Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia Jeff P. Sharman 1, Miklos Egyed, Wojciech Jurczak , Alan Skarbnik, John M. Pagel , Ian W. Flinn , Manali Kamdar, Talha Munir, Renata Walewska, Gillian Corbett, Laura Maria Fogliatto, Yair Herishanu, Versha Banerji, Steven Coutre , George Follows, Patricia Walker, Karin Karlsson, Paolo Ghia , Ann Janssens, Florence Cymbalista, Jennifer A. Woyach , Emmanuelle Ferrant, William G. Wierda , Veerendra Munugalavadla, Ting Yu, Min Hui Wang and John C. Byrd

Median treatment exposure was 46.6 months for acalabrutinibobinutuzumab and 45.7 months for acalabrutinib monotherapy (Table 1); no new safety signals were observed. The most common any-grade AEs (≥30%) were diarrhea, headache, and neutropenia for acalabrutinib-obinutuzumab; diarrhea and headache for acalabrutinib monotherapy; and neutropenia, infusion-related reaction, and nausea for obinutuzumab-chlorambucil (Table 1). AEs occurring more frequently in the acalabrutinib-containing arms included headache, diarrhea, fatigue, arthralgia, cough, and upper respiratory tract infection. Headaches, while common, were typically low grade; none led to treatment discontinuation. Among patients receiving acalabrutinib-obinutuzumab, neutropenia, fatigue, and arthralgia were more frequent relative to acalabrutinib alone. The obinutuzumab-chlorambucil arm had more frequent neutropenia, nausea, and infusion-related reactions relative to both acalabrutinib-containing arms, though differences in AE reporting could be due to the longer treatment exposure in the acalabrutinib-containing arms versus the comparator arm. In the acalabrutinib-containing arms, most of the common AEs decreased in incidence over time, and most events occurred more predominantly during the first year of treatment (Supplementary Table 3). Incidence and time to onset of AEs leading to discontinuation of acalabrutinib-containing treatment are described in Supplementary Table 4.
Events of clinical interest (ECIs), including cardiovascular events, were similar in both acalabrutinib arms (Table 1). In addition, the cumulative incidences of atrial fibrillation and hypertension over time were low and similar across treatment groups (Supplementary Fig. 4).
With a median follow-up of 46.9 months, the efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy were maintained with low rates of treatment discontinuation. Median PFS was not reached for either acalabrutinib-containing arm, and PFS continued to be significantly longer for both acalabrutinib-containing arms versus obinutuzumab-chlorambucil. Consistent with the primary report [9], the acalabrutinibcontaining arms continued to demonstrate significantly greater PFS benefits versus obinutuzumab-chlorambucil in high-risk genomic subgroups, including del(17)(p13.1) and/or mutated Cardiac events (grade ≥3) that occurred in >1 patient (other than atrial fibrillation) include atrioventricular block complete (n = 3), angina pectoris (n = 2), myocardial ischemia (n = 2), and myocardial infarction (n = 2). c Cardiac events (grade ≥3) that occurred in >1 patient (other than atrial fibrillation) include acute myocardial infarction (n = 3), cardiac failure (n = 2), and myocardial infarction (n = 2). d Defined as any serious or grade ≥3 hemorrhagic event, or any-grade hemorrhagic event in the central nervous system.
TP53 and unmutated IGHV, with longer-term treatment. Of note, the estimated PFS rate at 48 months trended in favor of the acalabrutinib combination versus acalabrutinib monotherapy, consistent with findings from preclinical studies demonstrating that, in contrast to ibrutinib, acalabrutinib does not interfere with the anti-tumor immune-mediated mechanisms of anti-CD20 monoclonal antibodies [10,11]. In the acalabrutinib-containing arms, the CR/CRi rate increased from the primary analysis at 28.3 months (acalabrutinib-obinutuzumab: 24.0%; acalabrutinib: 7.8% [9]) to the current report at a follow-up of 4 years (30.7% and 11.2%, respectively). In high-risk subgroups, CR/CRi rates were numerically higher with the acalabrutinib combination versus monotherapy; however, the study was not powered for this comparison. Further research is needed to assess the efficacy benefits of acalabrutinib-obinutuzumab combination therapy. With longer-term follow-up, the tolerability profile of the acalabrutinib-containing arms was consistent with that of the primary analysis. Incidences of the most common AEs, such as headache, diarrhea, neutropenia, and fatigue, were generally unchanged or saw a slight increase from the primary analysis [9]. Though cross-trial comparisons are limited, the efficacy results from this study are aligned with those from the iLLUMINATE study of ibrutinib-obinutuzumab in a similar patient population at a median follow-up of 31.3 months [4]. In that study, median PFS (assessed by IRC) was not reached; the estimated 30-month PFS rate was 79% with ibrutinib-obinutuzumab. Atrial fibrillation and hypertension rates with ibrutinib-obinutuzumab (12 and 17%, respectively) in iLLUMINATE [4] were higher than the atrial fibrillation/flutter and hypertension rates reported with acalabrutinib-obinutuzumab in the present study (4 and 8%). Discontinuation due to AEs was similar with ibrutinibobinutuzumab (16%) in the iLLUMINATE study and with acalabrutinib-obinutuzumab in the present study (13%). By comparison, a head-to-head study of acalabrutinib versus ibrutinib (ELEVATE-RR; NCT02477696) at a median follow-up of 40.9 months demonstrated non-inferiority for PFS (primary endpoint) and a statistically significantly lower incidence of atrial fibrillation/flutter with acalabrutinib versus ibrutinib (9% vs 16%, respectively) in patients with previously treated CLL [12]. In ELEVATE-RR, hypertension incidence was also statistically higher with ibrutinib versus acalabrutinib (23% vs 9%).
Based on these updated results, ELEVATE-TN shows continued efficacy at 4 years and a significant PFS benefit in the acalabrutinib-containing arms regardless of high-risk status. PFS benefit is seen particularly with acalabrutinib-obinutuzumab, although this combination resulted in a higher incidence of AEs compared with acalabrutinib monotherapy. No new safety signals were observed with acalabrutinib-containing treatment with longer-term follow-up. The safety of acalabrutinib-containing treatment was consistent with the primary analysis [9], with a low incidence of ECIs, particularly cardiovascular AEs (atrial fibrillation/flutter and hypertension) and low rates of treatment discontinuation despite longer treatment exposure. Findings illustrate the flexibility to tailor acalabrutinib treatment as monotherapy or combination treatment and support acalabrutinib as a combination partner with obinutuzumab in the first-line CLL setting.