AZ’s Calquence Hits Endpoint In Second CLL Phase III Study
Executive Summary
The results move AstraZeneca closer to challenging AbbVie and Johnson & Johnson’s blockbuster Imbruvica in the blood cancer market.
A Phase III trial of AstraZeneca PLC’s Calquence has met its primary endpoint, marking the second time in as many months that the drug has passed a pivotal test.
AstraZeneca secured rights to the BTK inhibitor in 2015 when it paid $2.5bn for a majority stake in Acerta Pharma BV. Since then, the company has won approval for Calquence (acalabrutinib) in relapsed and refractory mantle cell lymphoma (MCL), a rare cancer, and initiated a late-phase development program designed to give it access to the larger chronic lymphocytic leukaemia (CLL) opportunity. (Also see "AstraZeneca's Calquence Steps Into Blood Cancer Ring With Mighty Imbruvica" - Scrip, 31 Oct, 2017.)
The Phase III results released this week further AstraZeneca’s pursuit of the CLL market. Investigators enrolled 535 adults with previously-untreated CLL and randomized them to receive Calquence, either as a monotherapy or with Roche’s Gazyvaro (obinutuzumab), or a control regimen of Gazyvaro in combination with the chemotherapy chlorambucil.
At an interim data review, the Calquence-Gazyvaro combination demonstrated statistically significant improvements in progression-free survival (PFS) over the control regimen. That resulted in the trial meeting its primary endpoint and AstraZeneca stopping the study early.
Calquence also delivered statistically-significant improvements in PFS over the control regimen when given as a monotherapy. The monotherapy PFS assessment is a secondary endpoint in the study.
The success comes one month after AstraZeneca stopped another Phase III trial of Calquence early for similar reasons. In the previous trial, AstraZeneca linked Calquence to statistically-significant PFS improvements in previously-treated CLL patients. That trial compared Calquence in combination with Roche’s Rituxan (rituximab) to either Gilead Sciences Inc.’s Zydelig (idelalisib) or Teva Pharmaceutical Industries Ltd.’s Treanda (bendamustine).
AstraZeneca plans to use data from the two Phase III trials as the basis for regulatory submissions in CLL later this year. However, at this stage it is hard to gauge whether Calquence poses a major threat to AbbVie Inc. and Johnson & Johnson’s blockbuster Imbruvica (ibrutinib), the incumbent CLL drug, as AstraZeneca has yet to share much data.
The only Phase III numbers published to date come from the trial in previously-treated CLL patients. That study linked Calquence to a 69% reduction in the risk of disease progression. After 12 months, the PFS rate in the Calquence arm was 88%, compared to 68% in the control cohort.
That divergence was enough for the trial to hit its primary endpoint but if Calquence is to become a big drug for AstraZeneca, it will need to outperform Imbruvica, not Zydelig and Treanda. An ongoing Phase III is comparing Calquence to Imbruvica in previously-treated CLL.
For now, analysts are relying on cross-trial comparisons to assess whether Calquence has an edge over Imbruvica. In a Phase III trial in previously-treated CLL patients, Imbruvica achieved a 12-month PFS rate of 84%. The figure is four percentage points below the PFS rate recorded by Calquence but confounding factors, such as the fact that subjects in the Imbruvica clinical trial were more heavily pretreated, may limit the reliability of the comparison.
If Calquence and Imbruvica ultimately prove to be similarly effective, AstraZeneca’s attempts to win market share may rest on safety and tolerability data. There is scope to improve on Imbruvica, which a survey by analysts at Deutsche Bank suggests causes challenging side effects in 20% of patients. At least 10% of patients discontinue treatment.
Calquence’s approved label in MCL is free from certain warnings that regulators applied to Imbruvica. AstraZeneca thinks the side effect profile of Calquence has helped it claim around 40% of the MCL market in the US. Analysts at Bryan Garnier tipped Calquence to control 30% of the US and European market when it won approval in 2017.
Comparable penetration in CLL would turn Calquence into a big drug for AstraZeneca but it is unclear from the data published to date whether it will have a significant safety advantage. Notably, the rate of atrial fibrillation seen in the Calquence study came in just below that reported in the Imbruvica trial.
“This calls into question whether this will be an aspect of differentiation and may suggest this is a class effect of BTK inhibitors,” analysts at Deutsche Bank wrote in a note to investors on 6 June.
Calquence may have an advantage in other areas, though. While 6% of patients in the Imbruvica trial suffered from grade 3 and above hypertension, the condition is absent from the list of adverse events seen in more than 5% of subjects in the Calquence trial. In addition, a smaller proportion of patients dropped out of the Calquence arm, although the Deutsche Bank analysts nonetheless called the 11% discontinuation rate “relatively high.”