BTK Inhibitors Show Continued Promise in CLL

Brian T. Hill, MD, PhD

Data from recent studies continue to demonstrate the potency and tolerability of BTK inhibitors as monotherapy and in combination for the treatment of patients with chronic lymphocytic leukemia (CLL) both in the frontline and relapsed/refractory settings, said Brian T. Hill, MD, PhD.

For example, one phase II study tested the feasibility of the second-generation BTK inhibitor acalabrutinib (Calquence) in patients intolerant to ibrutinib (Imbruvica). Results showed that the overall response rate (ORR) was 72% with acalabrutinib in relapsed/refractory patients.¹ At a median follow-up of 19 months, the median progression-free survival (PFS) had not been reached, but the 18-month PFS rate was 73.5%.

Acalabrutinib has also been evaluated with the CD20-directed monoclonal antibody obinutuzumab (Gazyva) in both patients with treatment-naïve and relapsed/refractory CLL. Updated data presented at the 2019 European Hematology Association Congress showed that the combination induced an ORR of 95% in treatment-naïve patients and 92% in the relapsed/refractory patients.² The CR rate was 31.6% with the combination as frontline treatment and was 7.7% in the relapsed/refractory setting. Median PFS had not been reached at 3 years in either arm.

Furthermore, ibrutinib has shown sustained efficacy in patients with relapsed/refractory CLL, according to the final analysis of the phase III RESONATE trial presented at the 2019 ASCO Annual Meeting.³ At a follow-up of 6 years, median PFS in the ibrutinib arm was 44.1 months compared with 8.0 months in high-risk patients treated with ofatumumab (Arzerra; HR, 0.11; 95% CI, 0.08-0.152; P < .0001). In the intent-to-treat population, the ORR in the ibrutinib arm was 91%.

In an interview with OncLive, Hill, an assistant professor of Hematology/Oncology at Cleveland Clinic, highlighted the latest data with BTK inhibitors in CLL.

OncLive: What are the main takeaways from the RESONATE trial?

Hill: The RESONATE trial was a randomized prospective trial for patients with previously treated CLL who received the then-standard of care versus the BTK inhibitor ibrutinib. This study was done right around the time the drug was being FDA approved, and now we have very long follow-up of 6 years. What's remarkable about the study is that with longer follow-up, we know the PFS is about 44 months in patients treated with ibrutinib; this is statistically significantly better compared with chlorambucil. We now know there are some long-term toxicities, such as atrial fibrillation, which we are seeing in about 12% of patients, and there is also the risk of major hemorrhage.

With indefinite long-term therapy with these BTK inhibitors, we are seeing slow but continued rates of discontinuation. Although there are no new safety signals, I would say this reinforces the notion that with long-term exposure to this drug in CLL, there is potential for toxicity.

What are some unanswered questions that remain with ibrutinib in CLL?

In the relapsed setting, we do have alternatives to ibrutinib now. We have venetoclax (Venclexta), which can be used in combination with rituximab (Rituxan) in the relapsed/refractory setting. According to recent data from the MURANO trial, we know that if you treat with this combination for 2 years, a significant proportion of patients will achieve what we call an undetectable minimal residual disease state. Patients could potentially discontinue further therapy and eliminate the need for continuous therapy that's associated with [increased] cost and toxicity.

Could you provide insight on the phase II study evaluating acalabrutinib in patients with relapsed/refractory CLL who were intolerant to ibrutinib?

Due to the success of ibrutinib, which is obviously a very potent BTK inhibitor, there has been significant interest in developing second-generation oral BTK inhibitors. Acalabrutinib is an oral, twice-daily BTK inhibitor, and the study showed that you can actually treat patients who are intolerant to ibrutinib with acalabrutinib. Of the 60 patients studied, about 25% had discontinued ibrutinib due to toxicity concerns, such as atrial fibrillation. The response rate was maintained in this patient population, with an ORR [plus ≥late partial response] of about 77%, which is pretty impressive in the ibrutinib-intolerant population. I will point out that the rate of atrial fibrillation in the study was significantly lower—only 3 of the patients developed this adverse event; this suggests that acalabrutinib doesn't have the off-target effect we see with ibrutinib.

What does this mean for sequencing?

There are head-to-head trials of ibrutinib and acalabrutinib [being conducted] in the frontline setting. The studies are awaiting final analysis, and it actually may take many years for there to be enough events for us to determine if the treatments are noninferior to one another.

What sets acalabrutinib apart from ibrutinib and other agents in this space?

What's unique so far about acalabrutinib is that there are really only 2 FDA-approved agents in this class of BTK inhibitors. Although it does have unique toxicities, including headache, that we don't see with ibrutinib, it's general mild and self-limiting. The bleeding risk with acalabrutinib seems to be a class effect because we also see it with ibrutinib. However, what’s unique [about the agent] is the lower incidence of other toxicities [that are observed with its use], like atrial fibrillation and hypertension.

What did you take away from the 3-year follow-up data of acalabrutinib combined with obinutuzumab in relapsed/refractory CLL?

In this study, the investigators sought to use acalabrutinib in combination with a next-generation monoclonal antibody. This was done in a cohort of both treatment-naïve and relapsed/refractory patients. What was known from prior studies is that the addition of rituximab to ibrutinib does not improve PFS in untreated patients. This is an exploratory story to determine the safety of the combination and to see whether there is potential for further exploration of this combination.

What's notable is that ORR is very high, over 90% of the patients responded. The CR rate was modest, but higher in the treatment-naïve arm. The tolerability was pretty comparable with what we have seen with BTK inhibitors combined with monoclonal antibodies.

Are there are any other ongoing trials that may address some unanswered questions?

There is a randomized frontline trial testing the notion that the addition of a monoclonal antibody to a BTK inhibitor may provide clinical benefit. The study is going to randomize patients to receive either acalabrutinib monotherapy or acalabrutinib plus obinutuzumab. That's going to be an important study [that we hope will answer the] question of whether there are certain BTK inhibitors that benefit from the addition of a next-generation monoclonal antibody.

Is there biomarker work ongoing that should be highlighted?

We know that certain molecular features correspond with poorer response to chemotherapy, and it turns out this is also true for targeted agents. The 17p deletion in CLL is well known to confer inferior outcomes and shorter response rates to BTK inhibitors. Complex cytogenetics also appear to portend poor outcomes. For those patients, it may be useful to bring in novel therapies like the addition of venetoclax, a BCL-2 inhibitor. This question is being addressed in frontline studies.

References

1. Rogers K, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Sweden. Abstract 266768.
2. Woyach JA, Rogers K, Bhat S, et al. Acalabrutinib with obinutuzumab in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: 3-year follow-up. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Sweden. Abstract 266177.
3. Barr PM, Munir T, Brown JR, et al. Final analysis from RESONATE: six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib. J Clin Oncol. 2019;37(suppl 15; abstr 7510). doi: 10.1200/JCO.2019.37.15_suppl.7510.