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Oncologist. 2021 Mar; 26(3): 242–249.
Published online 2021 Feb 10. doi:10.1002/onco.13685
PMCID: PMC7930415
PMID: 33486852
Julio Delgado,
1,3 Filip Josephson,2,4 Jorge Camarero,2,5 Blanca Garcia‐Ochoa,2,5 Lucia Lopez‐Anglada,5 Carolina Prieto‐Fernandez,5 Paula B. van Hennik,2,6 Irene Papadouli,1 Christian Gisselbrecht,7 Harald Enzmann,2,8 and Francesco Pignatti1
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Abstract
On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment‐naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE‐CL‐007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression‐free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06–0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13–0.3) arms compared with the ChlObi arm. The second trial (ACE‐CL‐309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20–0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit‐risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU.
Implications for Practice
Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit‐risk ratio was determined to be positive.
Keywords: Chronic lymphocytic leukemia, Acalabrutinib, European Medicines Agency, Bruton tyrosine kinase
Short abstract
This article summarizes the EMA scientific review of the application leading to regulatory approval for acalabrutinib for treatment of leukemia.
Introduction
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries. The World Health Organization (WHO) describes CLL as a leukemic, lymphocytic lymphoma, being only distinguishable from small lymphocytic lymphoma (SLL) by its leukemic manifestation (≥5,000 monoclonal B cells per microliter in the peripheral blood) [1, 2]. Major progress has been made in the identification of predictive biomarkers, particularly TP53 aberrations (either deletions of chromosome 17p or TP53 mutations) [3, 4].
The treatment of CLL has evolved significantly over the last 2 decades, initially with the advent of fludarabine‐based combinations and later with the addition of monoclonal antibodies targeting CD20. Indeed, fludarabine plus cyclophosphamide plus rituximab (FCR) became the standard of care, whereas bendamustine plus rituximab (BR) and chlorambucil plus obinutuzumab (ChlObi) were recommended for patients who could not tolerate FCR [5, 6, 7, 8, 9, 10, 11, 12, 13]. Patients whose tumors harbor TP53 aberrations have an inferior outcome when treated with these conventional agents [10]. In the last decade, agents targeting Bruton tyrosine kinase (BTK) (ibrutinib), BCL2 (venetoclax) or PI3Kδ (idelalisib) have shown relevant efficacy in patients with CLL, particularly those with TP53 aberrations, and are all approved in the European Union (EU) [12, 14, 15, 16]. Specifically, ibrutinib is approved (a) in monotherapy or in combination with rituximab or obinutuzumab for the treatment of treatment‐naïve (TN) CLL and (b) in monotherapy or in combination with BR for the treatment of relapsed or refractory (RR) CLL. Venetoclax is approved (a) in combination with obinutuzumab for the treatment of TN CLL, (b) in combination with rituximab for the treatment of RR CLL, and (c) in monotherapy for the treatment of patients with TP53 aberrations failing ibrutinib/idelalisib or in those without TP53 aberrations failing both chemoimmunotherapy and ibrutinib/idelalisib. Finally, idelalisib is approved (a) in combination with rituximab or ofatumumab for the treatment of RR CLL and (b) as first‐line therapy in patients with TP53 aberrations who are ineligible for other therapies.
On October 14, 2019, AstraZeneca AB, Sweden, applied for a marketing authorization via the European Medicines Agency (EMA) centralized procedure for acalabrutinib (trade name Calquence) for the treatment of CLL. Acalabrutinib had been designated orphan medicine by the European Commission in March 2016. To qualify for orphan designation, a medicine must be intended for the treatment, prevention, or diagnosis of a life‐threatening or chronically debilitating disease; the prevalence of the condition in the EU must not be more than 5 in 10,000; and the medicine must be of significant benefit to those affected by the condition.
The review was conducted by the Committee for Medicinal Products for Human Use (CHMP), and a positive opinion was issued on July 23, 2020. The approved indication in the EU is as follows: “Calquence monotherapy or in combination with obinutuzumab is indicated for treatment of adult patients with previously untreated CLL. Calquence monotherapy is indicated for treatment of adult patients with CLL who have received at least one prior therapy.” This article summarizes the scientific review of the application leading to the regulatory approval of acalabrutinib in the EU.
Nonclinical Aspects
Acalabrutinib is a selective inhibitor of BTK, a Tec family tyrosine kinase normally expressed in B cells, myeloid cells, mast cells, and platelets. Targeted inhibition of BTK with ibrutinib and acalabrutinib leads to antitumor activity in various B‐cell malignancies, including CLL [17]. in vitro assays showed that acalabrutinib inhibits BTK, ERBB4, and BLK, whereas ibrutinib displayed inhibitory activity toward eight out of nine kinases. In comparison with ibrutinib, acalabrutinib possessed reduced activity for TEC, EGFR, and ITK and no activity on Src‐family kinases. As a result, ibrutinib inhibited T‐cell activation, EGFR activation of epidermal cells, and natural killer (NK)‐cell killing, whereas acalabrutinib showed no or little activity [18].
Pharmacology
The pharmaco*kinetics of acalabrutinib were studied in mice, rats, dogs, monkeys, and human tissues. The single‐dose pharmaco*kinetic properties of acalabrutinib were characterized by high clearance and short half‐life after oral administration in all nonclinical test species. The drug was also evaluated in a phase I–II multicenter, open‐label, dose‐escalation clinical trial in patients with RR CLL (ACE‐CL‐001) [19, 20]. In this trial, the drug was rapidly absorbed and eliminated, with a mean half‐life of approximately 1 hour and no plasma accumulation. BTK occupancy was complete (99%–100%) 4 hours after dosing but decreased to 87%–95% before subsequent dose administration with once‐daily dosing. Twice‐daily dosing, on the other hand, improved BTK occupancy before administration to 97%, with complete loss of BTK phosphorylation at all time points evaluated [19]. The high selectivity of acalabrutinib was confirmed by the sustained platelet–vessel wall interactions in platelets isolated from patients receiving acalabrutinib (compared with a significant reduction in platelets isolated from patients receiving ibrutinib), as well as intact NK cell–mediated cytotoxicity in peripheral blood. Repeat‐dose toxicity was evaluated in mice, rats, and dogs. The drug was well tolerated at lower doses, although some hematology findings, mild liver toxicity, and lower spleen weight were observed in acalabrutinib‐treated animals.
Trial Design
The application was based on the pivotal phase III clinical trials ACE‐CL‐007 and ACE‐CL‐309 [21, 22]. Acalabrutinib had been previously evaluated as monotherapy [19, 20] or in combination with obinutuzumab [23] in two phase Ib–II clinical trials. In these trials, the recommended phase II dose was established at 100 mg twice daily, whereas obinutuzumab was added at the currently approved dose. No formal dose escalation was performed for the combined therapy.
ACE‐CL‐007
ACE‐CL‐007 was a randomized, multicenter, open‐label study of ChlObi (arm A), acalabrutinib in combination with obinutuzumab (AcalaObi) (arm B), and acalabrutinib monotherapy (arm C) in patients with TN CLL. Only unfit (creatinine clearance of 30–69 mL/min, or cumulative illness rating scale‐geriatric > 6) or elderly (≥65 years) patients were allowed in this trial. Treatment was administered in 28‐day cycles. In arms B and C, oral acalabrutinib was administered (100 mg twice daily) until progressive disease (PD) or unacceptable toxicity. In arm A, intravenous obinutuzumab was given on day 1 (100 mg), day 2 (900 mg), day 8 (1,000 mg), and day 15 (1,000 mg) of cycle 1 and on day 1 (1,000 mg) of cycles 2–6. In arm B, obinutuzumab was administered following the same schedule but with 1‐month delay (on cycles 2–7). In arm A, oral chlorambucil was administered (0.5 mg/kg) on days 1 and 15 of each of these six cycles. Patients allocated to arm A were able to cross over to receive acalabrutinib in case of PD.
ACE‐CL‐309
ACE‐CL‐309 was a randomized, multicenter, open‐label study of acalabrutinib (arm A) versus idelalisib plus rituximab (IR) or BR (arm B) in patients with RR CLL. Of note, the choice between IR or BR was at the discretion of the investigator. The study enrolled subjects with at least one prior systemic therapy, but prior BCL2 or BTK/PI3K inhibitors were not allowed. Treatment was administered in 28‐day cycles. In arm A, oral acalabrutinib (100 mg twice daily) was administered until PD or unacceptable toxicity. In arm B, oral idelalisib (150 mg twice daily) was administered until PD or unacceptable toxicity in combination with intravenous rituximab (375 mg/m2 on day 1 of the first cycle, followed by 500 mg/m2 every 2 weeks for four doses and then every 4 weeks for three doses for a total of eight infusions). Alternatively, patients in arm B could receive intravenous bendamustine 70 mg/m2 on days 1 and 2 of each cycle in combination with intravenous rituximab (375 mg/m2 on day 1 of the first cycle, 500 mg/m2 on day 1 or cycles 2–6). Patients in arm B with confirmed PD could cross over to arm A.
In both trials, patients with prior history of significant cardiovascular disease, stroke, intracranial hemorrhage, bleeding diathesis, or requiring anticoagulation with vitamin K antagonists were excluded. In both trials, the primary endpoint was progression‐free survival (PFS) as assessed by an independent review committee (IRC). In trial ACE‐CL‐007, two comparisons were planned: the first between arm A and arm B (primary endpoint) and the second between arm A and arm C (key secondary endpoint).
Clinical Efficacy
ACE‐CL‐007
ACE‐CL‐007 randomized 535 subjects: 177 to arm A, 179 to arm B, and 179 to arm C. With a median follow‐up of 28 months, the primary endpoint showed a hazard ratio (HR) of 0.10 (95% confidence interval [CI], 0.06–0.17) in favor of arm B (AcalaObi). Moreover, the median IRC‐confirmed PFS was 22.6 months for arm A (ChlObi) (95% CI, 20.2–27.6), whereas it had not been reached for arm B (Fig. (Fig.1;1; Table Table1).1). Subgroup analyses consistently favored arm B, including patients with or without TP53 aberrations. The HR for the key secondary endpoint was 0.20 (95% CI, 0.13–0.30) in favor of arm C (acalabrutinib monotherapy). Subgroup analyses consistently favored arm C (acalabrutinib monotherapy) over arm A (ChlObi).
Figure 1
Kaplan‐Meier plots for progression‐free survival by independent review committee assessment (primary and key secondary endpoints) in study ACE‐CL‐007.Abbreviations: Acala, acalabrutinib; Obin, obinutuzumab.
Table 1
Key favorable and unfavorable of acalabrutinib therapy for adult patients with chronic lymphocytic leukemia (study ACE‐CL‐007 cutoff date: January 2019)
| Effect (previously untreated disease) | Arm B: acalabrutinib + obinutuzumab | Arm C: acalabrutinib | Arm A (control): chlorambucil + obinutuzumab | Uncertainties, strength of evidence |
|---|---|---|---|---|
| Favorable effects | ||||
| PFS by IRC | HR, 0.1 (95% CI, 0.06–0.17); p < .0001 | HR, 0.2 (95% CI, 0.13–0.3); p < .0001 | — | Median follow‐up, 28 mo Control arm: Event rate, 52% Median PFS, 22.6 mo |
| ORR by IRC, % | 93.9 (95% CI, 89.3–96.5) | 85.5 (95% CI, 79.6–89.9) | 78.5 (71.9–83.9) | |
| TTNT | HR, 0.14 (95% CI, 0.08–0.26) | HR, 0.24 (95% CI, 0.15–0.40) | Median not reached in any arm | |
| Unfavorable effects, % | ||||
| Grade ≥3 TEAEs | 70.2 | 49.7 | 69.8 | |
| Grade ≥3 SAEs | 32.6 | 29.6 | 19.5 | |
| Cardiac events | 14.0 | 14.0 | 7.7 | |
| Hypertension | 7.3 | 4.5 | 3.6 | |
| Neutropenia | 31.5 | 10.6 | 45.0 | |
| Bleeding | 42.7 | 39.1 | 11.8 | |
| Hepatotoxicity | 9.0 | 2.2 | 4.7 | |
| Infections | 69.1 | 65.4 | 43.8 | |
| Pneumonitis | 0.6 | 1.1 | 0.6 | |
| SPMs | 10.7 | 8.4 | 3.6 |
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Abbreviations: CI, confidence interval; HR, hazard ratio; IRC, independent review committee; ORR, overall response rate; PFS, progression‐free survival; SAE, severe adverse event; SPM, secondary primary malignancy; TEAE, treatment‐emergent adverse event; TTNT, time to next therapy.
Regarding other secondary endpoints, the IRC‐assessed overall response rate (ORR) was 78.5% (95% CI, 71.9–83.9), 93.9% (95% CI, 89.3–96.5), and 85.5% (95% CI, 79.6–89.9) for arms A, B, and C, respectively; time to next therapy (TTNT) was significantly prolonged for arm B (HR, 0.14; 95% CI, 0.08–0.26) and arm C (HR, 0.24; 95% CI, 0.15–0.40) compared with arm A; and there were no significant differences in terms of overall survival (OS), although the data were immature and crossover was allowed (25% of patients from arm A crossed over to acalabrutinib therapy).
ACE‐CL‐309
ACE‐CL‐309 randomized 310 subjects: 155 to arm A (acalabrutinib) and 155 to arm B (119 received IR and 36 received BR). With a median follow‐up of 16 months, the primary endpoint showed an HR of 0.31 (95% CI, 0.20–0.49) in favor of arm A (acalabrutinib). Moreover, the median IRC‐confirmed PFS was 16.5 months for arm B (95% CI, 14.0–17.1), whereas it had not been reached for arm A. Subgroup analyses consistently favored arm A (acalabrutinib), including patients with or without TP53 aberrations. These results were updated during the procedure, and at a median follow‐up of 22 months the HR for PFS was 0.27 (95% CI, 0.18–0.40) (Fig. (Fig.2;2; Table Table22).
Figure 2
Kaplan‐Meier plot for progression‐free survival by investigator assessment (primary endpoint) in study ACE‐CL‐309. Arm A corresponds to treatment with acalabrutinib, and arm B corresponds to treatment with idelalisib plus rituximab or bendamustine plus rituximab.Abbreviations: CI, confidence interval; HR, hazard ratio.
Table 2
Key favorable and unfavorable of acalabrutinib therapy for adult patients with chronic lymphocytic leukemia (study ACE‐CL‐309, cutoff date: January 2019)
| Effect (relapsed or refractory patients) | Arm A: acalabrutinib | Arm B: control | Uncertainties, strength of evidence | |
|---|---|---|---|---|
| Idelalisib + rituximab | Bendamustine + rituximab | |||
| Favorable effects | ||||
| PFS by IRC | HR, 0.31 (95% CI, 0.20–0.49); p < .0001 | — | Median follow‐up, 16 mo Control arm: Event rate, 44% Median PFS, 16.5 mo | |
| ORR by IRC, % | 81.3 (95% CI, 74.4–86.6) | 75.5 (95% CI, 68.1–81.6) | ||
| Median DOR by IRC | NR | 13.6 mo | ||
| Unfavorable effects, % | ||||
| Grade ≥3 TEAEs | 49.4 | 89.8 | 48.6 | |
| Grade ≥3 SAEs | 26.6 | 50.8 | 25.7 | |
| Cardiac events | 13.0 | 7.6 | 8.6 | |
| Hypertension | 3.2 | 4.2 | 0 | |
| Neutropenia | 21.4 | 50.8 | 37.1 | |
| Bleeding | 26.0 | 7.6 | 5.7 | |
| Hepatotoxicity | 4.5 | 28.0 | 8.6 | |
| Infections | 56.5 | 65.3 | 48.6 | |
| Pneumonitis | 1.9 | 6.8 | 0 | |
| SPMs | 11.7 | 2.5 | 2.9 | |
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Abbreviations: CI, confidence interval; DOR, duration of response; HR, hazard ratio; IRC, independent review committee; NR, not reached; ORR, overall response rate; PFS, progression‐free survival; SAE, severe adverse event; SPM, secondary primary malignancy; TEAE, treatment‐emergent adverse event.
Regarding other secondary endpoints, there were no statistical differences in ORR, and median TTNT had not been reached for any of the study arms, but HR was 0.35 (95% CI, 0.21–0.58) favoring arm A over arm B. There were no significant differences in OS, but the data were immature and crossover was allowed (23% of patients from arm B crossed over to acalabrutinib therapy).
Clinical Safety
The safety database comprised 1,040 subjects from nine studies (Mono HemMalig) in patients receiving acalabrutinib monotherapy (ACE‐CL‐309, ACE‐CL‐007, 15‐H‐0016, ACE‐CL‐001, ACE‐LY‐002, ACE‐LY‐003, ACE‐LY‐004, ACE‐MY‐001, and ACE‐WM‐001) and two studies (ACE‐CL‐007, ACE‐CL‐003) in patients with CLL receiving AcalaObi (ComboCLL, n = 223). Median time of follow‐up was 24.6 months for the Mono HemMalig pooled population and 29.8 months for the ComboCLL pooled population [19, 20, 21, 22, 23, 24, 25, 26].
ACE‐CL‐007
In ACE‐CL‐007, evaluation of adverse events (AEs) is complicated by the fact that the maximum time on therapy was 6 months for arm A but until PD or unacceptable toxicity for arms B and C. The median relative dose intensity was >98% in both acalabrutinib arms (arms B and C). The most frequent treatment‐emergent AEs (TEAEs) in patients from arm A were neutropenia (45.0%), infusion‐related reactions (39.6%), nausea (31.4%), diarrhea (21.3%), and pyrexia (20.7%). Most of these TEAEs were grade 1–2 apart from neutropenia (grade ≥3 in 41.4%). In patients from arm B, the most frequent TEAEs were headache (39.9%), diarrhea (38.8%), neutropenia (31.5%), fatigue (28.1%), contusion (23.6%), arthralgia (21.9%), cough (21.9%), upper respiratory tract infection (21.3%), and nausea (20.2%). Most TEAEs were grade 1–2 except for neutropenia (grade ≥3 in 29.8%). In patients from arm C, the most frequent TEAEs were headache (36.9%), diarrhea (34.6%), and nausea (22.3%). Only two grade 3 TEAEs were recorded in arm C (one case of headache and one case of diarrhea), with no grade ≥4 TEAEs in this arm. Second primary malignancies (SPMs) were observed in 3.6% of patients from arm A, 10.7% of patients from arm B, and 8.4% of patients from arm C, with basal cell cutaneous carcinoma being the most frequent histology. Atrial fibrillation (any grade) was recorded in 0.6%, 3.4%, and 3.9% of patients from arms A, B, and C, respectively, whereas grade ≥3 bleeding episodes were observed in 0%, 1.7%, and 1.7% patients from arms A, B, and C, respectively.
Deaths because of AEs were documented in 10 (5.9%), 4 (2.2%), and 6 (3.4%) patients from arms A, B, and C, respectively. Grade ≥3 severe AEs (SAEs) were observed in 19%, 32%, and 29% of patients from arms A, B, and C, respectively. Several events of clinical interest were also investigated based on prior studies with acalabrutinib and the approved BTK inhibitor ibrutinib and are displayed in Table Table11.
ACE‐CL‐309
In ACE‐CL‐309, the drug exposure was also different among cohorts. The actual median time on treatment was 15.7 months for acalabrutinib (arm A), 11.5 for IR (arm B), and 5.6 months for BR (arm B). The median relative dose intensity of acalabrutinib was 99.5%. The most common TEAEs in patients from arm A were headache (22.1%), neutropenia (19.5%), diarrhea (18.2%), anemia (14.9%), cough (14.9%), upper respiratory infection (14.3%), pyrexia (12.3%), thrombocytopenia (11.0%), pneumonia (10.4%), and respiratory tract infection (10.4%). Only one patient had a grade ≥3 TEAE (febrile neutropenia). In patients from arm B (IR group), the most common TEAEs were diarrhea (46.6%), neutropenia (44.9%), pyrexia (17.8%), cough (15.3%), upper respiratory tract infection (14.4%), thrombocytopenia (13.6%), rash (13.6%), nausea (12.7%), pneumonia (11.9%), and increased alanine aminotransferase (11.9%). Most TEAEs were grade 1–2. In patients from arm B (BR group), the most common TEAEs were neutropenia (34.3%), fatigue (22.9%), infusion‐related reaction (22.9%), nausea (20.0%), pyrexia (17.1%), constipation (14.3%), diarrhea (14.3%), thrombocytopenia (14.3%), anemia (11.4%), and upper respiratory tract infection (11.4%). Most TEAEs were grade 1–2. SPMs were documented in 11.7% of patients treated with acalabrutinib compared with 2.5% and 2.9% of patients treated with IR and BR, respectively. Atrial fibrillation (any grade) was recorded in 5.2%, 2.5%, and 2.9% of patients from arms A, B (IR group), and B (BR group), respectively. Grade ≥3 bleeding episodes occurred in 1.9%, 2.5%, and 2.9% of patients treated with acalabrutinib, IR, and BR, respectively.
Deaths because of AEs were observed in 15 (9.7%) and 18 (11.8%) patients from arms A and B, respectively, including three subjects who had already crossed over to acalabrutinib therapy. SAEs occurred in 28.6%, 55.9%, and 25.7% of patients who received acalabrutinib, IR, and BR, respectively, with most SAEs being of grade 3 or higher.
Benefit‐Risk Assessment
For patients with TN CLL, the PFS benefit observed in both experimental arms (arm B, AcalaObi; and arm C, acalabrutinib) compared with the control arm (arm A, ChlObi) was considered robust and clinically relevant. Moreover, the safety profile appeared similar that of the approved BTK inhibitor ibrutinib, including comparable rates of cardiovascular events (e.g., atrial fibrillation), diarrhea, cytopenia, and hemorrhage [14, 27, 28]. The potential impact of the experimental arms on OS could not be fully evaluated because of differences in drug exposure (until PD or unacceptable toxicity vs. fixed duration) and crossover. Regarding both experimental arms (B and C), the trial was not powered for that comparison, but point estimates for ORR and PFS numerically favored the combination arm. Toxicity was somewhat higher in patients receiving AcalaObi (higher frequency and severity of AEs), although this did not translate in a higher proportion of permanent discontinuations or a decreased relative dose intensity in the AcalaObi arm. The benefit‐risk ratio was considered positive for both experimental regimens, and it was therefore considered appropriate to approve both. Of note, the study ACE‐CL‐007 only enrolled older or comorbid patients, but, based on the precedent set for ibrutinib, the extrapolation of efficacy to younger or fitter patients was considered acceptable, and safety was not expected to be worse.
The use of ChlObi as control therapy was initially questioned for patients with TP53 aberrations. At the time of study initiation, European Society for Medical Oncology guidelines recommended a BCR inhibitor (e.g., ibrutinib) for patients with this molecular profile [29]. However, the applicant further justified the choice of comparator alluding to historical reasons, which was acknowledged and accepted. Still, data from the ACE‐CL‐007 study revealed a similarly favorable PFS for both experimental arms irrespective of TP53 status, with ORR as high as 83%–84% in patients with TP53 aberrations compared with 56% for the control arm.
For patients with RR CLL, the PFS benefit observed in the experimental arm (acalabrutinib) compared with the control arm (IR/BR) was deemed robust and clinically relevant, with retained activity in patients with TP53 aberrations. No major unexpected AEs were observed in the experimental arm. The major uncertainty was low maturity at data cutoff, with a PFS event rate of only 44% in the control arm. An updated analysis (per investigator assessment) based on 6 months of further follow‐up was provided, and with a PFS event rate of 58% in the control arm, the point estimates remained essentially unchanged. The final clinical study reports for studies ACE‐CL‐007 (including data on time to second subsequent therapy) and ACE‐CL‐309 are expected to be reviewed by the CHMP as postapproval data.
Regarding safety, final study reports from pivotal studies and safety updates from study D8220C00008, a phase IIIb, multicenter, open‐label, single‐arm study of acalabrutinib in subjects with CLL will be reviewed postauthorization. Moreover, the ongoing phase III randomized controlled trial ACE‐CL‐006 is currently comparing the efficacy and safety of acalabrutinib versus ibrutinib in patients with high‐risk RR CLL. Cardiac events beyond atrial fibrillation occurred at a higher rate in the acalabrutinib‐containing arms compared with comparator arms in both pivotal studies and must be further characterized. Data from ongoing studies, including a cohort of study D8220C00008, will provide information on the use of acalabrutinib in patients with moderate or severe cardiac impairment. Moreover, the inherent risk of patients with CLL to develop SPMs did not allow the CHMP to fully characterize the acalabrutinib‐related risk of SPMs, which are presently included as an important identified risk in the safety specifications. SPMs will also be further characterized in upcoming postauthorization studies.
Patients receiving anticoagulation were not included in these studies because of a high bleeding risk, and the same applied to proton pump inhibitors or strong CYP3A inducers or inhibitors to prevent pharmacologic interactions. Accordingly, the recommendation to avoid the coadministration of acalabrutinib and these agents was added to the Summary of Product Characteristics (SmPC) and endorsed by the CHMP.
The proposed indication for Calquence in the RR setting includes patients previously treated with ibrutinib or venetoclax, who were excluded from the ACE‐CL‐309 trial. The applicant provided external data reasonably supporting the use of BTK inhibitors in subjects previously treated with venetoclax and the use of acalabrutinib in patients intolerant (but not resistant) to ibrutinib. This is mechanistically expected and was added to the SmPC. Finally, the applicant proposed to add the term SLL to the indication, which was refused by the CHMP on the grounds that CLL and SLL are considered the same disease by the WHO [1].
Conclusion
Based on the review of data on quality, safety, and efficacy, the EMA CHMP concluded by consensus that the risk‐benefit balance of acalabrutinib monotherapy and acalabrutinib in combination with obinutuzumab was favorable for the treatment of adult patients with previously untreated CLL, and hence recommended the granting of the marketing authorization. Moreover, the risk‐benefit balance of acalabrutinib monotherapy was also favorable for the treatment of adult patients with relapsed or refractory CLL, also recommending the granting of the marketing authorization.
Author Contributions
Data analysis and interpretation: Filip Josephson, Jorge Camarero, Blanca Garcia‐Ochoa, Lucia Lopez‐Anglada, Carolina Prieto‐Fernandez, Paula B. van Hennik, Harald Enzmann
Manuscript writing: Julio Delgado, Filip Josephson, Jorge Camarero, Blanca Garcia‐Ochoa, Paula B. van Hennik, Irene Papadouli, Christian Gisselbrecht, Harald Enzmann, Francesco Pignatti
Final approval of manuscript: Julio Delgado, Filip Josephson, Jorge Camarero, Blanca Garcia‐Ochoa, Lucia Lopez‐Anglada, Carolina Prieto‐Fernandez, Paula B. van Hennik, Irene Papadouli, Christian Gisselbrecht, Harald Enzmann, Francesco Pignatti
Disclosures
The authors indicated no financial relationships.
Acknowledgments
The scientific assessment summarized in this report is based on important contributions from the rapporteur and corapporteur assessment teams, Committee for Medicinal Products for Human Use members, and additional experts after the application for a marketing authorization from the company. This publication is a summary of the European Public Assessment Report, the Summary of Product Characteristics, and other product data as published on the European Medicines Agency (EMA) Web site (https://www.ema.europa.eu/en/medicines). For the most current information on this marketing authorization, please refer to the EMA Web site. The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the regulatory agency/agencies or organizations with which the author(s) is/are employed/affiliated.
Notes
Disclosures of potential conflicts of interest may be found at the end of this article.
No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact moc.yeliw@stnirperlaicremmoc. For permission information contact moc.yeliw@snoissimrep.
Footnotes
For Further Reading: Paul J. Hampel, Timothy G. Call, Kari G. Rabe et al. Disease Flare During Temporary Interruption of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia. The Oncologist 2020;25:974–980.
Implications for Practice: Ibrutinib is a very effective treatment for chronic lymphocytic leukemia (CLL) but needs to be taken continuously. Side effects, such as increased bleeding risk with procedures, require temporary interruptions in this continuous treatment. Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well. Importantly, management with restarting ibrutinib led to quick clinical improvement. Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease.
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