Data Continue to Refine Frontline BTK Inhibitor Selection in CLL

Richard R. Furman, MD

Along with the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva), the BTK inhibitor–based regimens of zanubrutinib (Brukinsa) monotherapy and acalabrutinib (Calquence) plus obinutuzumab represent the preferred options in the National Comprehensive Cancer Network (NCCN) Guidelines for the first-line treatment of patients with chronic lymphocytic leukemia (CLL) without 17p deletions or TP53 mutations. Ibrutinib (Imbruvica) monotherapy is also listed as another recommended regimen.¹

Selecting between BTK inhibitor–based regimens as frontline therapy for patients with CLL relies on several factors, and the continued emergence of data surrounding acalabrutinib, zanubrutinib, and ibrutinib have helped guide these decisions, according to Richard R. Furman, MD.²

“The first NCCN Guidelines [that did not have] chemotherapy as a first-line preferred recommendation was version 3.2019. That was important because we [have] had a BTK inhibitor available to us since 2013, when ibrutinib was approved for [patients] with mantle cell lymphoma. It certainly took a while [for BTK inhibitors] to make it as the primary first choice for [patients with] CLL,” said Furman, who presented on frontline BTK inhibitor selection at the 41st Annual CFS^®.

Furman is an attending physician at NewYork-Presbyterian Hospital, as well as the Morton Coleman, MD, Distinguished Professor of Medicine and director of the CLL Research Center at Weill Cornell Medical College of Cornell University, both in New York, New York.

Ibrutinib Shifts the Treatment Paradigm

Ibrutinib was the first BTK inhibitor to enter the CLL paradigm when the FDA approved the agent in 2014 for use in patients who received at least 1 previous therapy.³ Frontline ibrutinib was approved by the FDA in March 2016.⁴

The phase 1b/2 PCYC-1102 trial (NCT01105247) evaluated single-agent ibrutinib in patients with treatment-naive CLL who were over 65 years of age and those with relapsed/refractory CLL who were at least 18 years of age.⁵ At a median follow-up of 87 months (range, 1-98) for previously untreated patients (n = 27) and 82 months (range, 0.7+ to 98) for those with relapsed/refractory disease (n = 67), the median progression-free survival (PFS) was not reached (NR; 95% CI, not evaluable [NE]-NE) and 52 months (95% CI, 38-70), respectively. The estimated 7-year PFS rates were 83% and 34%, respectively.

“What is so important about [the treatment-naive] group is the patients who progressed either had a 17p deletion or a NOTCH1 mutation. Therefore, if [if a patient is] what I consider to be genomically stable and low risk, the likelihood of [them] doing poorly on a [frontline] BTK inhibitor is actually quite small,” Furman said.

Acalabrutinib and Zanubrutinib Enter the Fray

In recent years, prospective trials have evaluated both zanubrutinib- and acalabrutinib-based regimens against prior standard-of-care therapies and ibrutinib in the frontline setting for patients with CLL.

The phase 3 ELEVATE-TN trial (NCT02475681), which helped support the FDA approval of acalabrutinib for the treatment of patients with CLL in November 2019,⁶ randomly assigned patients 1:1:1 to receive acalabrutinib plus obinutuzumab (n = 179), acalabrutinib monotherapy (n = 179), or obinutuzumab plus chlorambucil (n = 177). Patients needed to be at least 65 years of age or between 18 and 64 years of age with a Cumulative Illness Rating Scale (CIRS) score of more than 6 and a creatinine clearance between 30 mL/min and 69 mL/min.⁷

At a median follow-up of 28.3 months (interquartile range, 25.6-33.1), acalabrutinib plus obinutuzumab (HR, 0.10; 95% CI, 0.07-0.17; P < .0001) and acalabrutinib monotherapy (HR, 0.19; 95% CI, 0.13-0.28; P < .0001) both demonstrated a statistically significant improvement in PFS compared with obinutuzumab plus chlorambucil. The median PFS was NR in both the acalabrutinib plus obinutuzumab and acalabrutinib monotherapy arms vs 27.8 months for obinutuzumab plus chlorambucil. The estimated 4-year PFS rates were 87%, 78%, and 25%, respectively.

Although Furman noted the trial was not powered to compare acalabrutinib/obinutuzumab vs acalabrutinib, data from a post-hoc analysis showed that the combination of acalabrutinib and obinutuzumab did demonstrate a statistically significant improvement in PFS vs acalabrutinib alone (HR, 0.56; 95% CI, 0.32-0.95; P = .0296).

Notably, the risk for atrial fibrillation (HR, 0.98; 95% CI, 0.29-3.39) and hypertension (HR, 0.93; 95% CI, 0.40-2.17) were similar between the acalabrutinib/obinutuzumab and obinutuzumab/ chlorambucil arms.

“Looking at the adverse effects [AEs], this is really what is going to be most important in [making decisions] between all our different BTK inhibitors. [Patients treated with] acalabrutinib had an increased risk of headache and cough,” Furman said. “We do see cough repeatedly show up in different acalabrutinib AE [data], and I can’t explain that. The headaches are actually well described, and they happen typically about 30 minutes after the dose, and it seems to be ameliorated by caffeine or Tylenol. It might relate to calcitonin gene–related peptide.”

Zanubrutinib monotherapy was compared with bendamustine plus rituximab (Rituxan; BR) in previously untreated patients with CLL or small lymphocytic lymphoma (SLL) in the phase 3 SEQUOIA trial (NCT03336333), and findings from this study supported the FDA approval of zanubrutinib for the treatment of patients with CLL/SLL in January 2023.⁸

The trial enrolled treatment-naive patients with CLL/SLL who were at least 65 years of age, or those who were unsuitable for fludarabine, cyclophosphamide and rituximab (FCR) with a CIRS of more than 6 and a creatinine clearance of less than 70 mL/min. Patients without 17p deletions were randomly assigned 1:1 to receive zanubrutinib or BR. Those with 17p deletions were not randomly assigned and received zanubrutinib monotherapy or zanubrutinib plus venetoclax.⁹

Findings presented at the 17th Annual International Conference on Malignant Lymphoma in June 2023 showed that at a median follow-up of 43.7 months, patients without 17p deletions treated with zanubrutinib (n = 241) achieved a median PFS that was NR (95% CI, NR-NR) vs 42.2 months (95% CI, 38.4-49.8) for those given BR (n = 238; HR, 0.30; 95% CI, 0.21-0.43; P < .0001). The median overall survival (OS) was NR in both arms.

Head-to-Head Comparisons of BTK Inhibitors

The phase 3 ELEVATE-RR trial (NCT02477696) evaluated acalabrutinib vs ibrutinib in previously treated patients with high-risk CLL harboring 17p or 11q deletions. The noninferiority trial included PFS by independent review committee assessment as the primary end point. Secondary end points of incidence of any-grade atrial fibrillation/flutter, incidence of grade 3 or higher infections, incidence of Richter transformation, and OS were evaluated in a hierarchical order, and they were only tested if a difference was observed between the 2 arms.¹⁰

At a median follow-up of 41 months, the median PFS was 38.4 months in both arms, and the study met its primary end point for acalabrutinib vs ibrutinib (HR, 1.00; 95% CI, 0.79-1.27).

Furthermore, acalabrutinib was associated with lower risk of atrial fibrillation (HR, 0.52; 95% CI, 0.32-0.86) and hypertension (HR, 0.34; 95% CI, 0.21-0.54). There was no difference in the rates of grade 3 or higher infections between the two arms, and no additional secondary end points were assessed.

“I really want to focus on the AEs. What you can see [is that] headache and cough increased with acalabrutinib. Then diarrhea, arthralgia, hypertension, contusion, and atrial fibrillation increased in the ibrutinib arm,” Furman noted. “Focusing on hypertension, the [any-grade] risk was 8.6% with acalabrutinib vs 22.8% with ibrutinib. [Any-grade] atrial fibrillation [occurred] in 9.0% [of patients with] acalabrutinib vs 15.6% with ibrutinib…This was a little bit more of a heavily [pretreated] patient population, so we might expect a little bit more of an issue with atrial fibrillation.”

Zanubrutinib was then compared vs ibrutinib in the phase 3 ALPINE trial (NCT03734016) in patients with relapsed/refractory CLL who were naive to a BTK inhibitor.¹¹

At a median follow-up of 15 months, findings showed that zanubrutinib (n = 207) elicited an overall response rate (ORR) of 78.3% (95% CI, 72.0%-83.7%) vs 62.5% (95% CI, 55.5%-69.1%) for ibrutinib (n = 208). The complete response (CR) plus CR with incomplete hematologic recovery rates were 1.9% and 1.4%, respectively. Patients with 17p deletions also experienced an improved ORR with zanubrutinib (n = 24) at 83.3% vs 53.8% for ibrutinib (n = 26).

The 12-month event-free survival rates were 94.9% for zanubrutinib vs 84.0% for ibrutinib (HR, 0.40; 95% CI, 0.23-0.69; 2-sided P = .0007).

Regarding safety, the rates of any-grade atrial fibrillation/flutter were 2.5% for the zanubrutinib arm vs 10.1% for the ibrutinib arm (P = .0014).

“You could see that [any-grade] cardiac disorders were increased with ibrutinib at 25.1% vs 13.7% [for zanubrutinib], and [any-grade] atrial fibrillation was 10.1% vs 2.5%, [respectively]. That certainly is very significant,” Furman said. “Hypertension was [just over] 16% in both arms, and this is very interesting, suggesting that hypertension is something that might be associated with zanubrutinib.”

Comparing Acalabrutinib With Zanubrutinib?

A prospective, head-to-head study evaluating acalabrutinib vs zanubrutinib has not occurred, and Furman explained that it is unlikely to happen in the future. A match-adjusted indirect comparison (MAIC) matched patients treated with acalabrutinib-based regimens during ELEVATE-TN with those given zanubrutinib in SEQUOIA.¹²

Findings presented at the 2023 International Workshop on CLL showed that the 36-month PFS rates by investigator assessment were 95% (95% CI, 90%-97%) for acalabrutinib plus obinutuzumab (n = 124), 86% (95% CI, 78%-91%) for acalabrutinib monotherapy (n = 124), and 84% (95% CI, 79%-88%) for zanubrutinib monotherapy (n = 241).

However, Furman cautioned against the inherent biases that could be associated with these types of analyses. “This is the sort of statistical windfall that generates a lot of confusion for most of us,” he said.

In the setting of BTK inhibitor intolerance, Furman pointed to data that support a change in BTK inhibitors in the absence of disease progression.

A phase 2 trial (NCT02717611) evaluated acalabrutinib in patients with relapsed/refractory CLL who were intolerant to ibrutinib. These patients (n = 60) received ibrutinib for a median treatment duration of 5.7 months, with 60% of patients receiving ibrutinib for less than 2 months. Forty percent of patients then treated with acalabrutinib experienced 27 recurrences of AEs; however, 67% of the recurrences (n = 18) were at a lower grade, 30% (n = 8) were at the same grade, and 4% (n = 1) were at a higher grade.¹³

“When [a patient is] intolerant to one of these [BTK inhibitors], they will probably be able to tolerate another one of these drugs. The most important thing to do [in the case of intolerance] is stay within the class and keep trying until you find what works,” Furman concluded.

Editor’s note: Dr Furman reported receiving research funding from Acerta/AstraZeneca/ BeiGene, Janssen, and TG Therapeutics; consulting for AbbVie, Acerta/AstraZeneca, BeiGene, Genentech, Janssen, Loxo Oncology, Morphosys, Pharmacyclics, Sanofi, TG Therapeutics, Verastem, and X4 Pharmaceuticals; and serving on a data and safety monitoring board for Incyte.

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