Acalabrutinib is a second-generation Bruton kinase inhibitor, which has activity against chronic lymphocytic leukaemia (CLL) in both the treatment-naïve and relapsed/refractory (R/R) setting. Bruton kinase plays a critical role in B-cell proliferation and survival.
The evidence supporting the protocol in R/R patients comes from the phase 3 multicentre randomised ASCEND trial.r This was after a multicentre phase 1/2 trial investigating acalabrutinib monotherapy for R/R CLL/small lymphocytic lymphoma (SLL), which showed an overall response rate (ORR) of 94% and estimated progression-free survival (PFS) at 45 months follow up of 62% (95% CI 51-71%).rr
In ASCEND, between 2017 and 2018, 310 patients with R/R CLL were randomised to receive either acalabrutinib monotherapy (100mg bd) or investigator’s choice. Investigator’s choice was either rituximab + bendamustine (bendamustine 70mg/m2 on day 1 and 2 of a 28-day cycle, for 6 cycles, and rituximab 375 mg/m2 on day 1 of cycle 1, and 500mg/m2 on day 1 of cycle 2 through 6) or rituximab + idelalisib (idelalisib 150mg bd until progressive disease (PD) or unacceptable toxicity, with rituximab 375mg/m2 on day 1 of therapy, followed by 500 mg/m2 every two weeks for four doses, then every four weeks for three doses). Acalabrutinib was administered until PD or unacceptable toxicity. Crossover to the acalabrutinib arm was allowed for patients with PD on the control arm. The median age of participants was 67, and the median number of prior therapies was one (range one to eight in the treatment arm). 16% of patients harboured del(17p), 24% a TP53 mutation and 19% had unmutated immunoglobulin heavy chain variable (IGHV). Patients with significant cardiovascular disease were excluded, as were those with previous exposure to BTK, BCL2, PI3K or SYK inhibitors.
The primary endpoint was PFS. Secondary endpoints were ORR, duration of response (DOR) and overall survival (OS).
A second phase 3 multicentre international randomised trial (ELEVATE-TN), compared the efficacy of acalabrutinib both as a single agent, and in combination with obinutuzumab, with chlorambucil plus obinutuzumab, in patients with untreated CLL.r
Between 2015 and 2017, 535 patients were randomised 1:1:1 to receive acalabrutinib 100mg bd as a single agent, acalabrutinib 100mg bd plus obinutuzumab (day 1 (100mg), day 2 (900mg), day 8 (1000mg) and day 15 (1000mg) of Cycle 2, and 1000mg on day 1 of cycles 3-7) or chlorambucil (0.5mg/kg days 1-15 on cycles 1 to 6, plus obinutuzumab on day 1 (100mg), day 2 (900mg), day 8 (1000mg) and day 15 (1000mg) of cycle 1, and 1000mg on day 1 of cycles 2-6). Acalabrutinib was administered until PD or unacceptable toxicity. Crossover to acalabrutinib was allowed for patients who progressed on the chlorambucil arm.
Eligible patients were aged 65 years or older, or over 18 years and younger than 65 years with a creatinine clearance of 30-69 mL/min, or a Cumulative Illness Rating Scale for Geriatrics score greater than 6. Patients with significant cardiovascular disease were excluded, as well as those taking vitamin K antagonists. The median age of participants was 70. 9% of patients harboured del(17p), 11% a TP53 mutation and 63% had unmutated IGHV (which is higher than the rate of unmutated IGHV typically seen in treatment-naïve CLLr).
The primary endpoint was PFS, and secondary endpoints were ORR, time to next treatment and OS.
In R/R settings, after a median follow up of 16.1 months, the median PFS was significantly longer with acalabrutinib monotherapy, compared to investigators choice (not reached v. 16.5 months; HR 0.31 95% CI 59-75%) (Figure 1). The estimated 12-month PFS was 88% for acalabrutinib monotherapy (95% CI 81% to 92%), and 68% for investigator’s choice (95% CI 59-75%). The PFS benefit was preserved in patients with del(17p), del(11q), TP53 mutations or unmutated IGHV.r
Figure 1. Progression-free survivalr
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ORR was not statistically different between the study and control arms. Median DOR was superior in the acalabrutinib arm (NR for acalabrutinib v. 13.6 months (95% CI 11.9 months to NR)) for investigators choice (HR 0.33; 95% CI 0.19 to 0.59; p < 0.0001). Median OS was not reached and was not different between the two study arms (Figure 2).
Figure 2. Overall survivalr
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The acalabrutinib arms in patients with untreated CLL in the ELEVATE-TN trialr, in terms of the primary endpoint, demonstrated superior efficacy over the control arm. After a median follow up of 28.3 months, median PFS was not reached in both acalabrutinib arms, versus 22.6 months in the chlorambucil-obinutuzumab arm (for the acalabrutinib monotherapy arm HR 0.20, p<0.0001) (Figure 3). The 24 month estimated PFS was 87% for acalabrutinib monotherapy (95% CI 81-92%), 93% for acalabrutinib + obinutuzumab (95% CI 87-96%) and 47% for chlorambucil + obinutuzumab (95% CI 39-55%). These results were preserved in patients with del(17p), del(11q), TP53 mutations or unmutated IGHV. Acalabrutinib + obinutuzumab was associated with a reduced risk of progression compared to acalabrutinib monotherapy in a post-hoc analysis (HR 0.49, 85% CI 0.26-0.95).
Figure 3. Progression-free survivalr
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ORR were significantly superior in the acalabrutinib arms, though CR rates were low, in keeping with studies of other BTKi. Median OS was not reached in any arm, with no significant differences between treatments (Figure 4).
Figure 4. Overall survivalr
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Tabulated summaries from both the ASCEND (Table 1)r and ELEVATE-TN (Table 2)r trials are shown below. Overall, acalabrutinib had an acceptable toxicity profile.
In ASCEND, ≥ grade 3 adverse events (AEs) occurred in 45% of patients receiving acalabrutinib. The most common ≥ grade 3 AEs were neutropenia (16%), anaemia (12%) and pneumonia (5%). Similar results were seen in the acalabrutinib monotherapy arm in ELEVATE-TN. In the earlier Phase 1/2 trial, ≥ grade 3 AEs were seen in 66% of patients, including infections (23%), neutropenia (14%) and pneumonia (11%).r
Rates of ≥ grade 3 major bleeding occurred in 1% of patients receiving acalabrutinib in the ASCEND trial. Rates of ≥ grade 3 bleeding were higher in the acalabrutinib arms in ELEVATE-TN (2.2% to 4.5%, versus 1.8% in the control arm). No cases of pneumocystis jiroveci pneumonia (PJP) were reported in the acalabrutinib arm in ASCEND, with two cases in the control arm (both patients taking idelalisib). It was not reported whether patients were taking PJP prophylaxis or not. ELEVATE-TN did not report on PJP rates.
Second primary malignancies (SPMs) were increased in the acalabrutinib arm in ASCEND (14% v. 5%), as they were in ELEVATE-TN (9-11%). In both trials, these were dominated by non-melanomatous skin cancers. Only one myeloid SPM was diagnosed in each trial in patients taking acalabrutinib.
Atrial fibrillation of any grade was only slightly increased, occurring in 5% of patients on acalabrutinib v. 3% on investigators choice in ASCEND and 3-4% in acalabrutinib-containing arms versus 1% in the control arm in ELEVATE-TN. Rates were higher (7%) in the phase 1/2 trial.
Treatment discontinuation due to treatment-related AEs was similar in both ASCEND and ELEVATE-TN (9-11%). Of interest, this rate was 17% for patients receiving bendamustine + rituximab and 47% receiving idelalisib + rituximab in ASCEND.
Fatal AEs occurred in 4% of patients receiving acalabrutinib in ASCEND, versus 4-6% in the comparator arms. Fatal AEs occurred in 3% of patients receiving acalabrutinib in ELEVATE-TN.
Table 1. Treatment-emergent AEs. ASCEND R/R CLLr
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Table 2. Treatment-emergent AEs. ELEVATE-TN Treatment naïve CLLr
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