Rationale for Requested Change: On behalf of AstraZeneca, this letter respectfully requests the National Comprehensive Cancer Network (NCCN) Panel for “B-Cell Lymphomas” to add acalabrutinib in combination with bendamustine + rituximab (BR) as a Category 2A regimen in first-line therapy of MCL based on the evidence in the abstract and presentation “Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: Results from the phase 3, double-blind, placebo-controlled ECHO trial” (Wang et al). [1]
The median age of mantle cell lymphoma (MCL) patients is approximately 71 years. [2] Generally, patients in this age group suffer from various comorbidities and are not suitable for aggressive induction therapy or autologous stem cell transplant. Currently the standard of care approach in clinical practice is to give these patients bendamustine with rituximab (BR), however with the advent of targeted therapies such as BTK inhibitors (BTKis), investigators are exploring the efficacy and safety of including these agents in this group of patients. [3,4] Selecting the best treatment for newly diagnosed MCL patients is critical as progression-free survival (PFS) shortens significantly with subsequent lines of therapy, and this remains a significant unmet need for these patients. [5] With ibrutinib being withdrawn from the market for MCL, and considering the discontinuation rate of ibrutinib due to adverse events in elderly MCL patients, the need for exploring acalabrutinib in this setting with its superior safety profile is quite urgent. [6,7,8] This interim analysis of ECHO demonstrates a significant improvement in the independent review committee (IRC) assessed PFS for acalabrutinib + BR compared to standard of care therapy (placebo + BR) and a positive trend for overall survival (OS) in elderly patients with treatment naïve (TN) MCL. [1] Importantly, ECHO incorporated a cross-over design, whereby eligible patients who progressed in the control arm were permitted to receive acalabrutinib as subsequent treatment. This trial was conducted during the COVID-19 pandemic, a factor which influenced patient outcomes. [9] Although there was a prevalent incidence of COVID-19 related events in both arms of the trial, whereby more patients were impacted in the treatment cohort, patients in the ABR arm still sustained an overall PFS benefit and favorable trend for OS without excess in toxicities for most AEs compared to the PBR arm. PFS and OS are reported for both intention-to-treat (ITT) and an FDA pre-specified COVID-19 death censored analysis, both of which resulted in a positive outcome for the acalabrutinib plus BR treatment arm over that of the control arm.
ECHO (ACE-LY-308, NCT02972840) is a randomized, double-blind, placebo-controlled, multi-center Phase III trial evaluating the efficacy and safety of acalabrutinib plus BR (ABR) compared to BR plus placebo (PBR) in adult patients at or over 65 years of age with previously untreated MCL. Patients were randomized to receive either acalabrutinib or placebo on 28-day treatment cycles, plus bendamustine on days 1 and 2 and rituximab on day 1. After 6 cycles of acalabrutinib or placebo in combination with BR, patients achieving a partial or complete response (PR or CR) would receive rituximab maintenance for 2 years. Patients with at least stable disease (SD) at end of induction then continued either acalabrutinib or placebo until disease progression or unacceptable toxicity. Patients who progressed during PBR therapy could crossover to acalabrutinib monotherapy upon meeting eligibility criteria.
In this interim analysis, 598 patients were included (299 patients in each group) with a median follow up of 45 months. The median age of patients was 71 years, and baseline characteristics were well-balanced between groups, including high risk features.
ECHO met its primary endpoint at the pre-specified interim analysis by demonstrating a statistically significant improvement in IRC-assessed PFS for patients receiving ABR compared to PBR. An additional 16.8 months in median PFS was gained with the addition of acalabrutinib to BR; 66.4 months (95% CI 55.1, NE) for ABR compared to 49.6 months (36.0, 64.1) for PBR (HR 0.73; 95% CI 0.57, 0.94; P=0.0160). Overall response rate (91% ABR vs. 88% for PBR) and complete response rate (66.6% ABR vs. 53.5% PBR) were also both improved for ABR compared to PBR. Despite 69% of patients receiving 2L BTKi (n=51 within the trial crossover group), there was a positive trend for OS with ABR compared to PBR (HR 0.86; 95% CI 0.65, 1.13; P=0.2743), with 97 deaths (32.4%) in the ABR group and 106 deaths (35.5%) in the PBR group. OS will continue to be assessed with longer follow-up. The ECHO analysis considered the pre-specified FDA request for AstraZeneca to report data with censoring of COVID-19 related deaths, in addition to the ITT population analysis. After censoring for COVID-19 deaths, the median PFS was not estimable (NE) with ABR (95% CI 66.4, NE), compared with 61.6 months (49.6, 68.9) with PBR (HR 0.64; 95% CI 0.48, 0.84; P=0.0017). The same analysis was performed for OS, and both groups had an improvement in median OS with NE (NE, NE) for ABR and NE (73.8, NE) for PBR after censoring for COVID-19 related deaths. After censoring, there was a continued positive trend for overall survival with ABR; HR 0.75 (95% CI 0.53, 1.04; P=0.0797).
ECHO demonstrated safety and tolerability of acalabrutinib consistent with its known safety profile, and no new safety signals were identified. The median treatment exposure was 29 months (range, 0.1-80.1) in the ABR arm and 25 months (0.03-76.4) in the PBR arm. In the safety data analysis, 297 patients were included in each group. Grade >3 treatment-emergent adverse events (TEAE) occurred in 264 patients (88.9%) in the ABR arm and 262 patients (88.2%) in the PBR arm. Discontinuation due to AEs was reported in 42.8% of patients in the ABR arm, compared to 31.0% of patients in PBR; COVID-19 related events were the primary cause leading to discontinuation in 10.4% and 6.4% of patients, respectively. Grade >3 SAEs were reported in 64.3% of patients in the ABR arm vs. 55.9% of patients in the PBR arm. Grade >3 infection occurred in 41.1% vs 34% of patients in the ABR and PBR groups, respectively. Any-grade COVID-19 events were reported in 121 patients (40.7%) in the ABR arm and 88 patients (29.6%) in the PBR arm, with COVID-19 deaths reported in 9.4% and 6.7% of patients, respectively. Grade >3 events of clinical interest include neutropenia (35.4% vs 37% PBR), pneumonia (8.8% ABR vs 6.4% PBR), hypertension (5.4% ABR vs 8.4% PBR), secondary primary malignancies excluding non-melanoma skin cancer (5.4% ABR vs 6.7% PBR), atrial fibrillation (3.7% ABR vs. 1.7% PBR), and major bleeding (2.0% ABR vs 3.4% PBR).
This data demonstrates that an acalabrutinib-based regimen in combination with bendamustine and rituximab achieves significantly improved efficacy in progression free survival with a positive trend in overall survival in treatment-naïve MCL, with a consistent and well-tolerated safety profile.
References:
[1] Wang M, Mayer J, Belada D, et al. Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: Results from the phase 3, double-blind, placebo-controlled ECHO trial. [abstract and presentation]. European Hematology Association (EHA) Hybrid Congress. June 13-16, 2024. Madrid, Spain and Virtual.
[2] Armitage JO, Longo DL. Mantle-Cell Lymphoma. N Engl J Med. 2022;386(26):2495-2506. https://doi.org/10.1056/NEJMra2202672.
[3] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): B-cell lymphomas. Version 2.2024. April 30, 2024. [https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf].
[4] Martin P, Cohen JB, Wang M, et al. Treatment Outcomes and Roles of Transplantation and Maintenance Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts. J Clin Oncol. 2023;41(3):541-554. https://doi.org/10.1200/JCO.21.02698. [5] Minson A, Hamad N, Di Ciaccio P, et al. Death from mantle cell lymphoma limits sequential therapy, particularly after first relapse: Patterns of care and outcomes in a series from Australia and the United Kingdom. Br J Haematol. 2024;204(2):548-554. https://doi.org/10.1111/bjh.19179.
[6] Janssen Pharmaceutical Companies of Johnson & Johnson. Update on IMBRUVICA® (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications [press release]. Published April 6, 2023. https://www.jnj.com/media-center/press-releases/update-on-imbruvica-ibrutinib-u-s-accelerated-approvals-for-mantle-cell-lymphoma-and-marginal-zone-lymphoma-indications.
[7] Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized Phase III trial [article and supplementary appendix]. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. www.doi.org/10.1200/JCO.21.01210.
[8] Gaitonde P, Cai L, De Miranda, et al. Matching-Adjusted indirect comparisons of the efficacy and safety of acalabrutinib versus ibrutinib in relapsed/refractory mantle cell lymphoma. Blood. 2022;140 (Suppl 1): 3646–3647. https://doi.org/10.1182/blood-2022-169661.
[9] US Food and Drug Administration (FDA). Conduct of clinical trials of medical products during the COVID-19 public health emergency. Guidance for industry, investigators, and institutional review boards. March 2020; updated January 27, 2021. https://public4.pagefreezer.com/browse/FDA/17-05-2021T12:50/https://www.fda.gov/media/136238/download.
