Acalabrutinib (A) and ibrutinib (I) are both highly effective Bruton tyrosine kinase (BTK) inhibitors approved for the treatment of chronic lymphocytic leukemia (CLL) and given as continuous treatments until disease progression or unacceptable toxicity.
Venetoclax (V) is a B-cell lymphoma-2 (BCL-2) inhibitor prescribed in combination with obinutuzumab (V+O) for a fixed (12-cycle) duration in treatment-naïve CLL patients.
At the American Society of Hematology Annual Meeting and Exposition held in Atlanta, GA, in Dec. 2021 (ASH 2021), Dr. Matthew Davids of Dana Farber Cancer Institute in Boston presented data to compare different drugs and drug combinations across clinical trials.
This type of research is fraught with problems, including concerns that the groups being compared are truly similar and that the trials are measuring the same outcomes. Trials that do head-to-head comparisons make for the best data.
The way these researchers tried to overcome the difficulties was to weigh the baseline comparisons and figure that into the data.
Individual patient data were weighted to match the aggregate baseline characteristics of:
- A ± obinutuzumab (A+O) from ELEVATE-TN (Sharman et al. ASCO 2021)
- I monotherapy arm from the ALLIANCE trial (Woyach et al. NEJM. 2018)
- The V+O arm from the CLL-14 trial (Al-Sawaf et al. Lancet Oncol 2020).
These are three major influential CLL trials reviewed on this website and the web.
- This Matching-Adjusted Indirect Treatment Comparison or MAIC included 47-months of data from ELEVATE-TN trial, 38-months of data from the ALLIANCE trial, and 40-months of data from the CLL-14 trial.
- In the A vs I comparison, the progression-free survival or PFS (hazard ratio [HR] 0.83 and overall survival or OS (HR 0.69) numerically favored A, but the difference was not statistically significant.
- The A vs V+O comparison did not show significant differences in PFS (HR 0.96) and OS (HR 0.99).
- For A+O vs. I, significant differences in PFS (HR 0.48) and OS (HR 0.41) were observed.
- For A+O versus V+O, significant differences were observed for PFS (HR 0.38) and OS (HR 0.43).
- Significant differences in more serious adverse events, AEs in favor of A and A+O were observed versus I for atrial fibrillation, hypertension, decreased neutrophil count, and decreased platelet count.
- Compared with V+O, patients treated with A had significantly lower rates of febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, non-melanoma skin cancer, and secondary primary malignancies excluding non-melanoma skin cancer. In addition, for A+O vs V+O, significantly lower rates of infusion-related reaction, neutropenia, and non-melanoma skin cancer were observed among patients treated with A+O.
Based on these MAIC results, A and A+O are associated with a more favorable safety profile versus both I and V+O.
These MAIC results demonstrate that A+O is associated with a significant efficacy benefit versus both I and V+O with longer follow-up.
A limitation of this MAIC is not including all potential prognostic as a trade-off to conserve the effective sample size. As stated in my introduction, comparison across trials is fraught with possible missteps, and the only rigorous way to compare drugs is to compare the drugs in head-to-head studies. For many reasons, these trials may never happen, so this type of retrospective Matching-Adjusted Indirect Treatment Comparison is an attempt to understand better how these drugs compare.
When deciding on any frontline therapy, one should carefully look at the trial data for the options in consideration, but not stop there.
Next, one needs to weigh how closely your circumstances match those of the group being studied.
Finally, one needs to carefully consider how one’s treatment preferences and other medical conditions influence the decision about your “best” therapy.
Here is the actual ASH 2021 article for review: Matching-Adjusted Indirect Treatment Comparison (MAIC) of Acalabrutinib Alone or in Combination with Obinutuzumab Versus Ibrutinib or Venetoclax Plus Obinutuzumab in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia.
Here is my short video monologue on this research.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.