Positive results from the ECHO Phase III trial showed AstraZeneca?s CALQUENCE (acalabrutinib) in combination with bendamustine and rituximab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and showed a favorable trend in overall survival (OS) compared to standard-of-care chemoimmunotherapy (bendamustine plus rituximab) in previously untreated patients with mantle cell lymphoma (MCL). These results were presented in a late-breaking oral presentation at the European Hematology Association (EHA) 2024 Hybrid Congress in Madrid, Spain (#LBA3439). Results showed the CALQUENCEcombination regimen reduced the risk of disease progression or death by 27% compared to standard-of-care chemoimmunotherapy (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.57-0.94; p=0.016).

Median PFS was 66.4 months for patients treated with the CALQUENCE combination (n=299) versus 49.6 months with standard-of-care chemoimmunotherapy (n=299). The secondary endpoint of OS showed a favorable trend for the CALQUENCE combination compared to standard-of-care chemoimmunotherapy, further supporting the clinical benefit of this combination (HR 0.86; 95% CI 0.65-1.13; p=0.2743). The OS data were not mature at the time of this analysis and the trial will continue to assess OS as a key secondary endpoint.

The ECHO trial enrolled during the pandemic period, and a pre-specified analysis censoring for COVID-19-related deaths was conducted to assess the impact. PFS was further improved in both arms, with the CALQUENCE combination reducing the risk of disease progression or death by 36% (HR 0.64; 95% CI 0.48-0.84; p=0.0017). Median PFS was not reached among patients treated with the CALQUENCE combination versus 61.6 months for standard-of-care chemoimmunotherapy (HR 0.64; 95% CI 0.48-0.84; p=0.0017).

A favorable trend was seen for OS in this analysis for the CALQUENCE combination (HR 0.75; 95% CI 0.53-1.04; p=0.0797). The safety and tolerability of CALQUENCE was consistent with its known safety profile, and no new safety signals were identified. Grade 3 or higher adverse events (AEs) due to any cause occurred in 88.9% (n=264) of patients treated with the CALQUENCE combination and 88.2% (n=262) of patients treated with standard-of-care chemoimmunotherapy, including Grade 3 or higher atrial fibrillation in 3.7% (n=11) and 1.7% (n=5) of patients, Grade 3 or higher hypertension in 5.4% (n=16) and 8.4% (n=25), Grade 3 or higher major bleeding in 2.0% (n=6) and 3.4% (n=10), and Grade 3 or higher infections in 41.1% (n=122) and 34.0% (n=101), respectively.

Serious AEs and Grade 5 events were balanced across arms (69% [n=205] versus 62% [n=184], and 12.1% [n=36] versus 10.1% [n=30], respectively). AEs leading to discontinuation were observed in 10.4% (n=31) and 6.4% (n=19) of patients for the CALQUENCE combination and placebo arms respectively. AEs related to COVID-19 were seen in the trial, including Grade 5 events which occurred in 9.4% (n=28) of patients treated with the CALQUENCE combination and 6.7% (n=20) of patients treated with standard-of-care chemoimmunotherapy.

In addition to these compelling data, AstraZeneca data at EHA 2024 shows how the Company is advancing a diverse and innovative pipeline spanning multiple modalities including next-generation T cell engagers, cell therapy and antibody drug conjugates, to enable the creation of novel combination regimens across a range of blood cancers. Results from the ongoing Phase I, dose-escalation trial of AZD0486, a novel CD19xCD3 T cell engager, showed durable responses in patients with heavily pretreated relapsed/refractory follicular lymphoma with a median follow up of 11 months. Complete response rates of 84% were seen at doses of AZD0486 of 2.4 mg and above.

Data also showed how cytokine release syndrome (CRS) events were effectively mitigated by the double step-up dosing schedule and no immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed. In an oral presentation, preliminary data was shared from an investigator-initiated trial of AstraZeneca?s first hematology cell therapy, GC012F (AZD0120), in patients with transplant-eligible high-risk, newly diagnosed multiple myeloma. Early results showed that GC012F had an overall response rate of 100%, a minimal residual disease-negative stringent complete response rate of 95%, and was well tolerated.

Grade 1-2 CRS was experienced by 27% (6/22) of patients and no ICANS or neurotoxicity was observed. GC012F is a novel BCMAxCD19 dual-targeting autologous chimeric antigen receptor T therapy (CAR-T) created using the next-day FasTCAR manufacturing platform pioneered by Gracell Biotechnologies, a wholly owned subsidiary of AstraZeneca. Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE.

Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage.

In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.