A year and a half after getting its next-gen BTK inhibitor approved in chronic lymphocytic leukemia (CLL), AstraZeneca is back with long-term data that suggest the drug stands a fighting chance against J&J and AbbVie’s first generation blockbuster Imbruvica.
At a median follow-up of 40.9 months, Calquence matched Imbruvica for a median progression-free survival of 38.4 months in patients who had previously been treated for CLL, AstraZeneca announced at ASCO. But when it came to cardiac events, Calquence bested its longstanding rival, with a 9.4% incidence of all-grade atrial fibrillation, compared to a 16% rate in the Imbruvica arm (p= 0.02). Atrial fibrillation is an irregular heartbeat that can lead to stroke or heart failure.
The news — which comes as AstraZeneca struggles in vaccines — represents another win in Pascal Soriot’s effort to establish the company as a leader in oncology.
“Cardiac adverse events are an important consideration for treating chronic lymphocytic leukemia patients with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment,” John Byrd, lead investigator of AstraZeneca’s ELEVATE-RR trial, said in a statement.
CLL is the most common type of leukemia in adults, with more than 21,000 new cases reported in the US so far this year. In patients with the disease, too many blood stem cells in the bone marrow become abnormal lymphocytes, which have difficulty fighting infections. As the number of abnormal cells grows, there’s less room for healthy white and red blood cells and platelets, AstraZeneca said.
Calquence was approved for CLL back in November 2019, both as a monotherapy in second-line patients and as a combination treatment with Roche’s Gazyva in frontline patients. But the Elevate-RR trial is the first to compare the two BTK inhibitors head-to-head in CLL, and should help AstraZeneca carve out a space in the market.
Calquence bagged $522 million in sales last year, compared to Imbruvica’s global sales of $5.3 billion.
Elevate-RR enrolled 533 patients with a form of CLL that doesn’t respond to treatments like chemotherapy. In addition to lower incidence of atrial fibrillation, AstraZeneca says those in the Calquence arm also saw a lesser frequency of other side effects, including bleeding events, hypertension and infections.
“The safety and tolerability of Calquence in Elevate-RR was consistent with the known profile of Calquence,” the company said in a statement.
In the Calquence arm, adverse events led 14.7% of patients to discontinue the treatment, versus 21.3% of patients in the Imbruvica arm. All-grade cardiac events were seen in 24.1% of Calquence patients and 30% of Imbruvica patients. All-grade bleeding events were recorded in 38% of Calquence patients versus 51.3% of Imbruvica patients. Hypertension was seen in 9.4% and 23.2% of patients in the respective arms. And all-grade infections were seen in 78.2% versus 81.4% of the patients.
However, a greater number of patients in the Calquence arm experienced second primary malignancies excluding non-melanoma skin cancer (9% versus 7.6% in the Imbruvica arm).
AstraZeneca also read out four-year data from its Phase III Elevate-TN trial, in which Calquence “continued to show a strong PFS benefit” as a combination therapy or monotherapy in previously untreated CLL patients, the company said.
After a median follow-up of 46.9 months, Calquence and Gazyva reduced patients’ risk of disease progression or death by 90% compared to Gazvya and the chemotherapy chlorambucil, AstraZeneca said. As a monotherapy, Calquence reduced the risk of disease progression or death by 81%, according to the data. Median progression-free survival wasn’t met in either arm at the four-year follow-up.
According to AstraZeneca, estimated PFS rates for the combination therapy and monotherapy are 87% and 78%, respectively, compared to 25% for chlorambucil plus Gazyva.
“Tolerability is a critical factor in treating patients with chronic lymphocytic leukemia who often remain on medicines for many years and experience multiple comorbidities,” Dave Fredrickson, executive VP of AstraZeneca’s oncology business unit, said in a statement.
Calquence and Imbruvica could soon have some new competitors, including BeiGene’s Brukinsa, which demonstrated a “statistically significant lower risk of atrial fibrillation or flutter” in a head-to-head trial with Imbruvica back in April. And back in December, Eli Lilly said it would but its own BTK inhibitor LOXO-305 against Imbruvica in two head-to-head studies.