Fixed-Duration Venetoclax/Obinutuzumab Provides Robust PFS Benefit in Untreated CLL

Othman Al-Sawaf, MD

Venetoclax (Venclexta)-based fixed-duration therapies have shown a benefit in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), including those with high-risk features, according to Othman Al-Sawaf, MD, who added that such regimens have the added advantage of reduced long-term toxicity.

The combination of venetoclax plus obinutuzumab (Gazyva) maintained a progression-free survival (PFS) benefit vs chlorambucil plus obinutuzumab in previously untreated patients with CLL in 5-year follow-up data from the phase 3 CLL14 trial (NCT02242942) presented at the 2022 EHA Congress.¹

At a median follow-up of 65.4 months, patients in the venetoclax/obinutuzumab arm achieved a median PFS that was not reached compared with 36.4 months in the chlorambucil/obinutuzumab arm. The 5-year PFS rates were 62.6% and 27.0%, respectively (HR, 0.35; 95% CI, 0.26-0.46; P < .0001).

“While the study was not primarily aimed at patients with high-risk disease, we did have a fraction of patients who had an unmutated IGHV status, which carries certain high-risk disease features. Over 60% of the patients in both arms had an unmutated IGHV status, and approximately 12% had TP53 aberrations,” Al-Sawaf said. “In those high-risk groups, we saw the efficacy of venetoclax and obinutuzumab.”

In an interview with OncLive®, Al-Sawaf, a physician in the Division of Hematology, Immunology, Infectiology, Intensive Care, and Oncology at the University Hospital of Cologne in Germany, discussed the 5-year follow-up data of the CLL14 trial and emphasized the importance of fixed-duration treatments in high-risk patients with CLL.

OncLive^®: Could you expand on the primary goals of the CLL14 study?

Al-Sawaf: The CLL14 study, which ran between 2015 and 2016, addressed patients with previously untreated CLL with coexisting conditions. The aim was to investigate whether there was a difference in the PFS of patients who receive either chemoimmunotherapy with chlorambucil and obinutuzumab–so an oral chemotherapy in combination with the CD20-antibody infusion of obinutuzumab–compared with venetoclax and obinutuzumab, [with both regimens] given over 12 cycles. This is an oral BCL2 inhibitor in combination with the same CD20 antibody, obinutuzumab.

The study had a primary end point of PFS and multiple secondary end points, including overall survival [OS], minimal residual disease [MRD] negativity, safety/tolerability, and quality of life. We provided the primary readout of the study in 2019 when the primary end point was first met. Now we are continuing to follow up on our patients within this study, as per protocol, for up to 9 years after last patient enrollment.

At the 2022 EHA Congress, we presented the 5-year results from this study and [discussed] the long-term outcomes of these patients after being off study treatments for at least 4 years with a median observation time of 65 months.

What data were seen at the 5-year follow up?

We saw that at 5 years, 62.6% of patients [in the venetoclax/obinutuzumab arm] were without any PFS events compared with the chlorambucil/obinutuzumab arm, [where] we saw a 5-year PFS rate of 27.0%. This was significantly inferior to our experimental arm with a BCL2 inhibitor and a CD20 antibody.

This confirmed that although the patients received treatment for just 12 cycles, the vast majority of patients maintained their remission for more than 4 years after treatment completion, highlighting that the fixed-duration approach is feasible and effective in this group of patients.

How did the venetoclax and obinutuzumab perform in high-risk patients?

The median PFS for patients who received venetoclax and obinutuzumab in the presence of TP53 aberrations was 49 months. This means that the majority of patients maintained remission for several years after end of treatment, despite having TP53 aberrations.

For [patients with] unmutated IGHV status, we saw that the median PFS was 64 months. Patients who had high-risk features also maintained remissions for several years, although we noticed that deletion 17p remained an independent prognostic factor for PFS, together with high disease burden before start of treatment.

What stands out about these data?

There are some interesting observations that we can make with a longer observation period. For example, we clearly demonstrated the benefit of having fixed-duration approaches that are currently in development in CLL. [In particular], the toxicity profile benefits from fixed-duration treatments [is good for patients]. Virtually all toxicity occurs only when patients are on treatment. Once the patient stopped treatment, there was no prolonged treatment toxicity.

We saw patients benefit and enjoy a long treatment-free period that didn’t contain any treatment-related toxicity or adverse effects, highlighting the benefit that we gain when we establish and administer fixed-duration approaches.

Another thing we have seen is with each follow up that we are doing in this study, the OS difference is still not significant between both arms. But we do see that the hazard ratio is dropping step-by-step, indicating that in the long run, we may eventually see an OS difference. We took an in-depth look at second-line therapies that the patients are receiving, and we saw that the majority of patients [from both arms] are receiving targeted agents. This may be one explanation as to why we haven’t seen OS differences. Most patients have been able to receive state-of-the-art targeted agents as salvage options, thereby gaining further disease control for several years.

How efficacious was the fixed-duration treatment in patients with detectable MRD?

We provided several in-depth analyses of MRD dynamics. [After] more than 4 years since patients finished treatment, 18% of the patients in the venetoclax and obinutuzumab arm are still with MRD levels below 10^-4, which suggests a fraction of patients achieved long-term, MRD-negative remissions. On the other hand, there are certain disease dynamics that we observed over time where we saw subsequent increases of MRD levels, showing that, eventually, these patients will relapse.

But we can confirm that patients who achieved undetectable MRD levels below 10^-5 or 10^-6 had excellent long-term PFS compared with patients who remained MRD positive, which we identify as a high-risk group. In the context of venetoclax/obinutuzumab, the OS in these patients seemed to be impaired when patients didn’t achieve undetectable MRD at the end of treatment. This shifts the focus now in our field toward finding better options and strategies for patients who remain MRD positive after a fixed-duration approach, since these patients seem to have impaired long-term outcomes.

Also noteworthy is a study that was presented in addition to the CL14 study, which is the phase 3 CLL13 trial [NCT02950051], which [addressed] a somewhat similar question and explored venetoclax-based, fixed-duration approaches in patients with previously untreated CLL, but in patients who were younger and fit. The CLL13 study, in contrast to CLL14, evaluated patients without comorbidities who were young and eligible for intensive chemotherapies.

The readout of this study was also presented at the 2022 EHA Congress. It hoped to get a broad impression of feasibility, efficacy, and tolerability of venetoclax and obinutuzumab in all [patients in the] frontline setting of CLL.

What still needs to be addressed regarding fixed-duration treatments in CLL?

The ongoing question [is] which group of patients benefits most from continuous approaches and targeted approaches? Further questions [remain about] the best combination of different targeted agents, particularly in the frontline setting. Is it a triple or double combination? What does it mean for the long-term sequencing of agents in CLL in newly diagnosed and in relapsed/refractory disease?

[Although we have] alternative BTK inhibitors that overcome some of the challenges we have in terms of toxicity, [one topic to look at over the next few years is] MRD guidance and finding the best strategies for patients who remain MRD positive. Several studies now identify these patients as being at a particular risk of adverse outcomes. This is the direction that randomized studies must go to explore how we can improve outcomes for this group of patients.

Reference

1. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 5- year results of the randomized CLL14 study. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S148