Higher Doses of Ibrutinib/Venetoclax Not Linked With Higher Responses in Relapsed/Refractory MCL

Pipeline Report: March 2022

The combination of ibrutinib given at 420 mg and venetoclax at 200 mg elicited an objective response rate of 93.8% in patients with relapsed/refractory mantle cell lymphoma, according to results of a phase 1 dose-finding study.

Craig A. Portell, MD

Craig A. Portell, MD

The combination of ibrutinib (Imbruvica) given at 420 mg and venetoclax (Venclexta) at 200 mg elicited an objective response rate (ORR) of 93.8% (95% CI, 73.6%-99.7%) in patients with relapsed/refractory mantle cell lymphoma (MCL), according to results of a phase 1 dose-finding study (NCT02419560) published in Blood Advances.

The 420-mg and 200-mg doses of the BTK and BCL-2 inhibitors, respectively, were determined to be the optimal dosing combination for this patient population. Additional data showed that the dose-limiting toxicity (DLT) incidence was 6.2% (95% CI, 0.3%-26.4%).

The ORR benefit was not observed at higher doses of the combination, and toxicity reports were also more common. Treatment resistance was reported in nearly all arms, lead study author Craig A. Portell, MD, of the Division ofHematology/Oncology, Department of Medicine, at the University of Virginia, and coinvestigators wrote in the study.

“Our study would suggest that [ibrutinib at] 420 mg by mouth daily and [venetoclax at] 200 mg by mouth daily has a similar response rate to other studies of the combination,” the authors stated. “At this dose, there were fewer dose interruptions or reductions than previously reportedand improved toxicity profile.”

In November 2013, the FDA approved ibrutinib for the treatment of patients with MCL who have received at 1 one prior therapy.

Patients with relapsed MCL are often treated with BTK inhibitors; however, there is an unmet need for patients who experience relapse following this class of agents. In preclinical models, the addition of venetoclax to ibrutinib has demonstrated synergy. While the combination has been evaluated in other studies with antitumor activity, there have been limited dose findings with the regimen.

In the current, multicenter dose-finding study, investigators sought to determine the optimal dose combination of ibrutinib and venetoclax through a continual reassessment method in 35 patients with relapsed MCL. The trial was conducted at the University of Virginia, Washington University in St. Louis, City of Hope, and Emory University.

Patients eligible for enrollment had not previously been treated with a BTK inhibitor, had measurable disease that was relapsed/refractory to at least 1 chemotherapy-containing regimen, an ECOG performance status of 0 to 2, and were not at high risk for tumor lysis syndrome. 

There were 6 combinations of the BTK and BCL-2 inhibitors given at the following doses: oral ibrutinib tested at 280 mg, 420 mg, and 560 mg daily and oral venetoclax at maximum doses of 200 mg and 400 mg daily.

Venetoclax was first administered at 100 mg, then at 20 mg daily for 2 days, 50 mg for 5 days, and 100 days for 7 days before beginning the allocated dose of ibrutinib; venetoclax was given at a ramped-up approach based on the assigned dose level.

Ibrutinib plus 100 mg of venetoclax was then continued for 1 week before escalating the BCL-2 inhibitor to the maximum allocated dose.

“We hypothesized that doses lower than the single-agent dose [560 mg of ibrutinib and 400 mg of venetoclax] could achieve similar efficacy with limited toxicity,” the authors noted.

The combination regimens continued for six 28-day cycles, and patients were monitored for safety during treatment intervals.

The breakdown of dosing regimens was as follows: ibrutinib at 280 mg plus venetoclax at 200 mg (n = 2; arm A), ibrutinib at 420 mg plus venetoclax at 200 mg (n = 16; arm B), ibrutinib at 280 mg plus venetoclax at 400 mg (n = 8; arm C), ibrutinib at 560 mg plus venetoclax at 200 mg (n = 4; arm D), and ibrutinib at 420 mg plus venetoclax at 400 mg (n = 5; arm E).

Overall, the mean age was 63 years (range, 49-82), 83% of patients were male, and 43% had previously underwent an autologous stem cell transplant; 51% of patients were refractory to their last line of therapy. Patients either had 1 (57%), 2 (37%), or 3 (6%) prior lines of therapy. At time of study enrollment, most patients (77%) had stage IV disease. Nearly half (49%) of patients had low Mantle Cell Lymphoma International Prognostic Index score at enrollment.

The primary end point was incidence of DLT; secondary outcome measures included incidence and severity of adverse events (AEs), ORR, complete response (CR) rate, progression-free survival (PFS), and overall survival (OS).

Regarding TLS events, 1 occurred with the starting dose of 100 mg venetoclax but none were seen at the 20-mg dose. This led to a pause in the study enrollment and a change to the initial venetoclax dosing.

One patient was not allocated to the 560-mg of ibrutinib and 400-mg of venetoclax arm. A total 71.4% of patients completed the 6 cycles of combination therapy; 17.1% had disease progression or relapse prior to finishing treatment, and 8.6% of patients had an AE that led to treatment discontinuation.

Further results showed that across all dosing arms, the ORR was 82.3% (95% CI, 65.5%-93.2%) and the CR rate was 42.4% (95% CI, 25.5%-60.8%). There were differences in response or progression demonstrated between the arms.

Regarding safety, 3 DLTs occurred in the form of grade 4 neutropenia (arm E), grade 3 diarrhea (arm E), and grade 3 respiratory disorder (arm B).

Of the 25 patients who completed the study treatment after 6 months, 56% continued to receive ibrutinib (560 mg; n = 9 and lower doses, n = 5), and 44% had other types of treatment that comprised of chemotherapy (n = 3) and unknown (n = 8).

At a median follow-up of 26.7 months (range, 5.5-53.4) for all alive patients, the median PFS overall was 10.7 months; the median OS was 28.3 months. In arm B, the optimal dosing combination, the median PFS and OS were not reached at a median follow-up of 22.9 months (range, 5.6-53.4).

“Survival should be interpreted with caution given the study treatment only lasted for 6 cycles,” the authors stated. “In those who finished 6 cycles of combination therapy, there was an improvement in PFS for those that continued [ibrutinib] over other treatments; however, the limited numbers did not reach statistical significance [P = .10].”


Portell CA, Wages NA, Kahl BS, et al. Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Blood Adv. 2022;6(5):1490-1498. doi:10.1182/bloodadvances.2021005357

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