EFFICACY and SAFETY of ZANUBRUTINIB VS. VENETOCLAX+IBRUTINIB in the TREATMENT-NAIVE (TN) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A MATCHING-ADJUSTED INDIRECT COMPARISON (MAIC).

Munir, T.; Mohseninejad, L.; Rakonczai, P.; Xu, S.; Yang, K.; Cohen, A.; Vezan, R.; Martinez-Calle, N.

EFFICACY and SAFETY of ZANUBRUTINIB VS. VENETOCLAX+IBRUTINIB in the TREATMENT-NAIVE (TN) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A MATCHING-ADJUSTED INDIRECT COMPARISON (MAIC).

All Authors

Munir, T.

Mohseninejad, L.

Rakonczai, P.

Xu, S.

Yang, K.

Cohen, A.

Vezan, R.

Martinez-Calle, N.

LTHT Author

Munir, Talha

LTHT Department

Oncology
Haematology

Publication Date

2024

Item Type

Conference Abstract

Subject

ADULT , AGED , LEUKAEMIA , CONTROLLED CLINICAL TRIALS AS TOPIC , DIAGNOSIS , DRUG THERAPY , WOMEN , INCIDENCE , MEN , PROBABILITY , MODELS, STATISTICAL , QUALITY OF LIFE , DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS , CHEMOTHERAPY , ANTINEOPLASTIC AGENTS , ANTIBODIES, MONOCLONAL

Abstract

Background: Zanubrutinib (zanu) is a highly effective Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of CLL. The phase 3 SEQUOIA trial (NCT03336333) evaluated the efficacy and safety of zanu in TN CLL patients with no del17p mutations (arm A, zanu; arm B, bendamustine+ rituximab), and with del17p mutations (arm C, zanu). The combination of fixed duration BCL-2 inhibitor venetoclax (V) plus the BTKi ibrutinib (I) was approved by the European Medicine Agency (EMA) for the treatment of TN CLL. V+I has been evaluated in GLOW (NCT03462719) including older/comorbid patients and excluding the del17p/TP53 population and in CAPTIVATE (NCT02910583) including younger/fitter patients and no restrictions on del17p and TP53. As no head-to-head clinical study comparing zanu vs V+I exists, an indirect comparison is required to evaluate the efficacy and safety of the two treatments. Aim(s): To conduct a population adjusted indirect comparison between zanu and V+I and reduce potential bias due to differences in study populations. Method(s): Since SEQUOIA and the V+I studies cannot be linked through a common control arm, two unanchored MAICs were conducted, matching individual patient data (IPD) from arm A of SEQUOIA vs the V+I arm of GLOW, and pooled arm A+C of SEQUOIA vs the V+I arm of CAPTIVATE. Adjustments for age, sex, geographic region, CLL stage, cancer type, cytogenetic mutations, complex karyotype, ECOG, bulky disease, time from diagnosis, beta2-microglobulin, and creatinine clearance were considered based on availability and magnitude of imbalance between populations. Weighted Cox regression was used to derive relative treatment effect estimates. Given that matching variables mainly impact efficacy and not safety, the primary safety comparison did not apply weights used in the efficacy comparison; naive comparison was carried out as the primary approach. Result(s): For PFS, unadjusted comparison between zanu in SEQUOIA arm A (n=241) and V+I in GLOW (n=106) indicated potential treatment benefit in favor of zanu (HR=0.71 [95%CI: 0.39-1.28, p=0.2578]). After matching, the two treatments were similar (HR=0.84 [95%CI: 0.45-1.59, p=0.5977]). The unadjusted comparison between zanu in SEQUOIA arm A+C (n=352) and V+I in CAPTIVATE (n=159) also indicated a similar treatment effect for zanu and V+I (HR=1.00 [95%CI: 0.65-1.52, p=0.9874]). After matching, the HR=0.78 (95%CI: 0.38-1.62, p=0.5099) showed a potential benefit for zanu. For safety, significantly lower incidence was indicated for zanu vs V+I in both GLOW and CAPTIVATE with regards to multiple adverse events (AEs) (Figure). Sensitivity analyses exploring the impact of using different sets of matching factors in the efficacy comparisons and population matching in safety comparisons showed consistent results. Summary/Conclusion: Due to low sample size of V+I studies and the high variability in population characteristics, the relative treatment effect estimates had a wider probability range. However, the adjusted estimates of the relative treatment effect suggest a potential trend for PFS benefit in favor of zanu vs V+I. Comparison of AE incidence rates across SEQUOIA and V+I studies identified a significantly better safety profile for zanu vs V+I, despite longer treatment exposure for zanu (median 44 months) compared to V+I (median 13.8 months in both trials) and no adjustment for differences in treatment exposure were made in the safety comparisons. The observed safety differences between zanu and V+I suggest considerable impact on patients' quality of life, that should be weighted at the time of treatment decision-making in TN CLL. (Table present).