Regulatory Decision Summary for Calquence

Mantle cell lymphoma (MCL) is a form of B-cell non-Hodgkin lymphoma (NHL). It is a serious and life-threatening disease. In this response to a Notice of Deficiency (R-NOD), efficacy and safety data supporting the proposed indication for Calquence are derived from long-term follow up (total of 24 months) of a single-arm pivotal phase II study (ACE-LY-004) with 124 subjects enrolled. These subjects had histologically documented MCL and had relapsed after ≥1 (but not >5) prior treatment regimens and used the intended therapeutic regimen (100 mg bid as monotherapy). The primary endpoint was investigator-assessed Objective Response Rate (ORR) according to the Lugano classification for NHL.

The R-NOD contains a rationale and sufficient evidence supporting the validation of the complete response (CR) rate endpoint based on the Lugano classification as a surrogate of clinical benefit in patients with MCL At the 24-month update, the ORR was 80.6% (95% Confidence Interval [CI] 72.6%, 87.2%) and the CR rate was 42.7% (95% CI 33.9%, 51.9%). There is a high concordance rate between the Independent Review Committee (IRC)-based and the investigator-based assessments. This supports the primary efficacy endpoint.

Most of the patients who were responding to Calquence treatment kept their response for a significant duration with median duration of response (DOR) of 25.7 months.

Progression Free Survival (PFS) and Overal Survival (OS) were also reported in the study. However, the impact of Calquence on PFS and OS is uncertain because, without a comparator arm, PFS and OS can only be considered as exploratory endpoints. Nevertheless, the response rate results, in particular the complete metabolic response rate results, are likely to be associated with long-term clinical benefit, as suggested by the relatively long median DOR.

The safety profile in MCL patients was mainly derived from the pivotal single-arm phase II study. Additional risks have been identified in the overall safety profile of Calquence from 612 patients with hematologic malignancies receiving acalabrutinib monotherapy at doses ranging from 100 mg twice daily to 200 mg twice daily.

The most common adverse drug reactions reported in patients receiving Calquence were headache, bruising, diarrhea, nausea, and rash. Serious adverse reactions included second primary malignancies, atrial fibrillation, serious hemorrhage and serious infections.

A high rate of patients with grade 1 or 2 creatinine increased (91.8% of subjects) was noted, although no subject had a grade 3 or 4 creatinine increased event. The long-term effect of acalabrutinib on renal function has not been evaluated.

There are very limited clinical data on Calquence use in pregnant women. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy.

The important risks associated with Calquence, along with dosage adjustment recommendations in the events of grade ≥3 adverse reactions, are appropriately communicated andmanaged in the Product Monograph.

In conclusion, a NOC is recommended for Calquence for the treatment of patients with MCL who have received at least one prior therapy. Considering that MCL is a serious and life-threatening disease, the clinical benefits of Calquence therapy are considered to outweigh its risks for the proposed indication.