The treatment of patients with MCL who have received a cBTK inhibitor and stopped it due to toxicity or, more likely, disease progression, represent a major unmet need. In fact, it is fairly inevitable that patients on cBTK inhibitors will eventually progress. There have not been a lot of great treatment options available for these individuals. Historically, the options have included lenalidomide or lenalidomide plus rituximab, and these have had modest response rates. Bortezomib and participation in a clinical trial were other available options. 

We were thrilled a few years ago when the CAR T-cell product brexucabtagene autoleucel was approved by the US Food and Drug Administration. This drug has very high response rates of 91%, with complete response rates of 68%. However, this aggressive strategy is just not appropriate for some patients due to frailty or age. For other patients, the issue may be the logistics and timing that are involved or that the patient’s MCL is progressing too rapidly to get it under control. In addition, a number of individuals relapse even after CAR T-cell therapy. So, while this therapy has been a great addition, it has not solved the problem of treating the cBTK-exposed patient. 

Thus, we were all very excited about the approval of pirtobrutinib in January 2023. Pirtobrutinib, a noncovalent BTK inhibitor, has been studied in patients who have failed prior BTK therapy, either because of progression or intolerance. The single-arm, phase 1/2 BRUIN study evaluated pirtobrutinib and included 61 patients with MCL who had failed prior BTK inhibitor therapy. In this study, the overall response rate with pirtobrutinib was 52%, and 25% of those patients had a complete response. Pirtobrutinib was extremely well tolerated, with a favorable side-effect profile and a very low rate of discontinuation.

At present, the noncovalent BTK inhibitor pirtobrutinib or the CAR T-cell product brexucabtagene autoleucel are likely among the best options that we can reach for in the cBTK-failed setting. We do not have head-to-head data, and cross-trial comparisons are always a little risky; however, based on the available data, it would appear that, if a patient can get to a CAR T-cell product and if they are appropriate for that CAR T-cell product, they are more likely to get better disease control compared with a noncovalent BTK inhibitor. 

On the horizon, the global phase 3 BRUIN MCL-321 study is currently comparing pirtobrutinib with investigator's choice of the current standard-of-care cBTK inhibitors (ie, zanubrutinib or acalabrutinib), and, if this trial yields positive results, there could be a new label allowing pirtobrutinib for the second-line treatment of MCL. However, researchers are still trying to understand BTK inhibitor resistance in MCL. While many BTK inhibitor failures in chronic lymphocytic leukemia are due to BTK resistance mutations, this seems to be a little less common in MCL, and the exact mechanisms of resistance are a little less defined in MCL. In the relapsed setting, MCL starts acquiring TP53 mutations fairly regularly, which predicts resistance to just about every therapy. Unlike in chronic lymphocytic leukemia, where we have enough information to know that BTK inhibitors still perform quite well in patients with TP53-mutated and in 17p-deleted cases, we do not know how BTK inhibitors perform in TP53-mutated disease or how much that contributes to BTK failures. Investigators around the world are trying to sort that out right now.