BTK Inhibitors Continue to Offer Chemotherapy-Free Options for MCL Treatment

Michael Wang, MD

The use of Bruton’s tyrosine kinase (BTK) inhibitors have grown dramatically in the field of mantle cell lymphoma (MCL), providing a chemotherapy-free option for many patients.

At the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition, several studies were presented showing the value of BTK inhibitors in MCL, along with a potent option for when a patient fails therapy while receiving BTK inhibitor therapy.

Promising Triplets for Vulnerable Populations

Acalabrutinib With Venetoclax and Rituximab

BTK inhibitors have been shown to potentially improve results seen with first-line conventional chemoimmunotherapy. One study presented at ASH found that acalabrutinib (Calquence) when added to venetoclax (Venclexta) and rituximab (Rituxan), may help to provide a durable response in a vulnerable population.¹

“The unmet needs of this population, which is elderly patients with a newly diagnosed MCL, in the past and until now, internationally, we are treating these patients with chemotherapy. So, this study gave us a good result with chemo-free therapy that has a very superb safety and efficacy profile,” said Michael Wang, MD, a professor in the department of lymphoma and myeloma at MD Anderson Cancer Center, in an interview with Targeted Oncology™.

The study enrolled 21 patients with a median age of 66 (range, 51-85), with an ECOG performance status of 1 or less. Fifty-two percent of patients were intermediate risk and 19% were considered high risk.1

During the study, patients were administered 100 mg of acalabrutinib twice a day until disease progression or death, starting at cycle 1 day 1. Rituximab was administered at 375 mg on day 1 of each 28-day cycle for 6 cycles, followed by maintenance every other cycle for patients achieving complete response or partial response, through cycle 24. Venetoclax was administered via an initial 5-week ramp-up schedule to 400 mg a day through cycle 25.

The primary end points of the study included safety. Secondary end points included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). PET and CT scans were performed after 3, 6, 9, and 12 cycles, then every 6 cycles thereafter.

At the end of cycle, the ORR was 100% with a complete response (CR) rate of 90% and a partial response (PR) rate of 10%. The median duration of response was 19 months. Median PFS and OS were not reached, with the 1-year PFS rate being 89% (95% CI, 62–97). The 1-year overall survival (OS) was 95% (95% CI, 71–99). The median time to initial and best response.1

“Our study showed the triple combination of acalabrutinib plus venetoclax, and rituximab is tolerated very well, in patients with treatment naive MCL. And of the 4 patients who died on the study, all died due to COVID, unfortunately. Regarding the efficacy, we achieved a very unprecedented efficacy, with 100% of our patients responded to this triple combination. And the complete response rate was over 90% and the treatment with a higher rate of a moderate complete molecular response as well. So, the result of this analysis supports additional study,” said Wang.

ViPOR

As monotherapies, BTK inhibitors are often unable to induce deep responses. However, with triplets there is often continuous or maintenance therapy. The combination of venetoclax, ibrutinib (Imbruvica), prednisone, obinutuzumab (Gazyva), and lenalidomide (Revlimid) or the ViPOR regimen may potentially be an effective option without significant tumor lysis syndrome.2

“What ViPOR is, it's a novel combination targeted therapy regimen that simultaneously hits multiple key survival pathways utilized by B cell lymphomas for growth and survival, “said Christopher Melani, assistant research physician of the Lymphoid Malignancies Branch at the Center for Cancer Research, National Cancer Institute, in an interview with Targeted Oncology.

A phase 1/2 study was designed to test the efficacy of this combination. Phase 1 was a 3 + 3 dose-finding study was conducted while phase 2 is a dose-expansion study. At the time of data cutoff, 11 patients were enrolled and treated. Nine of these patients were treated in the relapsed/refractory dose-escalation portion while 2 patients were untreated in the dose-expansion study.

The median age of patients included in the study was 71 (range, 57-79) and 64% were male. Eighteen percent of patients were considered low-risk, 64% were considered intermediate-risk, and 18% of patients were considered high risk. Stage IV disease was seen in 91%of patients and bone marrow involvement was seen in 73% of patients. Extranodal disease was documented in 82% of patients. The median prior number of therapies in the relapsed or refractory population was 3 (range, 1-4). Forty-four percent of patients received a prior BTK inhibitor, 11% had received prior chimeric antigen receptor (CAR) T-cell therapy. Seventy-eight percent of patients were refractory to their last therapy. No patients received prior venetoclax or lenalidomide.²

Of the 11 patients enrolled, 10 were evaluable for response. The ORR was 100, with a complete response rate of 80%. All 8 patients who completed therapy achieved a complete response, 4 of which were post-BTK inhibitors. Six of those patients were refractory and 1 was post-CAR T-cell therapy. The DOR was not reached, with 90% of responses ongoing, ranging from 0.3 to 14.5 months at data cutoff. Median PFS and OS were not reached.

No dose-limiting toxicities were recorded in the 9 patients evaluable.

“The most common toxicity was hematologic, neutropenia, thrombocytopenia, anemia, but grade 3 or higher toxicities were actually very uncommon and occurred in under 20% of cycles. About 10% or less of patients actually required dose reductions or dose delays on therapy,” said Melani.

When BTK Therapy Fails

Research presented at ASH this year also addressed what to do if patients fail BTK inhibitors. Patients who fail BTK inhibitors tend to have a poor prognosis. Glofitamab is a T-cell engaging CD20/CD3 bispecific antibody. Glofitamab monotherapy may help to improve outcomes for patients who progress after BTK inhibitors.³

Tycel Jovelle Phillips, MD

“Glofitamab, being a bispecific antibody, in essence, has two binding epitopes. It'll bind to CD20, which is on the malignant B cell, and also bind to CD3, which is on the patient's T cell. And in that aspect, it brings it into close proximity with the hope of activating the T cell and causing a clonal T-cell expansion or to allow the patient's own immune system their T cells in this instance, to attack and kill off the tumor cells. Again, in this way, it's almost like an off-the-shelf CAR T product without the need for manufacturing. So, by using the patient's immune system, ideally, we can avoid some of the toxicities we see with some other mechanisms or treatments that we typically use for this patient population,” said Tycel Jovelle Phillips, MD, a clinical associate professor at the University of Michigan Health, in an interview with Targeted Oncology.

A phase 1/2 trial was designed to test glofitamab at several dose levels. At the time of data cutoff, 29 patients had received glofitamab. The median age of patients was 69 (range, 41-84) and 83% of patients had Ann Arbor Stage III-IV. The median prior lines of therapy was 3 (range, 1-6). Sixty-nine percent received prior BTK inhibitor therapy and 14% had prior lenalidomide therapy. Over half, 52%, were refractory to their first line of therapy. The median time since last therapy was 1.7 months.

In patients evaluated for efficacy (n = 21), the overall response rate was 81%, with a complete metabolic response rate of 66.7%. Similar responses were seen in patients who had received prior BTK inhibitors and those that have not. At a median follow-up of 2.4 months, 85.7% of patients with a complete response remained in remission.

Cytokine release syndrome (CRS) was the most common adverse event, occurring in 58.6% of patients. All incidents were grade 1 or 2, except for 1 incident of grade 4 CRS. Infusion-related reactions occurred in 24.1% of patients.

“A lot of these patients don't have access to a readily accessible treatment options post BTK inhibitors. A lot of these patients, they can't get to a CAR T center, or they don't want to necessarily separate from their families, they don't have a lot of great options and will succumb to the disease,” said Phillips. “So, the post BTK relapsed/refractory MCL patient [group] is still a patient [group] that has a very high need for new and novel treatments and even more treatments that can actually be given in the community and don't necessarily require being treated at a select center.”

_REFERENCES:

_{1. Wang M, Robak T, Maddocks K, et al. Safety and efficacy of acalabrutinib plus venetoclax and rituximab in patients with treatment-naïve (TN) mantle cell lymphoma (MCL). Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 3845.}

_{2. Phillips T, Dickinson M, Morschhauser F, et al. Glofitamab step-up dosing induces high response rates in patients (pts) with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most of whom had failed prior Bruton's tyrosine kinase inhibitor (BTKi) Therapy. Blood. 2021; 138 (1): 130. doi.org/10.1182/blood-2021-148949}

_{3. Melani C, Lakhotia R, Pittaluga S, Phase 1b/2 Study of Vipor (venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide) in relapsed/refractory and untreated mantle cell lymphoma: safety, efficacy, and molecular analysis. Blood 2021;138(1): 3537. doi: 10.1182/blood-2021-147032}