Acalabrutinib Plus Venetoclax and Rituximab Signals Safety, Efficacy in MCL

Michael Wang, MD

The triplet combination of acalabrutinib (Calquence) plus venetoclax (Venclexta), and rituximab (Rituxan) may provide an alternative option for patients with treatment naïve mantle cell lymphoma (MCL) who are unable to receive chemotherapy, according to data initial safety and efficacy findings from a phase 1b.

In the ongoing, multicenter, open-label study (NCT02717624), the initial analysis looked at 21 patients with MCL who had a median age of 66. Based on promising efficacy and safety observed with Bruton’s tyrosine kinase inhibitor therapy combined with an anti-CD20 monoclonal antibody, investigators of the study believe that the combination has the potential to improve upon fontline convention chemoimmunotherapy

In an interview with Targeted Oncology^TM, Michael Wang, MD, a professor in the department of lymphoma and myeloma at MD Anderson Cancer Center, discussed the safety, efficacy, and tolerability of acalabrutinib plus venetoclax and rituximab in MCL.

TARGETED ONCOLOGY™: Can you give an overview of the safety and efficacy of acalabrutinib plus venetoclax and rituximab in patients with treatment naïve MCL?

WANG: 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 patient who died on the study, all died due to COVID unfortunately. Regarding the efficacy, we achieved a very unprecedented efficacy, with 100% of our patient 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.

How was the study designed?

The study was designed to enroll 20 to 30 patients with MCL who never treated it before. The primary end point is the safety analysis, and the secondary objectives includes efficacy, complete response, partial response, and overall response. Acalabrutinib was given from cycle 1 day 1 at 100 mg BID, until disease progression or intolerance. Venetoclax was given on cycle 2 day 1 with a 5 week ramp up period of dose escalation through cycle 5 to 25. Rituximab was given on day 1 of every cycle for 6 cycles and then after that, every other cycle until cycle 24. So, this is how dose limiting toxicity was assessed from cycle 2 day 1 to cycle 3, day 2.

What was most interesting about the results of the study?

What is striking and noteworthy for this study in that number 1, the combination is very safe. The patients tolerated the therapy very well. There are no toxins deaths, unfortunately 4 patients died from COVID without any relationship to our study therapy. The other issue is that the efficacy is very, very high. One hundred percent of our patients responded to therapy, and the complete response rate by PET scan was 90%.

What was the safety of the triplet? Did you see anything out of the ordinary?

The study therapy was tolerated very well. The most common side effects included diarrhea, headache, and fatigue, but the majority of those side effects are grade 1 or 2. There's hardly any grade 3 or 4 toxicities except diarrhea.

With ibrutinib, we are always concerned about atrial fibrillation. However, among the 21 patients, none of the patients had atrial fibrillation with a steady combination, and bleeding, accord in 33% of patients. And they were all grade 1 or grade 2, there was no grade 3 or 4 bleeding.

What unmet need is this combination filling in this population?

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. In order to replace chemotherapy, we have tried to doublets, we have tried to ibrutinib with rituximab in the frontline. We published this article recently in Journal of Clinical Oncology, and the response rate is very high. However, the cardiotoxicity was noted with atrial fibrillation.

So, although the doublet is very efficacious, we think that with the triplicated chemo free therapy in the frontline, we will have a better efficacy analysis, and hopefully, without severe toxicities. This study just showed that the response rate could be so high and 100%, it cannot be better. The complete response is 90% by PET scan, it can hardly be better. And the side effect profile was very tolerable and very tolerable. And that's, a good study, a wonderful combination with a safety profile and highest response rate that can be attained during the clinical trial. However, I want to note that we only have 21 patients in this trial. And in order to confirm this result, we need to we need more patients in the future trials.

_REFERENCE:

_{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.}