Acalabrutinib Monotherapy Safe, Significantly Improves PFS in Relapsed/Refractory CLL

Paolo Ghia, MD, PhD

Among the most highly anticipated study results to be presented during the 2019 European Hematology Association (EHA) Congress were those of the phase III ASCEND trial, which investigated the use of acalabrutinib (Calquence) monotherapy in patients with previously-treated chronic lymphocytic leukemia (CLL), said Paolo Ghia, MD.

The global, randomized, multicenter, open-label phase 3 study randomized 310 patients 1:1 to receive either acalabrutinib, an orally-administered BTK inhibitor that is currently FDA approved to treat mantle cell lymphoma, or rituximab (Rituxan) plus the physician’s choice of either idelalisib (Zydelig) or bendamustine. The primary endpoint of the trial was progression-free survival (PFS) by an independent review committee. Secondary endpoints included overall response rate (ORR), duration of response, PFS assessed by investigator, and overall survival (OS). At a median follow-up of 16.1 months, acalabrutinib significantly prolonged PFS (HR 0.31; 95% CI, 0.20-0.49, P <.0001), providing a 69% reduction in risk of progression or death.

PFS rates at 12 months were 88% with acalabrutinib and 68% with the physician’s choice, and OS rates at 12 months were 94% and 91%, respectively. ORR was not found to be significantly different between the acalabrutinib or physician’s choice arms (81% versus 75%, respectively; P < .22).

Discontinuation due to adverse events (AEs) occurred in 11% of patients in the acalabrutinib arm versus 49% of patients in the physician’s choice arms. Among the common all-grade AEs observeds with acalabrutinib were headache (22%), neutropenia (19%), and diarrhea (18%). AEs of interest with acalabrutinib were atrial fibrillation (5.2%), bleeding (26%), grade 3 infections (15%), and second primary malignancies (6.5%).

In an interview with OncLive, lead investigator Ghia, Universitá Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, provided further insight into the findings from ASCEND and discussed the next steps for research with acalabrutinib in the treatment of CLL.

OncLive: There has been a great deal of excitement regarding the ASCEND trial during this year’s congress. Could you provide some background on the study?

Ghia: ASCEND is a phase III, multicenter, randomized between a novel BTK inhibitor, acalabrutinib, and then physician’s choice in relapsed/refractory CLL. [Physician’s choice] was between either bendamustine and rituximab or idelalisib plus rituximab, which I would say are the standard treatment options available now in CLL. Of course, bendamustine plus rituximab in immunotherapy is long-established in CLL. Idelalisib plus rituximab is part of the novel therapies, so there’s a much shorter history [with that combination], I would say. This is the first time that a BTK inhibitor alone was tested against immunotherapy or a novel therapy, so this is almost head-to-head against 2 different novel mecahnisms of inhibition.

Could you discuss the efficacy results seen with the BTK inhibitor?

The results are quite interesting because they show that acalabrutinib is more effective in comparison with the other two regimens. The PFS is not reached, while the PFS for the other 2 arms is around 16 months—very similar between the 2, chemotherapy or not. This [approach] is also associated with better toxicity profile. We don’t have all the AEs that are known to be part of the treatment with idelalisib. Almost 50% of the patients treated with idelalisib plus rituximab will develop diarrhea and colitis; this happens much less when we use acalabrutinib, and definitely doesn’t lead to colitis. There is a typical headache [associated] with acalabrutinib, which is transient, and there is some neutropenia like is also seen with chemotherapy.

Overall, the typical AEs of BTK inhibition are much less frequent, meaning that, for example, bleeding, which is a common AE of other BTK inhibitors here is present in only one-fourth, 25% of patients. There is a low frequency of atrial fibrillation, around 5%; of course, all of these AEs have to be evaluated with time, with a longer follow-up, and then we will see.

What are some other ways in which this drug compares with other BTK inhibitors in terms of safety profile?

That’s a tough question, meaning that as long as we don’t have data comparing drugs head-to-head, we cannot really tell. Indeed, there is an ongoing study, a randomized safety study comparing acalabrutinib with ibrutinib, so we will know about efficacy and we will know about toxicity. At the moment, the profile is favorable, as I said. Bleeding seems to be much less frequent, and also, the atrial fibrillation is really at a minimal frequency.

What are the next steps for research?

Acalabrutinib is currently tested in combination with venetoclax (Venclexta), for example, in double combination. It is also [being evaluated] in a triple combination with obinutuzumab (Gazyva), so the idea, which is now fashionable in the CLL field, is that we should combine BTK inhibition with other drugs in order to improve the depth of response in our patients. The study I presented was for treatment with relapsed/refractory CLL, but there has recently been a press release on another study involving acalabrutinib in treatment-naïve patients. In trial, acalabrutinib was evaluated either alone or in association with obinutuzumab, the anti-CD20 antibody, and compared with the gold-standard for immunotherapy in the elderly population, which is chlorambucil plus obinutuzumab.

The press release mentioned the fact that the primary endpoints were reached.

I believe that these two studies will serve as the basis for the approval and the registration in both the United States and in Europe. Therefore, maybe in the future, we can add a new BTK inhibitor to the algorithm of treatment for our patients.

Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelasib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606. http://bit.ly/2IQrrJ9.