How far can ibrutinib resonate? Free

In this issue of Blood, Burger et al¹ report on the final analysis of the RESONATE-2 study, a phase 3 randomized trial that evaluated ibrutinib vs chlorambucil as initial therapy for patients with chronic lymphocytic leukemia (CLL).

A decade ago, the RESONATE-2 study introduced the use of the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib in untreated patients, inaugurating the era of targeted therapies in frontline CLL.² Beyond reaffirming the superiority of ibrutinib over chlorambucil, this final update presents unique and valuable long-term data on ibrutinib with up to 10 years of follow-up.¹ In the ibrutinib arm, the median progression-free survival (PFS) has finally been reached (8.9 years) with a 9-year overall survival (OS) rate of 68% (see figure panel A). Extended follow-ups are becoming crucial in the context of an expanding therapeutic landscape for CLL.

Ibrutinib paved the way for targeting BTK in CLL and other B-cell malignancies. Its development in the first-line setting came from the comparison with chlorambucil and also with more intensive chemo-immunotherapy regimens.^3,4 The introduction of continuous therapy until progression or toxicity has reshaped our approach to CLL treatment. This strategy was justified by the gradual activity of ibrutinib with responses deepening over time. The RESONATE-2 final analysis highlights a continuous increase in the complete response rate up to year 7 (reaching 36%), a feature that challenges the surrogacy of response depth for predicting survival. No further improvement in response was observed thereafter. Whether fixed-duration BTK inhibitor monotherapy can be safely implemented remains an open question that the STAIR trial is currently addressing in frail patients (NCT04963946). In the early days of ibrutinib, the most significant advance was for patients with adverse genomic features, such as TP53 alterations, for whom chemoimmunotherapy yielded poor outcomes. These long-term exploratory analyses showed similar outcomes regardless of the immunoglobulin heavy-chain variable region gene (IGHV) mutational status or TP53 mutations. Despite the rise in effective time-limited combinations, the use of a covalent BTK inhibitor is retained as the preferred option for patients with TP53 alterations in several guidelines.⁵ 

Unlimited administration of ibrutinib is supported by its good tolerability, although cardiovascular events (atrial fibrillation, hypertension) remain a concern. Between years 9 to 10 of follow-up, the prevalence of hypertension was 26% and that of atrial fibrillation 9%. Adverse events that led to death occurred in 18.4% of patients in the ibrutinib arm. Dose reduction seems to be an adequate strategy for managing adverse events. Indeed, 25% of patients underwent a dose reduction, which led to improved ibrutinib tolerability in 88% of cases. Beyond disease progression, infection and second cancers, for which long-term analyses are crucial, remain major concerns in CLL. In this study, infection remained the main cause of adverse events that led to death (8 patients). The second malignancies observed in the ibrutinib arm included nonmelanoma skin cancers (24%), melanoma (1%), and nonskin cancers (17%). Only 1 case of myeloid malignancy (myelodysplastic syndrome) was observed, a rate that compares favorably with that typically seen following chemoimmunotherapy. At study completion, 27% of patients were still on ibrutinib.

Since the first-in-class ibrutinib, second-generation covalent BTK inhibitors (acalabrutinib and zanubrutinib) have emerged in frontline CLL treatment (see figure panel B). Head-to-head comparisons with ibrutinib showed their better cardiovascular safety profile and the PFS benefit of zanubrutinib over ibrutinib in the relapse/refractory setting.^6,7 However, the continuous BTK inhibition of covalent molecules leads to resistance through the acquisition of mutations that affect the binding site of BTK (C481 residue). The novel class of noncovalent BTK inhibitors has emerged to overcome this concern and remain active in the presence of these mutations. Even more recently, molecules that not only inhibit but also degrade the BTK protein are currently in development, representing a promising therapeutic avenue for BTK-mutated cases.

How could we do better than these already impressive efficacy results? Approved second-generation BTK inhibitors and limited-duration combinations (obinutuzumab-venetoclax⁸ and ibrutinib-venetoclax⁹) offer new treatment angles but comparisons between targeted therapy regimens had been lacking. Recently, the FLAIR trial demonstrated the PFS and OS superiority of the ibrutinib-venetoclax combination, guided by minimal residual disease (MRD), when compared with ibrutinib as continuous therapy.¹⁰ Data from the CLL17 trial (NCT04608318) that compared 3 treatment regimens (fixed-duration ibrutinib-venetoclax, fixed-duration obinutuzumab-venetoclax, continuous ibrutinib) will be key to establish the future standard of care for frontline CLL therapy. Promising combinations of various BTK and BCL2 inhibitors are likewise, under active investigation.

Our next challenges will consist of better accounting for patient heterogeneity and higher resolution assessment of efficacy and safety. Refining objectives through novel end points and setting innovative designs, such as MRD-guided treatment duration and de-escalation protocols will be key to minimizing toxicity without compromising efficacy.

Conflict-of-interest disclosure: R.G. reports receiving research funding from Johnson and Johnson, AbbVie, AstraZeneca, BeOne, Roche, Lilly, and Amgen; honoraria for serving on advisory board or for presentations from Johnson and Johnson, AbbVie, AstraZeneca, BeOne, and Lilly; and travel funding from Johnson and Johnson, AbbVie, AstraZeneca, BeOne, and Lilly.