Acalabrutinib with or without obinutuzumab outperforms chemo-immunotherapy in patients with treatment-naïve chronic lymphocytic leukaemia

ELEVATE-TN is a global, phase III, multicentre, open-label study in patients with treatment-naïve chronic lymphocytic leukaemia. With a median follow-up of 46.9 months, the superior efficacy of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy over chemo-immunotherapy with obinutuzumab-chlorambucil was maintained, with an increase in complete response since the interim analysis and low rates of discontinuation.

Bruton’s tyrosine kinase (BTK) is an essential protein for B-cell receptor signalling with a critical role in chronic lymphocytic leukaemia (CLL) tumour cell migration, adhesion, proliferation and survival. Acalabrutinib is a next-generation, potent, highly selective BTK inhibitor approved for the treatment of CLL and small lymphocytic lymphoma (SLL). Early results of the pivotal phase III ELEVATE-TN study, with a median follow-up of 28.3 months, demonstrated superior efficacy of acalabrutinib with or without obinutuzumab compared to chemo-immunotherapy with the combination of obinutuzumab and chlorambucil, with an acceptable tolerability profile in patients with treatment-naïve CLL. At EHA 2021, results from a four-year update of ELEVATE-TN were reported.

ELEVATE-TN study design

The ELEVATE-TN study enrolled adult patients with untreated CLL who were at least 65 years old or less than 65 years with medical comorbidities. Other key inclusion criteria included an ECOG performance status of 2 or less and an adequate haematologic, hepatic, and renal function. Patients with significant cardiovascular disease were excluded from the study. In total, 535 patients were randomised in a 1:1:1 ratio to acalabrutinib plus obinutuzumab (A+O), acalabrutinib monotherapy (A) or fixed duration (six cycles) obinutuzumab plus chlorambucil (O+Clb). Crossover from O+Clb to A was allowed after independent review committee (IRC)-confirmed progression. The primary endpoint of the trial was IRC-assessed progression-free survival (PFS) of A+O vs. O+Clb. The median age of the patients enrolled in the study was 70 years, 14% had a 17p deletion (del(17p)) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable region (IGHV). At the time of the data cut-off, treatment was ongoing in 74.9% and 69.3% in the A+O and A arms, respectively. In total, 69 patients crossed over from O+Clb to the A arm. Median treatment exposure was 46.6 months, 45.7 months and 5.6 months for A+O, A, and O+Clb respectively.

Four-year efficacy and safety update

At a median follow-up of 47 months, PFS was significantly prolonged in the acalabrutinib-containing arms, compared to O+Clb arm with 48-months PFS rates of 87%, 78% and 25% for A+O, A, and O+Clb arms, respectively. In a post-hoc analysis of A+O vs. A alone, a hazard ratio (HR) of 0.56 in favour of the A+O regimen was reported (p= 0.0296). Acalabrutinib-containing regimens also prolonged PFS in high-risk genomic subgroups, including those with a del(17p) and/or mutated TP53 and in patients with unmutated IGHV. In these subgroups, the median PFS was not reached (NR) in acalabrutinib-containing arms, while it was reported at 17.5 and 22.2 months, respectively in the O+Clb arms. Overall response rates (ORR) were significantly higher with acalabrutinib-containing regimens, with 96.1% and 89.9% for the A+O and A arms, respectively, as compared to 82.5% for O+Clb. The rates of complete response, including those with incomplete blood count recovery increased from the interim analysis at 28.3 months to approximately four years in the acalabrutinib-containing arms (from 24.0% to 30.7% [A+O] and from 7.8% to 11.2% [A]). Median OS was NR in any treatment arm with a trend towards significance in the A+O group (A+O vs. O+Clb, p= 0.0604). The estimated 48-month OS rates were 93% (A+O), 88% (A), and 88% (O+Clb).

Incidences of the most common adverse events (AEs) were generally unchanged from the interim analysis. AEs that occurred more frequently in the acalabrutinib-containing arms included headache, diarrhoea, fatigue, arthralgia, cough, and upper respiratory tract infections. For patients treated with O+Clb, neutropenia, nausea and infusion-related reactions were more commonly reported. In the acalabrutinib arms, the incidence of most of the common AEs decreased over time, with most events occurring during the first year of treatment. The cumulative incidence over time for any-grade events of atrial fibrillation and hypertension were very low across all three treatment arms.

Conclusion

With a follow-up of 46.9 months, the efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib alone was maintained relative to obinutuzumab and chlorambucil. In addition, the safety of acalabrutinib plus obinutuzumab and acalabrutinib alone was consistent with interim findings, including a low incidence of cardiovascular events and low rates of treatment discontinuation, despite longer treatment exposure. In conclusion, acalabrutinib with or without obinutuzumab demonstrates durable disease control, tolerability and flexibility to tailor treatment as a monotherapy or combination therapy in treatment-naïve CLL patients.

Reference

Sharman J, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: ELEVATE-TN 4-year follow-up. Presented at EHA 2021; abstract S148.