Summary Basis of Decision for Calquence

Clinical Pharmacology

The active ingredient of Calquence, acalabrutinib, is a potent, highly selective small-molecule inhibitor of Bruton's tyrosine kinase (BTK), with minimal off-target kinase activity. Bruton's tyrosine kinase is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.

Acalabrutinib forms a covalent bond with Cys481 in the BTK adenosine triphosphate pocket, permanently inactivating the enzyme and resulting in the inhibition of proliferation and survival signals in malignant B cells. Acalabrutinib has an active metabolite, ACP-5862, that is also a covalent inhibitor of BTK.

In patients with B-cell malignancies dosed with 100 mg Calquence twice daily, median steady state BTK occupancy of ≥95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.

The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies. The data support the use of Calquence for the specified indication.

For further details, please refer to the Calquence Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Calquence in patients with mantle cell lymphoma (MCL) was evaluated in an open-label, multicentre, single-arm Phase II study (ACE-LY-004) that enrolled 124 previously treated patients. The patients had histologically documented relapsed or refractory MCL after 1-5 prior treatment regimens.

The patients were administered Calquence 100 mg orally twice daily until disease progression or unacceptable toxicity. The median age of the patients was 68 (range 42 to 90) years, 80% were male and 74% were Caucasian. At baseline, 93% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

The majority of patients (95%) had previously received rituximab as a single agent or part of a regimen. Common prior regimens included combination chemotherapy of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-based regimen [52%]); cytarabine (34%); bendamustine and rituximab-based regimens (22%); and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine (Hyper-CVAD [21%]). Eighteen percent of the patients had undergone stem cell transplant. At baseline, 24% and 76% of patients had refractory and relapsed disease, respectively, and 37% of patients had at least one tumour with a longest diameter of ≥5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The simplified MCL International Prognostic Index (MIPI) score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients, and 75% of patients had Ann Arbor Stage IV disease. The study did not include patients who received prior treatment with inhibitors of BTK.

The primary endpoint was investigator-assessed objective response rate (ORR) according to the Lugano classification for non-Hodgkin lymphoma (NHL).

The key secondary endpoints were investigator-assessed duration of response (DOR) according to the Lugano classification, progression-free survival (PFS) according to the Lugano classification, and overall survival (OS). In addition, ORR, DOR and PFS according to the Lugano classification assessed by an independent review committee (IRC) were also included as secondary endpoints.

Upon review of the initial drug submission for Calquence, it was determined that it did not fulfill the requirements for a NOC with conditions. Furthermore, there were uncertainties around the validation of the primary endpoint as a surrogate of clinical benefit in the mantle cell lymphoma setting based on the Lugano classification. There were also uncertainties around the quality of the response due to the limited follow-up time. Finally, the long-term safety profile of Calquence was unknown and the submitted results failed to demonstrate an improvement in the quality of life of MCL patients treated with Calquence. These uncertainties precluded the issuance of a NOC. As a result, Health Canada issued a Notice of Deficiency (NOD) to the sponsor (see What steps led to the approval of Calquence?).

The sponsor responded to the NOD with a 24-month follow-up update of the ACE-LY-004 study. The median duration of treatment was 17.3 months and the median dose intensity was 98.7%. The median duration of follow-up was 26.3 months.

In the 24-month follow-up update, the ORR was 80.6% (95% CI: 72.6%, 87.2%) and the CR rate was 42.7% (95% CI: 33.9%, 51.9%). The median DOR was 25.7 months. Patients with CR had a median DOR over 28 months. The median DOR for patients with a partial response (PR) was approximately 17 months. This finding suggests that most of the patients who were responding to Calquence treatment kept their response for a significant duration.

The median investigator-assessed PFS was 19.5 months. However, without a comparator arm, PFS can only be considered as an exploratory endpoint. Furthermore, it cannot be compared with historical data as the events of progressive disease were based on different criteria set.

The median OS had not been reached. Without a comparator arm, OS can only be considered as an exploratory endpoint.

The 12-month follow-up data showed a high concordance rate for the investigator assessment and the IRC assessment of ORR and CR (91% and 94% respectively). An IRC assessment was not conducted for the 24-month update, but a similar concordance was expected. The median PFS and the median DOR from the 24-month follow-up data were also expected to be consistent between the IRC and the investigator assessment.

Overall, the sponsor addressed the issues stated in the NOD. The response to the NOD contained a rationale and sufficient evidence supporting the validation of the CR rate endpoint based on the Lugano classification as a surrogate of clinical benefit in patients with MCL.

The submission was found to be in compliance with the Food and Drugs Act and Regulations. The results from the clinical pivotal study supports the efficacy of Calquence for the proposed indication.

Indication

The New Drug Submission for Calquence was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Calquence (acalabrutinib) is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

For more information, refer to the Calquence Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety profile of Calquence (acalabrutinib) in MCL patients was mainly derived from the pivotal single-arm Phase II study (ACE-LY-004), described in the Clinical Efficacy section (see the Clinical Efficacy section). Additional risks were identified in the overall safety profile obtained from 612 patients with hematologic malignancies, who received acalabrutinib monotherapy at doses ranging from 100 mg twice daily to 200 mg twice daily.

The most common (≥20%) adverse events (AEs) of any grade reported in patients receiving acalabrutinib were headache, diarrhea, fatigue, cough, nausea, contusion, and upper respiratory tract infection. The majority of AEs reported were grade 1 or 2 in severity and generally did not lead to acalabrutinib discontinuation. The most frequently reported (≥2%) serious adverse events (SAEs) included pneumonia (6%) and pyrexia (3%). Some cases of atrial fibrillation were observed during the ACE-LY-004 study.

In addition, the following safety findings were found in the 24-month update obtained from patients with MCL in the ACE-LY-004 study.

• Lymphocytosis occurred in 32% of patients with MCL. There was no apparent increased risk of tumour lysis syndrome observed in patients who had lymphocytosis. However, the risk of leukostasis cannot be ruled out.
There was a high incidence of grade 1 or grade 2 events of increased levels of creatinine (91.8%) None of the patients had a grade 3 or grade 4 event of increased levels of creatinine. However, the long-term effect of Calquence on renal function has not been evaluated.
Grade 3 and grade 4 events of increased levels of uric acid occurred in 17.9% and 9.0% of patients, respectively.
Calquence was associated with grade 2 and grade 3 events of increased levels of blood pressure.
Major hemorrhage events were reported for 1 patient (0.8%) in the ACE-LY-004 study but in the overall safety database it was reported for 15 patients (2.5%).
An increased risk of infections, including hepatitis B reactivation and progressive multifocal leukoencephalopathy cannot be ruled out.
SAEs of interstitial lung disease (ILD) were reported in the ACE-LY-004 study. The relationship with Calquence is unclear due to the presence of confounding factors in these patients and the absence of additional ILD events in the overall safety database.

In a randomized, double-blind, double-dummy, placebo- and positive-controlled, four-way crossover electrocardiogram assessment study, single-dose administration of acalabrutinib 100 mg and 400 mg (4 times the maximum recommended single dose) was not demonstrated to affect the QTcF interval, the QRS duration, or the PR interval in healthy subjects (number of subjects = 44).

No post-marketing data were available to add additional safety information.

Acalabrutinib showed negative results in an in vitro bacterial reverse mutation assay, an in vitro chromosomal aberration assay, and an in vivo mouse micronucleus test. Despite these negative results, second primary malignancies have been observed in patients treated with Calquence.

Limited clinical data exist on the use of Calquence in pregnant women. Based on findings from animal studies, there may be a risk to the fetus from exposure to Calquence during pregnancy.

Appropriate warnings and precautions are in place in the approved Calquence Product Monograph to address the identified safety concerns.

A Serious Warnings and Precautions box has been included in the Calquence Product Monograph, which highlights that the treatment with Calquence should be initiated and supervised by a qualified physician experienced in the use of anticancer therapies. Furthermore, it specifies that concomitant use of Calquence with a strong cytochrome (CYP) P450 inhibitor CYP3A should be avoided, and recommends monitoring for an appropriate management of bleeding to prevent serious hemorrhage.

For more information, refer to the Calquence Product Monograph, approved by Health Canada and available through the Drug Product Database.