Monica D. Mead, MD, discusses the evolving use of the BTK inhibitors in the treatment of patients with MCL, the factors for selecting between ibrutinib, zanubrutinib, and acalabrutinib, and unmet needs for patients with MCL.
The continued emergence of data for BTK inhibitors, including ibrutinib (Imbruvica), zanubrutinib (Brukinsa), and pirtobrutinib (Jaypirca), have shifted the role of these agents in the treatment paradigm for patients with mantle cell lymphoma (MCL), including key findings the phase 3 TRIANGLE trial (NCT02858258), the phase 1/2 BGB-3111-AU-003 trial (NCT02343120), and the phase 1/2 BRUIN study (NCT03740529), according to Monica D. Mead, MD.
“Overall, this is a very exciting and dynamic time in MCL. We're seeing a lot of changes in our guidelines, as well as FDA approvals, so it's important to stay tuned for ongoing changes,” Mead said in an interview with OncLive® following her presentation on the treatment selection of BTK Inhibitors in MCL at a State of the Science Summit™ event
In the interview, Mead discussed the evolving use of the BTK inhibitors in the treatment of patients with MCL, the factors for selecting between ibrutinib, zanubrutinib, and acalabrutinib (Calquence), and unmet needs for patients with MCL. Mead is an assistant clinical professor of medicine, Hematologic Malignancy, at the University of California, Los Angeles (UCLA), UCLA Health, UCLA Jonsson Comprehensive Cancer Center, in Los Angeles, California.
Mead: I spoke on 3 different BTK inhibitors. The first was ibrutinib, and I reviewed the recent TRIANGLE data that were presented by Martin Dreyling, MD, [of University Hospital of Munich] at the 2022 ASH Annual Meeting. The second was zanubrutinib, and I discussed the single-arm, phase 2 BGB-3111-AU-003 study for zanubrutinib monotherapy. Finally, the third was the newest kid on the block: pirtobrutinib. I discussed the extended follow-up that was presented at the 2022 ASH Annual Meeting for pirtobrutinib monotherapy.
Overall, [its use] has changed quite a bit. As I discussed in my presentation, it was the first BTK inhibitor that was FDA approved. For years, it was the only 1 that we were using. Eventually, as we had additional approvals for both acalabrutinib and now zanubrutinib, overall, the use of ibrutinib has decreased. That's not due to less efficacy, but more so due to adverse effects [AEs].
Primarily in the CLL space, [investigators] looked at acalabrutinib and zanubrutinib compared with ibrutinib. Essentially, all 3 BTK inhibitors had very good efficacy, but ibrutinib had more substantial AEs. Due to those findings, it has been removed as a preferred BTK inhibitor in the NCCN guidelines. Also in clinical practice, its overall use has declined.
One of the points that I brought up was that [ibrutinib] is the most studied BTK inhibitor in the frontline setting. The TRIANGLE study was a frontline MCL trial [where patients] were randomly assigned to 3 different treatment arms. Two of those treatment arms incorporated Ibrutinib. Moreover, there's the [phase 3] SHINE trial [NCT01776840] that looked at ibrutinib in combination with bendamustine and rituximab [Rituxan] in a bit of an older patient population.
We now have 2 randomized, frontline MCL trials, and both of those have used ibrutinib. There are data to support using Ibrutinib. However, it's reasonable to extrapolate the findings of equivalent efficacy with a better toxicity profile that we found in the CLL setting to the frontline MCL setting. In my personal clinical practice, I'm unlikely to combine ibrutinib with chemotherapy, whether it be for younger, more intensive induction–eligible patients, or for my older, frailer patients where I might be considering bendamustine/rituximab. I would most likely substitute acalabrutinib or zanubrutinib in those settings, as well.
Zanubrutinib is a second-generation BTK inhibitor. Therefore, it has more precise binding to BTK, and it does not bind to some of the off-target receptors that ibrutinib does, hence it's more favorable toxicity profile. That more precise binding also lends to better pharmacokinetics with zanubrutinib, so you're getting earlier, deeper responses with zanubrutinib.
The follow-up for zanubrutinib is not as long as what we have for ibrutinib, but in the ibrutinib setting, we know that with longer follow-up, patients tend to have a deeper response. We're seeing similar findings in the zanubrutinib studies, as well.
In the extended follow-up for the AU-003 study, we found that the complete response rate continued to increase with longer follow up. [Zanubrutinib has produced] early responses, good efficacy, and a good toxicity profile. The AEs of interest, [such as] atrial fibrillation and significant bleeding, are quite low with zanubrutinib compared with ibrutinib.
There are still a lot of exciting and important questions that are remaining. The TRIANGLE data for ibrutinib combined with chemotherapy and ASCT in 2 of the 3 treatment arms, the outstanding question lies in the role of ASCT. The median follow-up presented was  months, and with the data that's been presented, the authors have concluded that there is sufficient efficacy seen with the addition of a BTK inhibitor to combination chemotherapy in the frontline setting. However, the jury is still out regarding the role of transplantation. Therefore, we are eagerly awaiting longer follow-up with the TRIANGLE data to understand if an ASCT benefits patients [more than] proceeding with rituximab and BTK inhibitor maintenance in the absence of a transplant.
The second most pressing question is how to manage a particularly challenging subset of patients with MCL: those with TP53 mutations. Studies using a few different agents have shown decreased efficacy of some of the agents in the TP53-mutated population, but we don't have a good solution for those patients at this time. Understanding more about how some of these other MCL-directed agents are performing in this patient population [is needed]. There are exciting ongoing clinical trials directed at trying to find a more creative solution for that very difficult-to-treat population.
It's nice to have options in discussing various BTK inhibitors with patients. As I've already alluded to, I am typically no longer discussing ibrutinib for the majority of my patients initiating new BTK inhibitor therapy. When trying to select between acalabrutinib vs zanubrutinib, I do discuss the different toxicity profiles. Between these 2, I am still favoring zanubrutinib based on its low rate of grade 3 AEs, and it can have a convenient once daily dosing.
I typically prioritize zanubrutinib in many of my patients; however, some patients end up wanting to go with acalabrutinib because we do have a longer follow-up with that agent compared with zanubrutinib.
The newest messages we have for physicians treating patients with MCL are [regarding] the incorporation of BTK inhibitors in the frontline setting. For younger patients with MCL, this is a very reasonable option. We now have the luxury of having multiple BTK inhibitors to select from, whether that be combining with chemotherapy in the frontline setting, or using single agents in the second or later lines of therapy.
Lastly, with respect to pirtobrutinib, it's currently approved in the second-line setting. We should stay tuned because there's a randomized study [the phase 3 BRUIN-MCL-321 trial (NCT04662255)] ongoing looking at standard BTK inhibitors in the second-line setting compared with pirtobrutinib, so we may [eventually] move that agent up into earlier lines of therapy.
Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/blood-2022-163018