Al-Sawaf Highlights the Benefit of Fixed-Duration Venetoclax/Obinutuzumab in CLL

The fixed-duration regimen of venetoclax (Venclexta) plus obinutuzumab (Gazyva) showed superior efficacy and deep responses of remission in patients with chronic lymphocytic leukemia (CLL) when compared with chlorambucil plus obinutuzumab, according to Othman Al-Sawaf, MD.¹ 

“We know that some BTK inhibitors might have an increased rate of atrial fibrillation or bruising or bleeding events, and for those patients or patients who have any sort of cardiac comorbidity, such as existing coronary heart disease or uncontrolled arterial hypertension, they might not be the best candidates for a BTK inhibitor,” explained Al-Sawaf. “For them, venetoclax/obinutuzumab might be a particularly [good] option.” 

In May 2019, the FDA approved the combination based on the phase 3 CLL14 trial, which showed that the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab/chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions.²

The extended follow-up from the trial was presented during the 2020 ASCO Virtual Scientific Program, and results showed that at 24 months, the estimated progression-free survival (PFS) rate was 88.2% in the venetoclax/obinutuzumab arm and 64.2% in the chlorambucil/obinutuzumab arm. However, no difference was observed with regard to overall survival (OS) in either arm. Venetoclax/obinutuzumab was also shown to have a low incidence of high-grade adverse effects (AEs) in patients with relevant comorbidities, and 80% of patients who received the combination completed treatment.

“This is now an additional option that we have, particularly for unfit patients for whom it is sometimes difficult to choose the best treatment depending on the coexisting conditions that they have and depending on the additional drugs that they are taking for [comorbidities, such as] hypertension or diabetes,” said Al-Sawaf.

In an interview with OncLive, Al-Sawaf, a physician with the University Hospital of Cologne in Germany, further discussed the data from the CLL14 trial with obinutuzumab/venetoclax and the benefits of a fixed-dose treatment in select patients with CLL.

OncLive: Could you discuss the advantages of fixed-duration therapy in CLL?

Al-Sawaf: In CLL, we have traditionally always treated our patients with fixed-duration treatments. When we were using chemoimmunotherapy, we usually treated our patients with 6 cycles of treatment, so we could tell our patients that for approximately half a year, they would need to regularly visit the doctor and get their chemotherapy or antibody infusions. [Many of the novel compounds] have mostly all been developed for use as continuous treatments that the patient may take orally, but they need to take it until disease progression or intolerable toxicity. Now we are seeing the shift back to trying to use novel compounds at fixed doses rather than as continuous treatment.

What was the design and objective of the CLL14 trial?

In CLL14, we're investigating patients with previously untreated CLL and coexisting conditions. We wanted to see whether particularly elderly patients and those who are not fit enough to receive intensive chemoimmunotherapy and were traditionally treated with mild chemoimmunotherapy, such as chlorambucil/obinutuzumab, which was the standard-of-care arm chosen for this trial. We wanted to see whether we can challenge that with a more effective therapy that is, at the same time, at least as tolerable as a mild chemoimmunotherapy. That's the background of CLL14, mainly improving the efficacy, but at the same time maintaining the tolerability, of mild therapy for our unfit patients.

What did the updated results show and was there a benefit seen across all patient subsets?

The follow-up analysis that we did is basically focused on trying to see the long-term benefits of venetoclax/obinutuzumab. In the current analysis, all patients have been off treatment for 24 months. Patients have taken their treatment for 12 cycles and have since stopped treatments, although they continue to be followed up. We are checking how deep the responses are at the moment and whether the patients have received the next line of therapy or experienced any long-term toxicities. That was basically the main aim of this follow-up: to see how sustainable the good efficacy that we saw last year during our primary analysis was.

The first main finding in that setting was that we saw a sustained PFS benefit for patients treated with venetoclax/obinutuzumab. At the moment, with this 3-year follow-up, we see a 3-year PFS rate of approximately 82% in patients treated with venetoclax/obinutuzumab in contrast with approximately 50% in those who received chlorambucil/obinutuzumab; that is a significant extension of PFS by venetoclax/obinutuzumab. We also see that [benefit] reflected across all risk groups, including patients who have TP53 aberrations and those who have unmutated IGHV status. 

Interestingly, now we also see that the benefit of venetoclax/obinutuzumab is higher in patients with mutated IGHV status. This differs with what we previously saw in the primary analysis, where we saw that patients who were treated with chemoimmunotherapy had a similar favorable PFS when they had a mutated IGVH status; this is in line with what we see with all sorts of chemoimmunotherapy. For patients treated with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR), when they have a mutated IGHV status, we can see long-term PFS rates of over 10 years. This has always been a group of patients that has benefited most from chemoimmunotherapy. With this follow-up analysis, we do see now that venetoclax/obinutuzumab even improves outcomes in this particular group of patients Thereby, all patients in all risk groups benefit from venetoclax/obinutuzumab.

What did the minimal residual disease (MRD) assessment show?

The MRD assessments are of particular interest for us because we are continuing to monitor it, although patients are off treatment and we are doing a very longitudinal analysis of MRD. What we see now is that approximately half of the patients are still with a detectable MRD after venetoclax/obinutuzumab, in contrast with only 7% of patients in the chlorambucil/obinutuzumab arm. This shows that there is, of course, a fraction of ultimately half of the patients who lose their undetectable MRD level.

On the other hand, the other half maintains their undetectable MRD levels 2 years after they stop treatment. Again, when we look at the next steps and see whether these elevated MRD levels [appear] in the 50% who lose their undetectable MRD levels, we see that only a small fraction of those patients really develops disease progression. We do see patients having detectable MRD, but not reaching the threshold of having a real disease progression. Then again, when we look at the few disease progressions we had, which is approximately 20 cases overall in the 216 patients with venetoclax/obinutuzumab, only 9 patients have actually required the next line of therapy. We see that the vast majority of patients, even though they might at some stage lose their MRD response, they won't require any therapy for several years.

Did any new safety signals emerge?

The first impression that we saw was a severe drop in any toxicity simply because, after 1 year, the patients don't require any additional treatment; therefore, all the toxicities that might occur with venetoclax, but also chlorambucil/obinutuzumab for that matter, drop. We don't see any long-term hematological toxicities, such as ongoing neutropenia or anemia. What we do see now, which is probably just due to the snapshot that is taken by doing follow-up analyses, is a slight increase in secondary malignancies. We see a rate of approximately 5% in the venetoclax/obinutuzumab arm compared with 2% in the chlorambucil/obinutuzumab arm. This doesn't reach any statistical significance, but we think it's fair to be cautious about it and to continue to follow up on this.

We don't see any clear pattern in those secondary malignancies, so it's not that we see an increased rate of acute myeloid leukemia or myelodysplastic syndromes—the malignancies that we see particularly after FCR, for instance. We don't see any signal like that, but we do see an overall increase in solid tumors with venetoclax, although, as I said, it doesn't reach statistical significance. We are continuing to follow up on this, specifically, because there are other trials that have even longer follow up on venetoclax than ours. For instance, in the MURANO trial, a similar pattern was not observed there, so we are cautious about it and are continuing to follow up and we'll see whether this is clinically meaningful or not.

Should the higher incidence of secondary malignancies deter patients from pursuing that regimen?

I don't think so, simply because the numbers are too low and it's possible that this is just by chance that we are seeing this different distribution of incidences. However, we'll see more about that in the next follow up and then we [will] know whether this is really critical. It's also not the case that we see an excessive number of deaths due to secondary malignancies or something that would make us particularly cautious that this has a direct impact on the patient's quality of life or OS. This is something that we don't see.

What is the clinical significance of these data?

What we can do now is to discuss with our patients their individual preferences. Some patients say that they do not want to get any infusions and they do not want to have regular visits with a hematologist—or at the very least, less frequent [visits]. For those patients, continuous treatments might be a very feasible option, so setting them on a continuous BTK inhibitor might be of particular value. On the other hand, some patients just want to know that they received the treatment for 1 year and that they can stop treatments; that seems to be much more favorable for them than a continuous treatment.

Then again, there are medical reasons to consider things like the toxicity profile; they are very different. For example, we know that some BTK inhibitors might have an increased rate of atrial fibrillation or bruising or bleeding events. For those patients or patients who have any sort of cardiac comorbidities, such as existing coronary heart disease or uncontrolled arterial hypertension, they might not be the best candidates for BTK inhibition. For them, venetoclax/obinutuzumab might be am option. On the other hand, a patient who has end-stage renal failure and doesn't have any capacities to receive any infusions, a single oral regimen might be more beneficial; it has become a more individual approach for patients with CLL.

References:

1. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial. J Clin Oncol. 2020;38(suppl 15; abstr 8027). doi:10.1200/JCO.2020.38.15_suppl.8027
2. FDA Prescribing Information for Venetoclax. https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed May 15, 2019.