ACE-CL-208 – A Phase 2 Study of Acalabrutinib in Ibrutinib-Intolerant Patients with Relapsed/Refractory CLL

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CLL Research: ACE-CL-208 – A Phase 2 Study of Acalabrutinib in Ibrutinib-Intolerant Patients with Relapsed/Refractory CLL

ACE-CL-208 is a phase 2 clinical trial of acalabrutinib in ibrutinib-intolerant and had relapsed (returned)/refractory (didn’t respond to prior treatment) chronic lymphocytic leukemia (CLL R/R). NCT02717611. The article outlining this study appears in the peer-reviewed medical journal Haematologica.

Dr. Kerry A. Rogers, M.D., is the principal investigator (PI) for this trial. Dr. Rogers is a CLL specialist at the James Comprehensive Cancer Center. The Ohio State University in Columbus operates the James Cancer Center.

At ASH 2020, Dr. Rogers gave an interesting oral presentation on the triple combination of ibrutinib, venetoclax and obinutuzumab (IVO) that we covered in January 2021.

 

Background - Acalabrutinib in Ibrutinib-Intolerant Patients

Targeted drugs that inhibit Bruton’s Tyrosine Kinase (BTK) are highly effective in treating CLL. These agents block signaling pathways by binding to BTK, an essential protein in the B-cell receptor pathway. BTK plays a role in the proliferation (rapid growth) and extended survival of malignant b-cells. The BTK inhibitor (BTKi) drugs interrupt the signals for proliferation and survival, resulting in control of CLL. The efficacy of BTK inhibition was demonstrated by ibrutinib (Imbruvica®), the first BTKi approved for CLL treatment.

Many patients have done exceptionally well on ibrutinib, with recent follow-up data from the RESONATE-2 study showing that more than 50% of study participants had not had disease progression after seven years. Unfortunately, some CLL patients are ibrutinib-intolerant. In a large retrospective study, adverse side effects were the most common cause of patients and providers deciding to discontinue ibrutinib. Some toxicities (side effects) require providers to use supportive care measures, such as steroids or pain relievers, while others require ibrutinib discontinuation, especially the more severe side effects. The rates of ibrutinib discontinuation due to adverse events (AEs) during extended follow-up are approximately 20%.

Acalabrutinib (Calquence®) is an oral BTKi approved by the FDA for treating CLL patients in 2019. Acalabrutinib binds to the same site as ibrutinib, also making it susceptible to the development of resistance. For this reason, acalabrutinib is not a choice for patients who have developed BTK resistance to ibrutinib. The design of this study is to determine if acalabrutinib is suitable for patients who are ibrutinib-intolerant. A promising new BTKi binds to BTK at another site and shows early efficacy in treating patients who developed BTK resistance. This drug was recently named pirtobrutinib and was formerly called LOXO-305.

The theory of why ibrutinib has a higher incidence of toxicities is that in addition to BTK, ibrutinib also binds strongly with several other signaling proteins. The side effects from the other proteins are known as “off-target” effects. Compared with ibrutinib, acalabrutinib is a more selective BTKi which means it binds BTK strongly and binds to fewer other proteins. Fewer off-target effects potentially give acalabrutinib an improved safety profile.

A low incidence of AEs, specifically atrial fibrillation and severe bleeding, have been reported with acalabrutinib.

Methods – ACE-CL-208

ACE-CL-208 is a multicenter, single-agent, phase 2 study enrolled adults who had ibrutinib-intolerance and for whom chemotherapy with a purine analog-based therapy (example, fludarabine) was not an option. The study used a two-option definition of ibrutinib-intolerance. The first definition of ibrutinib-intolerance is the patient discontinued ibrutinib due to a grade 3 or 4 adverse event(s) that persisted despite supportive care measures. The second definition of ibrutinib intolerance is the patient experienced grade 2 AEs related to ibrutinib that lasted for at least two weeks, whether the dose of ibrutinib was reduced or interrupted, despite optimal supportive care. [If you would like to know more about the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), please click here.] To be eligible, patients needed to have received at least one prior ibrutinib treatment for CLL and not be suitable for chemotherapy. After discontinuing ibrutinib, patients had to meet the International Workshop on CLL (iwCLL) 2018 criteria for progressive disease as a sign of continued disease activity. They could not receive any other treatment after ibrutinib.

In addition to being excluded for any CLL treatment after ibrutinib, patients were excluded if they had any persistent grade 3 or 4 AE attributed to ibrutinib or had evidence of progressive disease while on ibrutinib. Additionally, patients were excluded if they had evidence of active Richter transformation, or had ever received venetoclax (Venclexta®), or who had any significant cardiovascular disease such as symptomatic, untreated arrhythmias, congestive heart failure, or a heart attack within six months of screening. Patients with controlled, asymptomatic atrial fibrillation were permitted to join the study. Patients taking the anticoagulant drug warfarin (Coumadin®) were excluded, but other anticoagulant treatments were allowed.

Eligible ibrutinib-intolerant patients were treated with acalabrutinib 100mg twice a day until disease progression as long as they tolerated acalabrutinib therapy. Investigators used modified iwCLL guidelines to assess the response to treatment. The first assessment occurred three months after starting acalabrutinib.

The primary endpoint of ACE-CL-208 was investigator-assessed overall response rate (ORR) [according to iwCLL 2008 criteria.] The definition of ORR used was the proportion of patients who achieved a best overall response (BOR) of either complete response (CR), complete remission with incomplete bone marrow recovery (Cri), nodular partial remission (nPR), or partial remission (PR) at or before initiation of subsequent anticancer therapy. Secondary endpoints of efficacy included: duration of response (DOR; defined as the duration from initial response until documented progressive disease (PD); progression-free survival (PFS; defined as the time from the first dose to either disease progression or death. Additionally, secondary endpoints were time to next treatment (TNNT; defined as the time from the first dose to the start of subsequent anticancer therapy for CLL or death) and overall survival (OS; defined as the time from the first dose to death).

Results – ACE-CL-208 – Acalabrutinib in Ibrutinib-Intolerant Relapsed/Refractory CLL Patients

Between March 2016 and August 2017, sixty (60)patients enrolled in the ACE-CL-208 study. The median age of patients was 69.5 years (range: 43-88). The median time from CLL diagnosis to the first dose of acalabrutinib was 103.2 months (range: 10.3-307.9). Seventeen (28%) patients had deletion (17p). Clinicians determined that Thirty-one (52%) patients had Rai stage III or IV disease. The characteristics of the study patient cohort at enrollment appear below:

Efficacy of Acalabrutinib for Ibrutinib-Intolerant Patients:

The median duration of ibrutinib treatment was short at only 5.7 months (range: <1-55.5). Twenty-five percent ofibrutinib-intolerant participants (n=15) received ibrutinib for less than two months. Of these fifteen patients, only two discontinued acalabrutinib due to diagnosis with other solid-tumor cancers,

At a median follow-up of 34.6 months (range: 1.1-47.4), twenty-nine (48%) patients remained on acalabrutinib. Forty-Five (75%) patients had at least 12 months of treatment. The median acalabrutinib exposure was 32 months (range: 0.3-47.4). Thirty-one patients discontinued acalabrutinib, with the most common reasons being disease progression (n=14, 23%) and adverse events (AEs) (n=10, 17%). Other reasons for stopping acalabrutinib were patient decision (n=3), physician decision (n=3), and one case of comorbid anorexia.

The overall response rate (ORR) was 73% (n=44 of 60). Patients with deletion (17p) had a similar ORR of 71% (n=12 of 17). Three (5%) patients had complete remission (CR), two (3%) had complete remission with incomplete bone marrow recovery (Cri), thirty-nine (65%) had a partial response (PR), and three (5%) had a partial response with persistent lymphocytosis (PRL). Of the 13 patients who did not respond, four (7%) had stable disease, and one had disease progression. The remaining eight patients left the study before the first efficacy assessment at the end of cycle 3.

Median PFS “was not reached,” meaning that less than 50% of patients experience progressive disease during their follow-up period.

The estimated 24-month and 36-month PFS were 72% and 58%, respectively.

The median overall survival (OS) “was not reached”. The estimated 24-months and 36-month OS were 81% and 78%respectively.

Sixteen (27%) patients started a subsequent treatment for CLL, and the median TNNT was 44-months.

Safety of Acalabrutinib in ACE-CL-208 Study

The most frequent AEs of any grade with acalabrutinib were diarrhea (n=32, 53%), headache (n=25, 42%), contusion or bruising, (n=24, 40%), dizziness (n=20, 33%), upper respiratory infection (n=20, 33%) and cough (n=18, 30%).

The most frequent grade three or four AEs were pneumonia (n=9, 15%), neutropenia, or low neutrophil count (n=7, 12%), lymphocytosis [high lymphocyte count] (n=8, 13%) and thrombocytopenia [low platelets] (n=5, 8%).

To better understand acalabrutinib tolerability following ibrutinib discontinuation, researchers looked at the incidence of ibrutinib intolerance AEs during acalabrutinib therapy. Of the 60 participants, 27 ibrutinib-intolerance AEs occurred among 24 (40%) patients while receiving acalabrutinib. Sixty-seven percent of these AEs were lower grade on acalabrutinib than those patients experienced with ibrutinib. Only one patient had a higher grade AE on acalabrutinib than ibrutinib with an increased liver function test (LFT). In this patient, the LFT was grade 2 on ibrutinib and grade 3 on acalabrutinib. Two patients who had atrial fibrillation with ibrutinib experience this condition at a lower grade with (3 vs. 2) and (2 vs. 1).
Eleven deaths occurred during the study, with seven deaths due to AEs. Two of the seven AE-related deaths occurred while receiving acalabrutinib (1 each, pneumonia and subdural hematoma). The remaining five deaths occurred after the patient stopped acalabrutinib.

Conclusions – Acalabrutinib in Ibrutinib-Intolerant Relapsed CLL Patients

The Phase 2 ACE-CL-208 study shows that acalabrutinib is a good alternative in patients who are ibrutinib-intolerant because of unmanageable side effects. Acalabrutinib was well tolerated in a large proportion of this population. The ORR of 73% with the median PFS not being reached demonstrate durable disease control as expected with the BTKi class of drugs.

Ibrutinib and acalabrutinib are recommended therapies for relapsed/refractory CLL in the National Comprehensive Cancer Network (NCCN) Consensus Guidelines for CLL/SLL. Ibrutinib remains a viable choice for approximately 80% of those who take it. It enjoys the advantages of once-daily dosing and a more extended history of use in clinical trials and practice.

The Phase 3 ELEVATE R/R study released in June 2021 showed acalabrutinib to be “non-inferior” to ibrutinib in efficacy and having fewer and less severe side effects in the first head-to-head comparison of approved BTK inhibitors.

The use of acalabrutinib in ibrutinib-intolerant patients is a logical choice because the treatment uses the same drug class and thus preserves other agents for later use if or when needed. Using acalabrutinib in patients who developed resistance to ibrutinib is not advisable because they are both subject to the same resistance mutation.

Remember that the population of ACE-CL-208 and ELEVATE R/R were both patients who had relapsed on at least one prior therapy and efficacy in these patients in treatment naïve patients.

In our post next week we will cover acalabrutinib use in treatment-naïve patients.

 

 

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