Ibrutinib/Venetoclax Combo Demonstrates Sustained TEAE-Free PFS in First-Line CLL

Updated findings from the 67-month follow-up analysis of the phase 3 GLOW trial (NCT03462719), which compared frontline treatment with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) vs obinutuzumab (Gazyva) plus chlorambucil in frail, older patients with chronic lymphocytic leukemia (CLL), demonstrated sustained progression-free survival (PFS) and a significant improvement in toxicity-free PFS with the experimental regimen.

In a presentation at the 2024 ASH Annual Meeting, results showed that ibrutinib plus venetoclax reduced the risk of disease progression or death by 72.7% compared with the control arm (HR, 0.273; 95% CI, 0.186-0.401; P < .0001). The 66-month PFS rates were 51.7% for ibrutinib/venetoclax vs 18.1% for obinutuzumab/chlorambucil.

Toxicity-free PFS was defined as freedom from disease progression/death and grade 3 or higher treatment-emergent adverse effects (TEAEs). Findings showed that the median toxicity-free PFS was 51.6 months with the experimental regimen vs 30.2 months with the control treatment.

“We need to look at this landscape of different trial results [when selecting treatment in CLL]. We want to aim to improve not just survival, but quality of life for our patients,” said Carsten Utoft Niemann, MD, PhD. Niemann is an associate professor and clinical researcher at Rigshospitalet in Copenhagen, Denmark.

In an interview with OncLive®, Niemann discussed the implications of these findings on first-line treatment considerations in CLL, the integration of quality-of-life measures in treatment decision-making, and ongoing efforts to refine treatment strategies for this patient population.

OncLive: What was importance of this follow-up analysis of the GLOW trial?

Niemann: Looking at the [current] treatment landscape in CLL, we have so many good treatment options for our patients. GLOW enrolled patients who were frail or older, and this [represents] the majority of patients with CLL. [With additional follow-up data from GLOW,] we were looking to assess the longer-term perspective in terms of toxicity and efficacy.

In this landscape of a lot of different treatment options [for CLL], providing [additional data] assessments helps give us an idea what would be the best treatment options for specific patients.

What data were reported in this 67-month follow-up analysis?

We already knew that OS and PFS were improved with the combination of ibrutinib and venetoclax vs obinutuzumab and chlorambucil. [We then assessed whether] this improvement would be sustainable for a longer period of follow-up. That's what we found in the longer-term follow-up data presented [at ASH].

[We] also [assessed] the toxicity profile; [the treatment duration of] ibrutinib plus ventoclax was more than double the length compared with chlorambucil plus obinutuzumab, which was 6 total cycles given in less than 6 months.

What we see here [with additional follow-up] is that for grade 3 or higher TEAE–free PFS outcomes, we reported that the toxicity-free PFS was significantly improved by 21 months as compared [with] chlorambucil plus obinutuzumab, despite the longer length of treatment [with the] combination of ibrutinib and venetoclax.

Considering these results, how should oncologists approach the selection of first-line therapy for patients with CLL?

When looking at the patient population and considering treatment for CLL, we need to extrapolate [decisions based on data] from the GLOW trial, but also the [phase 3] CLL14 [NCT02242942], VISION [NCT03226301], and GAIA [NCT02950051] trials.

There are 2 different take-home messages from [these data]. [The first] being that on targeted treatment, whether it's ibrutinib [combined] with venetoclax or venetoclax with obinutuzumab, we see quite early improvement in quality of life while on treatment. Chemoimmunotherapy [regimens have been associated with] a slower and later improvement in quality of life.

For chemoimmunotherapy, the improvement is not to the same degree as we see for the targeted agent. For the triplet combination of ibrutinib, venetoclax, and obinutuzumab, we also see that the improvement in quality of life comes much later.

If we take the step to the VISION trial, ibrutinib plus venetoclax given as minimal residual disease–guided in the relapsed/refractory setting of CLL, we saw quite early improvement [in quality of life], even for this population [experiencing] relapse [with] a little bit more aggressive [disease]. Because [VISION] was randomized for patients achieving undetected MRD, we also saw a clinically significant improvement [in quality of life for] this large group of patients who stopped treatment based on the MRD results [compared with] the ones continuing therapy.

We need to figure out how to make smart combinations in surplus, whether it's a BTK inhibitor or BCL-2 inhibitor together with a CD20 monoclonal antibody.

Reference

Niemann CU, Munir T, Owen C, et al. First-line ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in elderly or comorbid patients with chronic lymphocytic leukemia: glow study 64-month follow-up and adverse event-free progression-free survival analysis. Blood. 2024;144(suppl 1):1871. doi:10.1182/blood-2024-203269