Ibrutinib Plus Venetoclax Provides Additional Fixed-Duration Regimen for Elderly Patients With CLL

Carsten Niemann, MD, PhD

As the first oral, fixed-duration combination regimen to demonstrate an overall survival (OS) advantage over standard chemoimmunotherapy in elderly, frail patients with chronic lymphocytic leukemia (CLL), ibrutinib (Imbruvica) plus venetoclax (Venclexta) could address the need for novel first-line regimens in this higher-risk population, according to Carsten Niemann, MD, PhD.

Four-year follow-up data from the phase 3 GLOW trial (NCT03462719) presented at the 2022 ASH Annual Meeting and Exposition showed that 87.5% of patients who received first-line, fixed-duration ibrutinib plus venetoclax were still alive compared with ​​77.6% of those who received chlorambucil (Gazyva) and obinutuzumab (HR, 0.487; 95% CI, 0.262-0.907; nominal P = .0205).

Moreover, in the ibrutinib and venetoclax arm, 91.5% of patients with unmutated IGHV and 93.5% of those with mutated IGHV did not require subsequent treatment at 3.5 years of follow-up.

“We now have an additional oral, time-limited treatment for the most common group in my clinic: frail, elderly patients,” said Niemann in an interview with OncLive^®. “Furthermore, it seems that this combination targets all [components] of [a patient's] disease, [indicating that] we may not need deep minimal residual disease [MRD] responses to [achieve] sustained clinical responses.”

In the interview, Niemann, chief physician and head of the Leukemia Laboratory in the Department of Hematology at Rigshospitalet Copenhagen University Hospital in Denmark, discussed the significance of new OS and progression-free survival (PFS) data from the GLOW trial, the potential relationship between treatment regimen, MRD status, and survival outcomes, and the importance of research into precision medicine approaches in CLL.

OncLive^®: Please provide some background on initial data and follow-up analysis reported from the GLOW trial.

Niemann: The GLOW trial compared [the activity of] ibrutinib and venetoclax with [chlorambucil] and obinutuzumab for frail patients with [genetic risk factors]. We tested whether we could improve outcomes for the most common population in CLL.

Earlier this year, we published a primary analysis from the trial demonstrating that PFS was superior with ibrutinib and venetoclax compared [with] the chlorambucil and obinutuzumab arm. At ASH 2022, [we presented] almost 4 years of follow-up [data] on OS for [these] patients.

What was the rationale for investigating the correlation between MRD kinetics and patient outcomes in this trial?

We are always looking to understand differences between treatments, and whether we can use the same proxy outcomes [to measure these differences]. MRD is essentially a proxy outcome we [can use to] measure whether we have an optimal treatment response early on, and correlate that with PFS. A direct correlation between MRD undetectable levels at 10^-4 and PFS has previously been demonstrated for chemoimmunotherapy and venetoclax with a CD20 antibody. We’re looking for [a similar relationship with] the combination of ibrutinib and venetoclax.

What key data from the 4-year follow-up analysis were shared at ASH this year?

A year ago, we demonstrated that PFS was not directly correlated [with] undetectable MRD rates at the end of treatment. [In our] longer follow-up [analysis], we see a correlation [between] shorter PFS [and] patients with unmutated IGHV who have detectable MRD. This means that patients who have IGHV mutations have a good PFS, whether they have achieved undetectable MRD or not. Patients [with] unmutated IGHV who achieve undetectable MRD levels [with] [ibrutinib and venetoclax] have a PFS above 90% at 3.5 years. A total of 67% of patients with unmutated IGHV and detectable MRD [showed an] inferior PFS [at 2 years post-treatment].

[We also found that] OS was superior for the ibrutinib and venetoclax arm [vs] the chlorambucil and obinutuzumab arm. [This] is the first time [that] we have demonstrated an OS benefit from [this] new, targeted, [time-limited treatment in] this patient population.

What is exciting about the OS data that emerged from this trial?

It is quite surprising to see an OS benefit for this patient population because we know that we have such good next-line treatment options. [Additionally,] we [saw] that 39 out of 41 patients receiving next-line treatment in the chlorambucil arm received either a BTK inhibitor or BCL-2 inhibitor. That seems to emphasize that [lower survival outcomes are] not due to lack of access to targeted agents for retreatment, and that it might be important to use more efficient treatment up front.

What else do results indicate about the relationship between treatment regimen, MRD levels, and PFS?

[It is important to] look at differences [seen] in targeting the different [components of a patient's] disease, [including] disease of the peripheral blood, the bone marrow, lymph nodes, and spleen. We looked at the lymph node responses for patients with detectable vs undetectable MRD in peripheral blood, and [found that] patients with detectable MRD in peripheral blood [still] have sustained lymph node responses.

This may indicate that different [treatment] combinations could have different correlations between undetectable MRD levels and PFS. [Specifically,] the combination of a BTK inhibitor and a BCL-2 inhibitor [may be] superior in terms of targeting all compartments of the disease. Thus, it may be that we do not need a steep, MRD response to achieve sustained PFS.

What next steps are planned for the investigation of this combination?

We always want longer follow-up for clinical trials to [see if] some patients would meet a plateau for PFS and undetectable MRD levels. We'll have to be patient and wait for a few more years to see this [data].

Now that we have a number of [available] combinations, we want to identify patients who would benefit most from [each] up-front treatment regimen. We need more information to identify the pattern of routine data, genetics, immune phenotyping, and the risk of specific adverse effects [AEs] for these patients. Essentially, [we want to] take this step towards precision medicine.

What other research stood out to you from the meeting?

I was excited to see data regarding the genetics of CLL and how [this] affects [patient] outcomes on different treatments. [Although] we are not yet there yet, we saw two abstracts presented from the [phase 3] GAIA trial [NCT02950051] [aiming to] identify patient subgroups who would benefit from a specific treatment. [Knowing] that [information] would help us move towards precision medicine [in our treatment approach].

[I was also interested in] the late breaking abstract comparing zanubrutinib [Brukinsa] and ibrutinib in relapsed/refractory CLL. We need to try to understand differences between different BTK inhibitors [in that population]. [The purpose of this research is] not [to identify] a new option for indefinite treatment with a BTK inhibitor, but to look for the best combination partner for a next-generation clinical trial.

[Lastly, my colleagues and I had] a poster presentation [on the use of] machine learning to identify patients with specific [treatment-related] AEs in CLL. Research in [both] CLL and general hematology [should shift focus towards] the huge amount of available data [in order] to improve patient outcomes.

Reference

​​Niemann C, Munir T, Moreno, C et al. Residual disease kinetics among patients with high-risk factors treated with first-line fixed-duration ibrutinib plus venetoclax (ibr+ven) versus chlorambucil plus obinutuzumab (clb+o): the Glow study. Blood 2022;140 (suppl 1):228-230. doi:10.1182/blood-2022-156070