Addressing Intolerance and Resistance to BTK Inhibition Is Next Frontier in CLL Drug Development

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The development of agents to address intolerance and acquired resistance to BTK inhibitors addresses 2 of the major unmet needs for patients with chronic lymphocytic leukemia.

The development of agents to address intolerance and acquired resistance to Bruton tyrosine kinase (BTK) inhibitors addresses 2 of the major unmet needs for patients with chronic lymphocytic leukemia (CLL), according to Anthony Mato, MD, MSCE.

“Why talk about BTK as a relevant target in 2022/2023? This gives us [the] opportunity to try to understand what the unmet needs are for [patients with] CLL in the relapsed or refractory setting, identify whether there are any limitations for the [approved] covalent BTK inhibitors, and identify whether any of the [approved and investigational] drugs address those limitations,” Mato said in a presentation during the 40th Annual CFS®. Mato, who is the director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York, New York, noted that although the first-generation irreversible BTK inhibitor ibrutinib (Imbruvica) has the most long-term data, other covalent and noncovalent agents are making a name for themselves in the space.

Approved in 2014 for patients with CLL who have received at least 1 prior therapy and for patients with CLL and deletion (del) 17p, ibrutinib is a covalent BTK inhibitor that went on to receive indications for patients with Waldenström macroglobulinemia, small lymphocytic leukemia, and mantle cell lymphoma or marginal zone lymphoma.1,2

Long-term outcomes from RESONATE-2 (NCT01722487; NCT01724346) demonstrated that treatment with ibrutinib (n = 136) had a sustained benefit as a first-line treatment option vs chlorambucil (n = 133). At 8 years’ follow-up, the median progression-free survival (PFS) was not met in the ibrutinib arm (95% CI, 82.1-not estimable) vs 15 months (95% CI, 10.2-19.4) in the chlorambucil arm (HR, 0.154; 95% CI, 0.108-0.220).3 At the time of analysis, 42% of patients remained on ibrutinib.

Intolerance to BTK Inhibitors

“RESONATE-2 was a trial for…older patients without a del(17p) [randomly assigned to] ibrutinib vs chlorambucil. Not the most exciting comparison, but it does give us [an] opportunity to look at ibrutinib from a long-term efficacy perspective,” Mato said. “It also allows us to try to understand some of the limitations associated with this class [of drugs],” he added, noting that the overall discontinuation rate at 7 years was 53%. Reasons for discontinuation are of interest when evaluating the role of BTK inhibitors for patients with CLL, Mato said, highlighting that these rates and their causes “help to identify the limitations associated with continuous BTK inhibitor strategy.”

In the long-term data, the discontinuation rate associated with toxicity for ibrutinib was 24%, and investigators noted that this lessened over time. Atrial fibrillation (n = 5), pneumonia (n = 3), and palpitations (n = 2) were cited as the only adverse effects (AEs) occurring in more than 1 patient on the study.3


Bearing in mind that these data reflect the controlled environment of the clinical trial setting, Mato presented data from a real-world study of toxicities and outcomes for patients treated with ibrutinib.4 Among 616 patients, 41% discontinued ibrutinib at a median follow-up of 17 months, with toxicity cited as the leading cause of discontinuation. For patients who discontinued after receiving ibrutinib in the first-line setting (n = 19), 63.1% did so because of toxicity; this rate was 50.2% among those who received ibrutinib in the relapsed setting (n = 231).4

The most common toxicities in the relapsed or refractory population were atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9.0%), and diarrhea (6.6%).4 “This study identified covalent BTK inhibitor intolerance as a major emerging issue in the field of CLL,” Mato said. “When you have a treatment strategy that’s continuous, if [a patient] can’t stay on the drug, you’re not likely to achieve long-term disease remission.”

Acquired Resistance Sets Stage for Newer Generations of Agents

Most patients who discontinue treatment with a covalent BTK inhibitor have an acquisition of a BTK C481 mutation, which renders the covalent inhibitor unable to bind the target, Mato explained. “This seems to occur [among anywhere] between 53% and 87% of patients depending on what series you look at,” he said, adding that assays to identify mutations also play a role. BTK C481 mutations are also a mechanism of resistance for the second-generation, FDA-approved covalent BTK inhibitor acalabrutinib (Calquence).5

Attempts to address resistance have been made with agents such as idelalisib (Zydelig) being evaluated as treatment options for patients who are double refractory, having disease progression on both a BTK inhibitor and venetoclax (Venclexta). However, with a median PFS of 4 months6 and a median overall survival (OS) of 3.6 months following BTK inhibition,7 the PI3K inhibitor does not represent an acceptable standard of care in the modern setting, Mato said, citing data from 2 studies of treatment options for patients with relapsed or refractory CLL.6,7

“This is probably the biggest unmet need in CLL in the relapsed/refractory setting besides Richter transformation,” Mato said. “An important question to ask [is] whether any of [the other BTK inhibitors] can help to address this question.”

Acalabrutinib and Zanubrutinib

“The 2 most common [drugs] are acalabrutinib, which is already approved [for patients with CLL], and zanubrutinib [Brukinsa], which is approved in lymphoma but will likely be approved [in time for] patients with CLL,” Mato said. In highlighting some of the data associated with the 2 agents, Mato said to keep the following questions top of mind: Does the drug address the question of intolerance? Does the drug address the question of resistance? “If the answer is yes to either question, then it’s a drug that’s worthy of consideration for patients.”

In the phase 3 ELEVATE-TN trial (NCT02475681), acalabrutinib was evaluated alone and in combination with the CD20 antibody obinutuzumab (Gazyva) in treatment-naïve patients with CLL. Compared with chemoimmunotherapy (obinutuzumab plus chlorambucil), the median PFS was not reached in the acalabrutinib arms vs 27.8 months with chemoimmunotherapy. The HR in the combination arm vs chemoimmunotherapy was 0.11 (95% CI, 0.07-0.16; P < .001). The HR for acalabrutinib alone vs chemoimmunotherapy was 0.21 (95% CI, 0.15-0.30; P < .001).8

“The [PFS] curves between acalabrutinib and acalabrutinib/obinutuzumab are widening, suggesting that obinutuzumab really does add something from a PFS perspective that may change the standard of care in the future,” Mato said. “That benefit is most [observed] in those with favorable-risk [disease], not those with the del(17p). And although not statistically significant, there is a trend toward improvement in OS.”

AEs of clinical interest included atrial fibrillation, major bleeding, and hypertension. For patients in the acalabrutinib combination (n = 178) and acalabrutinib alone (n = 179) arms, the rates of incidence were 6.2% and 7.3%, respectively, for atrial fibrillation, 6.7% and 4.5% for major bleeding, and 9.6% and 8.9% for hypertension.8

In moving away from a cross-trial comparison, Mato cited data from a head-to-head study of acalabrutinib and ibrutinib for patients with high-risk relapsed or refractory CLL—ELEVATE-RR (NCT02477696).9 The trial met the primary end point of noninferiority, with both agents eliciting a median PFS of 38.4 months (HR, 1.00; 95% CI, 0.79-1.27). Turning to AEs of clinical interest, Mato noted that atrial fibrillation was significantly lower in the acalabrutinib arm (n = 266) vs the ibrutinib arm (n = 263), occurring at a rate of 9.4% and 16.0%, respectively.9 Hypertension and interstitial lung disease also occurred at higher rates in the ibrutinib arm (23.2% and 6.5%, respectively) vs the acalabrutinib arm (9.4% and 2.4%, respectively).9

Zanubrutinib, though not approved for patients with relapsed or refractory CLL, was compared head-to-head with ibrutinib in the phase 3 ALPINE trial (NCT03734016). The primary end point was overall response rate; 78.3% of patients in the zanubrutinib arm (n = 204) achieved a response compared with 62.5% of patients in the ibrutinib arm (n = 207). The 12-month PFS rate was 94.9% vs 84.0%, respectively.10

Any-grade atrial fibrillation was reported in 2.5% of patients in the zanubrutinib arm compared with 10.1% of patients in the ibrutinib arm.10 “We get a window into a head-to-head comparison of the AE profiles for these drugs. Atrial fibrillation was better with zanubrutinib vs ibrutinib, though interestingly, hypertension was similar between the 2 drugs, emphasizing that not all next-generation BTK inhibitors are created equal,” Mato said.

Noncovalent Inhibitors Show Promise

Pirtobrutinib, a highly potent and selective noncovalent BTK inhibitor, has demonstrated similar in vivo activity for wild-type patients as has ibrutinib but a superior efficacy for patients with BTK C481–mutant disease, Mato explained. The agent is under investigation in the phase 1/2 BRUIN trial (NCT03740529), data from which show that in patients who have received at least 2 prior lines of therapy, the agent elicited a response rate of 68% (95% CI, 62%-74%) among 262 patients.11

“Pirtobrutinib is much more potent against BTK than any of the other kinase inhibitors,” Mato said. “The median number of prior therapies was 3, with all patients having received a covalent inhibitor and 41% of patients having previously received venetoclax. A very relevant population, [in whom we are] trying to address the question of resistance.” Mato added that 43% of patients had a resistance mutation.11

“Regardless of the reason of discontinuation of the prior covalent BTK inhibitor…the response rate was maintained across the [subgroups], whether patients were heavily pretreated or had poor-risk features. Even those who [were penta refractory]—those who had a BTK inhibitor, PI3K inhibitor, venetoclax, CD20-directed agent, and chemotherapy—the response rate was maintained. [Similar to what] we see with other covalent BTK inhibitors, responses appear to deepen over time,” Mato said, highlighting that for patients who were on treatment for at least 12 months (n = 119), the response rate was 73%.11

In terms of safety, only 1 patient permanently discontinued because of a treatment-related AE. “What I always like to do when I read the results of a new trial is look at the discontinuation rate due to intolerance and the median follow-up because that gives you a window into how well the drug is tolerated,” Mato said.

In looking ahead, Mato said, “Assuming one day the noncovalent [agents] will be approved, [the landscape for] CLL will become complicated in the next 12 to 24 months.”


  1. Imbruvica (ibrutinib) receives regular approval by U.S. FDA in chronic lymphocytic leukemia (CLL) and CLL patients with del 17p. News release. Janssen Pharmaceutical Companies of Johnson & Johnson. July 28, 2014. Accessed November 9, 2022.
  2. Imbruvica. Prescribing information. Pharmacyclics LLC; 2022. Accessed November 9, 2022.
  3. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450. doi:10.1182/bloodadvances.2021006434
  4. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879. doi:10.3324/haematol.2017.182907
  5. Calquence. Prescribing information. AstraZeneca; 2022. Accessed November 9, 2022.
  6. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815
  7. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-4058. doi:10.1182/bloodadvances.2021005083
  8. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x
  9. 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
  10. Brown JR, Hillmen P, Eichhorst B, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Clin Lymphoma Myeloma Leuk. 2022;22(suppl 2):S266. doi:10.1016/S2152-2650(22)01324-6
  11. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study. Blood. 2021;138(suppl 1):391. doi:10.1182/blood-2021-147599