Eradat Explores BTK Inhibitors for Relapsed/Refractory CLL After Frontline BCL-2 Therapy

Herbert A. Eradat, MD

Health Sciences Clinical Assistant Professor

Department of Medicine, Hematology/Oncology

UCLA Health Jonsson Comprehensive Cancer Center

Los Angeles, CA

CASE SUMMARY

History and presentation:

• 70-year-old White man with asymptomatic lymphocytosis identified 4 years previously
• Initially monitored; after 2 years, developed anemia, night sweats, and splenomegaly
• Treated with venetoclax (Venclexta) plus obinutuzumab (Gazyva)
• Relapsed 13 months later
• Current ECOG performance status: 1
• Palpable splenomegaly
• Largest node: 4.2 × 2.8 cm; all others < 3 cm

Comorbidities:

• Coronary artery disease
• High cardiovascular risk due to history of non–ST elevation myocardial infarction status post 2 stents

Medications:

• Simvastatin
• Amlodipine
• Clopidogrel (Plavix), aspirin

Workup:

• Laboratory values:
  • White blood cells: 35.0× 10³ cells/μL
  • Absolute lymphocyte count: 22.0 × 10³ cells/μL
  • Hemoglobin: 9.5 g/dL
  • Platelets: 80 × 10³/μL
• Lactate dehydrogenase: 255 U/L
• Karyotype: complex; 4 abnormalities
• Fluorescence in situ hybridization: 11q deletion (del[11q]); without 17p deletion (del[17p])
• IGHV: unmutated
• Mutations of interest: unmutated TP53
• Largest node on imaging: 4.2 × 2.8 cm
• Due to progression after BCL-2 treatment, decision made to start Bruton tyrosine kinase inhibitor treatment.

Targeted Oncology: What are the available Bruton tyrosine kinase (BTK) inhibitors for patients with chronic lymphocytic leukemia (CLL)?

ERADAT: Throughout the landscape, the available therapeutic BTK inhibitors are acalabrutinib [Calquence], ibrutinib [Imbruvica], and zanubrutinib [Brukinsa]. These are the covalent binding inhibitors, and then [there] is pirtobrutinib [Jaypirca], and the field does not stop there. There is nemtabrutinib [MK-1026] now, and there are more BTK inhibitors coming. Pirtobrutinib is a noncovalent inhibitor vs the first 3, which are covalent.

In terms of FDA approval, acalabrutinib is approved in treatment-naive and relapsed/ refractory CLL and in relapsed/refractory mantle cell lymphoma [MCL].¹ There are data in Waldenström macroglobulinemia, but it’s not approved there. Ibrutinib is approved in treatment-naive and relapsed/refractory CLL and also in Waldenström macroglobulinemia, [but] MCL and marginal zone indications have been pulled.^2,3 Zanubrutinib is approved across the board in CLL in the treatment-naive and relapsed/refractory setting, in MCL in the relapsed/refractory setting, in Waldenström macroglobulinemia, and also in marginal zone lymphoma.⁴ [With] pirtobrutinib, so far the data that are mature are in relapsed/ refractory MCL, [so] that’s the FDA label.⁵ It’s not yet approved for CLL; the studies are ongoing.

In terms of the dosing, acalabrutinib is 100 mg twice a day, ibrutinib is one 420-mg tablet daily, and zanubrutinib is either 160 mg twice a day or 320 mg once a day.^1,2,4 The pharmacokinetics data are identical, so you can pick depending on your patient’s preferences.

Q: What phase 3 study supports the use of zanubrutinib in CLL?

Highlighting the newest data, this is the ALPINE study [NCT03734016]. This was a randomized…open-label study for patients with relapsed/refractory CLL who have had 1 [or more] prior lines of therapy. They had to have measurable disease, [but] what was excluded was any Richter transformation, and any prior BTK inhibitors were excluded. Patients on warfarin…or vitamin K antagonists were excluded.

This was in second line and beyond. [Patients were randomly assigned] 1:1 to zanubrutinib vs ibrutinib. The primary end point was overall response rate [ORR], and the secondary end point was progression-free survival [PFS].

[As secondary end points] they also looked at atrial fibrillation and cardiac events, duration of response, and overall survival [OS], and patients were stratified according to age, 17p [deletion] status, and refractory status to prior lines of therapy. [Patients] were well balanced between the 2 arms, in terms of comorbidities….⁶ The median prior lines of therapy on this study was 1 in both arms. In terms of high-risk features like del(17p) and del(11q), those are very, very well balanced. [About] 22% of patients had [both TP53 mutation and] del(17p), and [approximately] 30% of the patients had del(11q), which is normally what you would see in the relapsed/refractory setting. The majority of patients, 73%, had unmutated IGHV status.

In terms of the prior lines of therapy, the majority of patients had an anti- CD20 monoclonal antibody as a prior line…83% of the patients had that and [approximately] 80% of patients had prior chemoimmunotherapy. Remember, at the time that this study started, chemoimmunotherapy was the standard strategy as the previous line of therapy and prior BTK inhibitors were excluded on this study.

Q: What were the efficacy and safety outcomes for this trial?

In terms of PFS, there was a very impressive improvement in PFS in favor of zanubrutinib.⁶ So at 24 months [the PFS rate] was 78% for zanubrutinib vs 65% for ibrutinib, and that was a consistently significant difference with an HR of 0.65 [95% CI, 0.49-0.86; P = .002].

That means a 35% reduction in the risk of progression if somebody went on zanubrutinib vs ibrutinib. If you look at the patient population with a TP53 mutation or del(17p) [or both], there is same pattern, [although] obviously the numbers are smaller here, so the [Kaplan-Meier] curves overlap…but clearly a trend in favor of zanubrutinib, and the HR here was 0.53 [95% CI, 0.31- 0.88]. What that translates into is a 47% reduction in the risk of progression in favor of zanubrutinib. The ORR with zanubrutinib was 83.5% vs 74.2% with ibrutinib, with 7.0% complete response [or complete response with incomplete bone marrow recovery] in the zanubrutinib arm vs [4.9%] with ibrutinib…but clearly, there is a difference in ORR… and [76.5%] partial response [PR] with zanubrutinib vs [69.2%] PR with ibrutinib [Figure⁶].

Looking at the safety data, [the arms are] relatively similar: 99% of patients in both arms had some adverse event [AE].⁶ If you’re looking at grade 3 or higher AEs, it was 67% for zanubrutinib vs 70% for ibrutinib, a little less in the zanubrutinib arm. Looking at [AEs] of interest, there were relatively similar degrees of neutropenia: 16% with zanubrutinib vs 13% with ibrutinib. Hypertension was 14% vs 11%, respectively. This is a little bit of an outlier, and…there was a little bit more hypertension in this study than what we’re typically seeing in our zanubrutinib-treated population. Beyond that, pneumonia is 6% in zanubrutinib vs 8% for ibrutinib. Atrial fibrillation was 1.9% with zanubrutinib vs 3.7% in the ibrutinib group, certainly higher there, and increase in blood pressure was 1.2% in the zanubrutinib group, vs 3.1% in the ibrutinib group, so there’s a trend toward increase in blood pressure and increase in atrial fibrillation events when you’re treating with ibrutinib.

The other area of interest was cardiac disorders and atrial fibrillation. What you can see, especially for atrial fibrillation or flutter, is the ibrutinib arm’s [rate] starts to rise, and after a while, it seems to plateau, but there very early on there is an increase in rates of atrial fibrillation and atrial flutter in patients who were treated with ibrutinib. At least safety wise, from a cardiac standpoint, it seems like it was favoring [zanubrutinib].

Q: Could zanubrutinib be compared with acalabrutinib?

There is no randomized trial of acalabrutinib vs zanubrutinib, and it would be a great question. Do we want a trial of acalabrutinib? I’m not sure it would never happen, but I’m not sure I want one either. There are so many more important questions that I’m not sure that that’s...my top priority. I think generally it’s great for patients to have choices, especially so you can select therapy for patients.

Q: What data support the use of acalabrutinib in the relapsed/ refractory setting?

Moving on to ELEVATE-RR [NCT02477696], this was the study of acalabrutinib vs ibrutinib, again in the relapsed/ refractory setting. This patient population had to have a reasonably good performance status that included all patients, including patients who had del(17p) or del(11q). In terms of stratification…it was based on 1 to 3 lines of [prior] therapy vs more lines of therapy. The primary end point here was noninferiority in terms of PFS. The secondary end points they were looking at also [included] atrial fibrillation events, [Richter] transformation events, and OS.

The 2 arms were very well balanced in terms of the patient characteristics.⁷ The median prior lines of therapy was 2. In terms of prior treatments that the patients received, most of the patients had received some sort of chemoimmunotherapy; it tended to be a purine analog in [approximately] 60% of the patients and an alkylator in [approximately] 90% of the patients. Presumably, a reasonable number of patients got something like FCR [fludarabine, cyclophosphamide, rituximab (Rituxan)], or BR [bendamustine (Bendeka) plus rituximab]–type strategies. But around 4% to 6% of patients had received things like alemtuzumab [Lemtrada] or lenalidomide [Revlimid] in prior therapy. In terms of the disease characteristics, this was also similar to what you would see in the relapsed/refractory setting, so nothing unusual.

The [Kaplan-Meier] curves [for PFS] were [also] overlapping. The HR was 1.0 [95% CI, 0.79-1.27], and the [median] PFS was essentially identical between acalabrutinib vs ibrutinib, at least in this study [38.4 months (33.0-38.6) for acalabrutinib vs 38.4 months (33.0-41.6) for ibrutinib].⁷ When you look at the subgroup analysis, [whether] you’re looking at the age or performance status, or whether you’re talking about prior lines of therapy or molecular characteristics, whether you’re talking about del(17p) or del(11q), there wasn’t a trend favoring one agent over the other.

There was a little bit more trend toward diarrhea with ibrutinib [46.0% any grade] in comparison with acalabrutinib [34.6%] in this study.⁷ There were more headaches in the acalabrutinib arm, 34.6% vs 20.2% in the ibrutinib arm, [though] very few, 1.5%, had grade 3 [or higher]. There were more arthralgias [22.8%] and definitely more hypertension [22.8%] in the ibrutinib arm [compared with 15.8 and 8.6%, respectively, with acalabrutinib], and the other is atrial fibrillation, 15.6% with ibrutinib vs 9.0% with acalabrutinib. When you’re talking about grade 3 or higher, it was 4.5% vs 3.4%, respectively, but there were more grade 1 and 2 atrial fibrillation events in the ibrutinib arm.

_REFERENCES

_{1. Calquence. Prescribing information. AstraZeneca; 2022. Accessed November 9, 2023. https://tinyurl.com/2vs945cy}

_{2. Imbruvica. Prescribing information. Janssen Biotech, Inc; 2020. Accessed November 9, 2023. https://tinyurl.com/5mw3dyza}

_{3. Update on Imbruvica (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. AbbVie. April 6, 2023. Accessed November 9, 2023. https://tinyurl.com/mwmc35u2}

_{4. Brukinsa. Prescribing information. BeiGene Ltd; 2023. Accessed November 9, 2023. https://tinyurl.com/v4upwbbf}

_{5. Jaypirca. Prescribing information. Eli Lilly and Company; 2023. Accessed November 9, 2023. https://tinyurl.com/3t89zdem}

_{6. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582}

_{7. 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}