Selection of Next-Gen BTK in CLL Limited By Lack of Direct Comparison

Nakhle Saba, MD

Associate Professor of Clinical Medicine

Tulane Cancer Center Member - Translational Oncology Research Program

New Orleans, LA

DISCUSSION QUESTIONS

• Consider the data presented for ALPINE (NCT03734016) and ELEVATE-RR (NCT02477696):​
  • How do you interpret the efficacy and safety outcomes?​
  • Can this data be cross-applied to first-line therapy?​

Mitchell Folbe, MD: It seems like, as far as safety, acalabrutinib [Calquence] seems to be better [than ibrutinib (Imbruvica)]. As far as efficacy, it’s good in one trial and the other trial seems to be pretty close.

Nakhle Saba, MD: You that mean for zanubrutinib [Brukinsa] vs ibrutinib, the efficacy is better, as opposed to for acalabrutinib vs ibrutinib it was [noninferior].^1,2

Folbe: Yes.

Deepa Jagtap, MD: We only had ibrutinib in the beginning, and everything is compared with it now. Efficacy wise, acalabrutinib is very similar, but definitely much safer, and I've had good response in my patients, even in patients with cardiac issues. Now with the approval of zanubrutinib, I feel that that is a front runner, and it is approved across many tumor types, so [we are getting] more experience with that drug, because of mantle cell and follicular [lymphoma]. Because it is also safe, it becomes the natural choice going forward. The main issue is the bleeding risk and the cardiac toxicity with ibrutinib. I also feel like hypertension and edema were adverse events from those drugs that used to make me reduce the dose.

Saba: Atrial fibrillation and cardiotoxicity are a concern. Hypertension, probably less so, but bleeding is a concern. The [rate of] high-grade and significant bleeding was not different between acalabrutinib vs ibrutinib, and it was not different between zanubrutinib vs ibrutinib.^1,2 It was the same. High-risk and significant bleeding are what keep me up at night. It's roughly around 4% across the board; add on anticoagulant or antiplatelet, and that will probably go higher, but that's a class-specific toxicity, and probably on-target toxicity by the direct effect on platelets. Don't let your guard down with regard to bleeds with any of these agents. You're still going to see something.

Can you extrapolate to the front line? Can you say that since zanubrutinib is superior to ibrutinib in the relapsed setting, it is superior to ibrutinib in the frontline? Or do you need to see head-to-head data in the frontline, which [likely] will not happen.

Rana Bilbeisi, MD: I think you can extrapolate it, because typically with trials, as they move forward in lines of therapy, the improvement in end points just gets better. If you had this as a someone who is naive to treatment, you're going to be even better improvement in progression-free survival compared with ibrutinib. I think you're going to see that efficacy is just better and better, just like we've seen in many clinical trials in the past. As they move it to frontline therapy, the progression-free survival and the overall survival tend to be better in those patients.

Saba: OK, so that's an extrapolation and an estimate. Without a head-to-head, no one can tell for sure. It's a personal opinion based on experience and extrapolation of data.

Vrushali Dabak, MD: On these relapsed trials, do we know what these patients got in their first line and was that compared? Was it similar between the patient populations?

Saba: Nearly everybody got chemoimmunotherapy, and those were roughly equivalent between the 2 arms. The median number of prior therapies was also balanced, and it was either 2 or 3, but you could not get a prior Bruton tyrosine kinase inhibitor [BTKI]. You cannot get a prior B-cell receptor pathway inhibitor…the B-cell receptor pathway could not be touched before being enrolled on these trials.

DISCUSSION QUESTION

• What impact do cardiac adverse events have on your choice of therapy?

Saba: Let’s focus a little bit on the cardiac adverse events such as atrial fibrillation and flutter. It is a class effect. We see it the highest with ibrutinib, and that's 16% to 17%. We keep seeing it across trials. In the long run, 16% to 17% of patients on ibrutinib have an atrial fibrillation or flutter, but if you do acalabrutinib or zanubrutinib, this number will drop. In that head-to-head trial with acalabrutinib, it was 9.2% all-grade and in the ALPINE with zanubrutinib, it was 7.1% all-grade.^1,2 Remember EKGs were done with zanubrutinib, but not with acalabrutinib. I'm not sure how much they missed on either arm, but for ibrutinib was 17% on ALPINE and 16% on ELEVATE-RR.

For anyone with cardiac comorbidities, would you [treat with BTKI]? Would you use cardio-oncology to optimize the risk of atrial fibrillation? Do you see any difference between zanubrutinib and acalabrutinib in terms of atrial fibrillation?

Jagtap: At least based on my experience, I've had more cases of atrial fibrillation with ibrutinib, and I used to hesitate to do this for patients who are older who have other cardiovascular risk factors or mild congestive heart failure, especially in light of bleeding problems and if they have to be on anticoagulation. But based on the limited experience, at least for a few years with acalabrutinib and zanubrutinib, I have not had this issue so much. [I see] a little bruising, but not so much atrial fibrillation. If they are otherwise good, I go for either of those.

_References:

_{1. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024;144(26):2706-2717. doi:10.1182/blood.2024024667}

_{2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}