Acalabrutinib With or Without Obinutuzumab Maintains Long-Term Survival Benefit in Untreated CLL

Acalabrutinib (Calquence) monotherapy or in combination with obinutuzumab (Gazyva) maintained a survival benefit vs obinutuzumab plus chlorambucil in patients with treatment-naïve chronic lymphocytic leukemia (CLL), affirming both treatment regimens are viable options for this patient population, according to Jeff P. Sharman, MD.

Data from a 5-year follow-up analysis of the phase 3 ELEVATE-TN trial (NCT02475681) presented during the 2022 ASCO Annual Meeting showed that the investigator-assessed median progression-free survival (PFS) was not reached for acalabrutinib alone and in combination with obinutuzumab compared with a median PFS of 27.8 months for obinutuzumab plus chlorambucil.¹ Acalabrutinib monotherapy (HR, 0.21; 95% CI, 0.15-0.30; P < .0001) and the combination regimen (HR, 0.11; 95% CI, 0.07-0.16; P < .0001) both achieved a significant PFS benefit vs obinutuzumab plus chlorambucil.

Additionally, the 5-year overall survival (OS) rates were 90%, 84%, and 82% for the acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and obinutuzumab plus chlorambucil arms, respectively.

In November 2019, the FDA approved acalabrutinib for the treatment of adult patients with CLL or small lymphocytic lymphoma, based on prior data from the ELEVATE-TN trial and the phase 3 ASCEND trial (NCT02970318).

“The ASCEND study, which was done at the same time [as ELEVATE-TN], allowed for approval [of acalabrutinib] in the relapsed and refractory setting. That gives us a broad flexibility to use acalabrutinib with or without obinutuzumab,” Sharman said.

In an interview with OncLive^®, Sharman discussed the meaning of the long-term follow-up data from ELEVATE-TN, the efficacy of the acalabrutinib regimens in patients with deletion 17p or TP53 mutations, and the factors to consider when adding obinutuzumab to acalabrutinib. Sharman is the director of Research at the Willamette Valley Cancer Institute and the medical director of Hematology Research for The US Oncology Network.

OncLive^®: How was efficacy maintained with longer follow-up in this study?

Sharman: It has been nice to monitor continued updates from the ELEVATE-TN study. This is a study that initially looked at randomly assigning patients to either acalabrutinib with or without obinutuzumab vs obinutuzumab with chlorambucil.

The initial study results were presented several years ago, with the first readout of the data showing superiority of the acalabrutinib-containing arms. What we’ve seen with longer follow-up is that the benefit of acalabrutinib continues, and we’re pleased to see that the PFS continues to demonstrate a significant benefit vs obinutuzumab/chlorambucil.

With the new data, we now have an OS benefit for acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil. We see continued ongoing benefits with the acalabrutinib monotherapy, but it hasn’t achieved an OS benefit.

Was PFS benefit seen in patients with high-risk markers, such as deletion 17P or TP53?

We absolutely saw a PFS benefit amongst all populations studied, including patients with IGHV unmutated vs mutated, and TP53-mutated or -deleted vs wild-type [disease]. All those groups benefited from acalabrutinib-containing regimens vs obinutuzumab/chlorambucil.

It was more difficult to demonstrate whether the addition of obinutuzumab added to that benefit because these were smaller subsets. But it's clear that in patients with high-risk markers, the targeted strategy is superior to the traditional chemoimmunotherapy approach.

Have there been any new safety signals with the updated dataset?

With the family of BTK inhibitors, we've been carefully monitoring for several potential safety signals, including hypertension and atrial fibrillation. We're not seeing much beyond baseline characteristics in this population. It appears as if we're not getting a new cardiovascular risk signal with further follow-up. In fact, the safety signals remain consistent with those we initially reported in the early reports from this dataset.

Were there any surprising data that you would like to highlight?

The only surprise in the data is that we are starting to see survival benefit for the combination of acalabrutinib/obinutuzumab over obinutuzumab/chlorambucil. It wasn't long ago that you never saw survival benefits in CLL studies. Now they seem to be relatively commonplace, and it is gratifying to see with longer-term follow-up that we're not only improving PFS, but OS as well.

What factors would you consider when deciding between acalabrutinib alone vs acalabrutinib plus obinutuzumab?

Since this study evaluated acalabrutinib with or without obinutuzumab, it does give insights into where we might want to use the obinutuzumab. When you add obinutuzumab to the regimen, you do get some additional toxicity, particularly in the form of infusional toxicity, which you're not going to have if patients are not getting infusions. But there's also greater neutropenia and perhaps some higher rates of infectious complications [with the addition of obinutuzumab].

However, we also see a PFS benefit with the addition of obinutuzumab over acalabrutinib alone. I ask myself this question: if I’m going to treat a patient with a BTK-containing regimen, are they sufficiently fit and able to do infusions? I don't necessarily give obinutuzumab to every patient, but those who seem like they are fit enough to add it, that's generally where I do so.

What would you like your colleagues to take away from this research?

Amongst BTK inhibitors that are out there, there's first-generation of ibrutinib [Imbruvica] and 2 second generation BTK inhibitors, acalabrutinib and zanubrutinib [Brukinsa]. There will probably be more in the future, but from a safety and tolerability perspective, we've seen head-to-head comparative data of the second-generation BTK inhibitors vs the first-generation BTK inhibitor. There are some tolerability advantages for the second-generation BTK inhibitors.

This is a very well-tolerated regimen, and as we're evaluating whether our patients are suitable for a BTK-based strategy, [acalabrutinib] has become my BTK agent of choice. I know that's true for many of my colleagues, as well.

References

1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: five-year follow-up of ELEVATE-TN. J Clin Oncol. 2022;40(suppl 16):7539. doi:10.1200/JCO.2022.40.16_suppl.7539
2. Project Orbis: FDA approves acalabrutinib for CLL and SLL. News release. FDA. November 21, 2019. Accessed August 16, 2022. https://bit.ly/3CkoHAS