Acalabrutinib with or without obinutuzumab demonstrated superior long-term efficacy over obinutuzumab + chlorambucil in patients with chronic lymphocytic leukaemia (CLL). Results from the 4-year follow-up of the ELEVATE-TN study confirmed previously published interim results. Physician’s Weekly spoke with senior author John Byrd Physician’s Weekly spoke with principle investigator, the D. Warren Brown Chair of Leukemia Research, Dr. John Byrd (Ohio State University College of Medicine, USA).

The 4-year follow-up results of the multicentre, open-label, phase 3 ELEVATE-TN study (NCT02475681), which was designed to compare efficacy and safety of acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in patients with treatment-naïve CLL results were presented by Dr. Jeff Sharman (US Oncology Network, USA) at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021 [1,2].

Acalabrutinib is a next-generation, potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a critical role in CLL tumour cell migration, adhesion, proliferation, and survival.

ELEVATE-TN enrolled 535 patients (median age 70 years) with previously untreated CLL with comorbidities and similar patient characteristics at baseline. Participants were randomised into 3 treatment arms: acalabrutinib + obinutuzumab  (n=179),  acalabrutinib monotherapy (n=179), and obinutuzumab + chlorambucil (n=177). Crossover from obinutuzumab + chlorambucil to acalabrutinib monotherapy was allowed after progression. The primary efficacy endpoint was progress-free survival (PFS) of acalabrutinib + obinutuzumab  versus obinutuzumab+ chlorambucil. Previously reported interim results demonstrated superior efficacy and acceptable tolerability of acalabrutinib ± obinutuzumab  [2].

Median follow-up time was 46.9 months (0.0–59.4 months). PFS was significantly prolonged in patients receiving acalabrutinib + obinutuzumab  versus obinutuzumab + chlorambucil treatment (P<0.0001), as well as in acalabrutinib monotherapy versus obinutuzumab + chlorambucil (P<0.0001), and in acalabrutinib + obinutuzumab  versus acalabrutinib monotherapy (P=0.0296). Median PFS was not reached in treatment arms acalabrutinib + obinutuzumab  and acalabrutinib monotherapy, and median PFS was 27.8 months with obinutuzumab + chlorambucil. The 48-month PFS rate was 87% for acalabrutinib + obinutuzumab, 78% for acalabrutinib monotherapy and 25% for obinutuzumab + chlorambucil (see Figure). Efficacy of acalabrutinib + obinutuzumab  was also superior in patients with del(17p) and/or mutated TP53 or unmutated IGHV.

Overall response rate was significantly higher in treatment arms containing acalabrutinib. The rate of complete response increased from the interim analysis to the 4-year follow-up analysis and was 30.7% in acalabrutinib + obinutuzumab, 11.2% in acalabrutinib monotherapy, and 13.0% in obinutuzumab + chlorambucil. The minimal residual disease status in patients also showed favourable outcomes for acalabrutinib + obinutuzumab. Median overall survival was not reached in any treatment arm. At 48 months, overall survival rates were 93%, 88%, and 88%, which was not statistically significantly different. At 60 months, there were still notably fewer deaths with acalabrutinib + obinutuzumab  compared with other treatment arms.

More than 25% of patients in any treatment groups experienced adverse events, as previously reported [2]. Neutropenia was more frequently observed in patients treated with acalabrutinib + obinutuzumab versus acalabrutinib monotherapy-treated patients, but less frequently than with obinutuzumab + chlorambucil. Most of the adverse events occurred in the first year of treatment and declined over time. No new safety signals were observed.

Physician’s Weekly spoke with senior author and principle investigator in the study, Prof. John Byrd.

Take-home message?

“This is a follow-up analysis to a randomized phase 3 study that was performed in previously untreated CLL patients who were not appropriate for intensive chemotherapy. It compared acalabrutinib monotherapy to acalabrutinib  plus obinutuzumab, and to chlorambucil and obinutuzumab. What this study shows with increasing follow-up in the paper that was published in Lancet [2], is that patients receiving either acalabrutinib or acalabrutinib plus obinutuzumab, have a higher response and progression-free survival as compared with chlorambucil and obinutuzumab this study also demonstrated that an unplanned analysis demonstrated that obinutuzumab might add to the efficacy of acalabrutinib.”

“Although, this sort of provides a juncture for future planning of studies because trials that have been done with rituximab in CLL, combined with ibrutinib have not shown benefits. And with a second-generation Bruton’s tyrosine kinase inhibitor, acalabrutinib and a third-generation anti-CD20 antibody obinutuzumab, there may still be a window open to improve by adding anti-CD20 antibody therapy to CLL treatment. Clearly, that will be something that needs to be looked at in further trials. This trial also showed, that with extended follow-up, the safety of acalabrutinib plus obinutuzumab  persisted, there were no new adverse events. It seems to be acceptably safe. The median duration of response that still has not been reached.”

“It is an exciting time in CLL. We have all of these exciting new therapies, including the second-generation BTK inhibitors and other targeted drugs. And we’re appreciative to the patients and physicians that enrolled their patients in studies that have really transformed CLL therapy to where we are at today.”

  1. Sharman J, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up. DOI: 10.1200/JCO.2021.39.15_suppl.7509 Journal of Clinical Oncology39, no. 15_suppl (May 20, 2021) 7509-7509.
  2. Sharman J, et al. Lancet 2020;395:1278–91.