Jennifer A. Woyach, MD

Long-term data with the combination of acalabrutinib (Calquence) and obinutuzumab (Gazyva) showcase the efficacy of the regimen in both patients with treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), explained Jennifer Woyach, MD.

“This regimen appears to be very safe, very tolerable over long periods of time, and very effective,” said Woyach, an associate professor at The Ohio State University Comprehensive Cancer Center.

At the 2019 ASCO Annual Meeting, Woyach presented 3-year follow-up data on the combination of acalabrutinib and obinutuzumab in both patients with treatment-naïve and relapsed/refractory CLL.

The study accepted patients who had a diagnosis of CLL or small lymphocytic lymphoma, measurable nodal disease, an ECOG performance status ≤2, and were ≥18 years old. The median age was 61 (range, 42-76). Patients were stratified into 2 groups: treatment-naïve patients over the age of 65 (n = 19) and those with ≥1 prior treatment (n = 26).

At a median follow-up of approximately 3.5 years, most patients (78%) remained on treatment. Results showed that the overall response rate was 95% in previously untreated patients and 92% in patients who had received prior treatment. Treatment-naïve patients had a 39-month progression-free survival (PFS) rate of 94.4%; in patients with previously treated disease, the 42-month PFS rate was 72.7%.

Regarding safety, the combination treatment was well tolerated overall, with low rates of grade ≥3 adverse events (AEs) or bleeding. Common AEs of any grade were upper respiratory tract infection (73%), increased weight gain (72%), maculopapular rash (66%), cough (64%), diarrhea (64%), headache (56%), nausea (54%), arthralgia (46%), and dizziness (46%). Common grade ≥3 AEs were decreased neutrophil count (24%), syncope (11%), platelet count decreased (9%), cellulitis (9%), weight increase (9%), hypertension (7%), and hypophosphatemia (7%).

In an interview with OncLive, Woyach discussed the 3-year follow-up from the single-arm study and the future of CLL treatment.

OncLive: Could you provide background to this study?

Woyach: We knew that BTK inhibition is very effective in CLL. Acalabrutinib is a second-generation irreversible BTK inhibitor, so it binds to the same target on BTK as ibrutinib (Imbruvica) and other irreversible inhibitors. However, it is quite a bit more selective than ibrutinib and there's minimal off-target activity, which is important for the safety profile and also potentially important for combination with antibodies. In this trial, we took acalabrutinib and combined it with the CD20-directed monoclonal antibody obinutuzumab, with the goal to see if we could improve response rates, complete response rates, and PFS.

We now have a 3.5-year follow-up on this study. We had 19 patients with treatment-naïve CLL and 26 patients with relapsed/refractory disease. At 3.5 years, 70% of patients remained on treatment and progression-free. In our treatment-naïve cohort, about 94% of patients are still progression-free and alive. Our relapsed/refractory cohort had a follow-up of 42 months, and about 73% of patients are still alive and progression-free.

What do these data inform about the usefulness of acalabrutinib?

Acalabrutinib is being investigated in a number of different ways. It's being looked at in frontline therapy, in patients who are intolerant to ibrutinib, and by itself in patients with relapsed disease. One important differentiating factor of acalabrutinib is, because it doesn't have any effect on ITK, at least preclinically, that would suggest that it's going to be a better agent to combine with CD20-targeted antibodies. We know that CD20-directed drugs are very effective in CLL, so this combination is scientifically driven and appears to be very effective.

Regarding the safety of acalabrutinib, how do you optimally manage any associated AEs?

Acalabrutinib is very well tolerated in CLL. The AEs that we see most commonly are headaches, which is one thing that is an acalabrutinib unique toxicity. It's usually a low grade; it goes away within a few months. The mechanism is not completely understood. The bleeding rate we saw on this study was 71%, which is relatively high, but for most of these patients it was a little bit of bruising or a little bit of petechiae. Only two patients had higher grade bleeding, which is important. We saw that infections were overall relatively common as you tend to expect in CLL. High-grade infections were very low.

We had 1 patient who came off [treatment] for vomiting, 1 patient came off for rash, and 1 patient who came off for diarrhea. The gastrointestinal toxicities, in most patients, are pretty easy to manage with over-the-counter things like Imodium for diarrhea, nausea medication for a short period of time, and medication for heartburn, but usually those side effects are pretty easily managed.

Are there other potential combination regimens with acalabrutinib that would be interesting?

In this study…we've already accrued 2 additional cohorts of patients: one in treatment-naïve disease and one in relapsed/refractory disease where we combine acalabrutinib with a CD20-directed antibody and venetoclax (Venclexta). In the frontline setting, it's acalabrutinib, venetoclax, and obinutuzumab; in the relapsed setting, it's acalabrutinib, venetoclax, and rituximab (Rituxan). We've seen a lot of combinations with a BTK inhibitor, a BCL-2 inhibitor, and then potentially CD20-directed antibodies. I'll be really excited to share those data when they’re available.

Could you comment on the ongoing trial that is a head-to-head comparison with ibrutinib in CLL?

That was in patients who have high-risk CLL. In comparing acalabrutinib with ibrutinib, those data are not mature yet. The study has been accrued for a while, but I imagine there are not a lot of progressions. I don't know when that will be available, but a lot of people are eagerly awaiting those data.

Is there anything else regarding acalabrutinib studies that you would like to mention?

There is a frontline study that has been accrued and not yet read out, which is acalabrutinib alone, versus acalabrutinib plus obinutuzumab, versus chlorambucil plus obinutuzumab. That's in the frontline setting and that is going to be important information to tell us whether acalabrutinib and a CD20-directed antibody would be an effective combination, if that actually comes to fruition in a clinical trial.

Looking at the field of CLL, how has it evolved and where is it going in the future?

That's a really interesting question and there were a lot of discussions at the 2019 ASCO Annual Meeting, especially in frontline CLL therapy. What should we be doing right now? Where should we be going in the future? For the most part, we've moved away from chemotherapy in CLL, aside from highly selected young patients who are fit, who have IgVH-mutated disease with the potential for cure with fludarabine/cyclophosphamide/rituximab.

For most patients now, there is no reason to give them chemotherapy in the frontline setting because we know ibrutinib, venetoclax, and obinutuzumab as well as ibrutinib/obinutuzumab are all more effective than our standard chemotherapy regimens. Right now, we're very lucky in CLL. For a patient with frontline disease, we have a lot of very effective options. It also is an opportunity for us to continue to do high-impact clinical trials and put our patients on them, so we know which of these therapies is best, and whether it's going to be better to use these agents in sequence or in combination.

Woyach JA, Rogers KA, Bhat SA, et al. Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up. J Clin Oncol. 2019;37(suppl; abstr 7500). meetinglibrary.asco.org/record/171946/slide.