinutuzumab (Gazyva) and venetoclax (Venclexta), as well as SYMPATICO (NCT03112174), a phase III trial of ibrutinib and venetoclax. Ongoing trials are also looking into chemoimmunotherapy regimens for MCL, including phase 1 studies of acalabrutinib (Calquence), bendamustine, and rituximab (NCT02717624) and bendamustine/rituximab/ibrutinib/venetoclax (NCT03295240).

References:

1. Jain P, Romaguera J, Srour SA, et al. Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/ refractory mantle cell lymphoma (MCL) [published online May 22, 2018].Br J Haematol. doi: 10.1111/bjh.15411.
2. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial.Lancet Oncol. 2016;7(1):48-56. doi: 10.1016/S1470-2045(15)00438-6.