1207 - A matching-adjusted indirect comparison of ELEVATE-TN versus SEQUOIA: acalabrutinib with and without obinutuzumab versus zanubrutinib in treatment-naïve chronic lymphocytic leukemia

Introduction:
The second-generation Bruton tyrosine kinase inhibitors acalabrutinib and zanubrutinib have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acalabrutinib with and without obinutuzumab was evaluated in the ELEVATE-TN RCT in treatment-naïve chronic lymphocytic leukemia (CLL) and zanubrutinib was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) without del(17p) in the SEQUOIA RCT. We used unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acalabrutinib with and without obinutuzumab versus zanubrutinib in patients with treatment-naïve CLL/SLL using individual patient data (IPD) from ELEVATE-TN and published aggregate data from SEQUOIA.

Methods:
In this unanchored MAIC, we weighted IPD for the acalabrutinib plus obinutuzumab and acalabrutinib monotherapy arms from ELEVATE-TN to match zanubrutinib baseline data from SEQUOIA. We included patients without del(17p) in ELEVATE-TN to ensure the patient population was similar to the SEQUOIA population.

The efficacy analysis evaluated investigator-assessed progression-free survival (INV-PFS) in randomized patients with baseline data (acalabrutinib+obinutuzumab, n=162; acalabrutinib monotherapy, n=163; zanubrutinib, n=241) using the October 2021 data cut-off (DCO) for ELEVATE-TN and the May 2021 DCO for SEQUOIA. Patients were matched based on variables considered prognostic/predictive of INV-PFS in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, cytopenia, del(11q), trisomy 12, IGHV status, and TP53 mutation. Pseudo-IPD for INV-PFS for zanubrutinib were obtained from Kaplan–Meier curves.

The safety analysis assessed odds ratios (ORs) of adverse events (AEs) in treated patients with baseline data (acalabrutinib+obinutuzumab, n=162; acalabrutinib monotherapy, n=162; zanubrutinib, n=240). Patients were matched based on characteristics considered relevant by clinical experts, which were age, ECOG score, and cytopenia. To compare the incidence of AEs, the ELEVATE-TN February 2019 DCO was used to match the median treatment exposure from the SEQUOIA May 2021 DCO. Confidence intervals (CI) of 95% were used in both analyses.

Results:
In the efficacy analysis, the acalabrutinib+obinutuzumab and acalabrutinib monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acalabrutinib+obinutuzumab and acalabrutinib monotherapy INV-PFS (Figure 1). Post-matching, 24-month INV-PFS was 96% (CI: 91–98) with acalabrutinib+obinutuzumab, which was higher than that with zanubrutinib (88%; CI: 82–92). The MAIC-weighted Cox hazard ratio (HR) showed INV-PFS to be superior with acalabrutinib+obinutuzumab versus zanubrutinib (HR: 0.33; 0.15–0.71; Figure 1A). Acalabrutinib monotherapy post-matching had a similar 24-month INV-PFS (92%; CI: 85–96) to zanubrutinib (88%; CI: 82–92) and no differences in the MAIC-weighted Cox HR were observed versus zanubrutinib (0.76; CI: 0.40–1.45) (Figure 1B).

In the safety analysis, the median treatment exposure was similar between acalabrutinib+obinutuzumab and acalabrutinib monotherapy (both 28 months) and zanubrutinib (26 months). The acalabrutinib+obinutuzumab and acalabrutinib monotherapy ESSs post-matching were 154 (95%) and 157 (97%), respectively. With acalabrutinib+obinutuzumab, there were no significant differences versus zanubrutinib in the odds of having any AE, any serious AE, atrial fibrillation/flutter, hypertension, and hemorrhage (Figure 2A). However, acalabrutinib+obinutuzumab was associated with higher odds versus zanubrutinib of having any grade ≥3 event (OR: 2.07; CI: 1.35–3.17), headache (OR: 5.79; CI: 3.44–9.73), fatigue (OR: 2.62; CI: 1.54–4.46), neutropenia (OR: 2.43; CI: 1.50–3.93), and arthralgia (OR: 1.87; CI: 1.10–3.18). Acalabrutinib monotherapy also showed no significant differences versus zanubrutinib in the odds of having any AE, any SAE, atrial fibrillation/flutter and hemorrhage. However, the odds of having hypertension were significantly lower (OR: 0.32; CI: 0.14–0.72) while the odds of having headache were higher (OR: 5.39; CI: 3.21–9.06) with acalabrutinib monotherapy versus zanubrutinib (Figure 2B).

Conclusions:
In this MAIC of ELEVATE-TN and SEQUOIA, acalabrutinib+obinutuzumab had a superior efficacy in terms of INV-PFS versus zanubrutinib, while acalabrutinib monotherapy and zanubrutinib had similar efficacies in patients with treatment-naïve CLL/SLL without del(17p). Acalabrutinib+obinutuzumab and acalabrutinib monotherapy generally had similar safety profiles to zanubrutinib; however, acalabrutinib+obinutuzumab was associated with higher odds of grade ≥3 AEs, headache, fatigue, neutropenia, and arthralgia, versus zanubrutinib. Acalabrutinib monotherapy was associated with higher odds of headache but lower odds of hypertension versus zanubrutinib. Our results systematically compare common regimens where randomized, prospective data are not available. Limitations of MAIC analyses mean the results should be viewed as hypothesis-generating.