Expert Confirms Efficacy, Safety in Final ASCEND Data With Acalabrutinib in Relapsed/Refractory CLL

Final results from the phase 3 ASCEND trial confirm earlier data that support the favorable safety and efficacy of acalabrutinib (Calquence) compared with standard-of-care regimens in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to Paolo Ghia, MD, PhD.

In the randomized, multicenter, open-label phase 3 trial evaluated acalabrutinib monotherapy (n = 155) versus idelalisib (Zydelig) plus rituximab (Rituxan; IdR; n = 119) or bendamustine (Bendeka)plus rituximab (BR; n = 36) in patients with relapsed/refractory CLL.

Results presented during the 2020 ASCO Virtual Scientific Program showed that, at a median follow-up of 22.0 months, acalabrutinib significantly prolonged PFS versus IdR/BR in patients with high-risk features, including those with del(17p)/TP53 mutations and unmutated immunoglobin heavy chain variable. Additionally, the estimated 18-month progression-free survival (PFS) rate was 82% with acalabrutinib and 48% with IdR/BR. The median overall survival was not reached in either treatment arm; the estimated 18-month OS rates were 88% for both arms.

The overall response rates reported appeared to be comparable between the arms. However, duration of response (DOR) was longer with acalabrutinib compared with idR/BR. Specifically, the median DOR had not been reached with acalabrutinib versus 18.0 months with idR/BR. The estimated 18-month DOR rate was 85.4% versus 49.4% in the investigative and control arms, respectively.

“Acalabrutinib is a second-generation BTK inhibitor. We know that BTK inhibition is a mainstay in the treatment landscape of CLL,” said Ghia. “Acalabrutinib, which appears to be very effective, even when compared with other novel therapies, which is very comforting for the physician. It is another welcome addition to our treatment armamentarium. The agent also showed a good toxicity profile. The drug appears to be safe, or at least safer, than idelalisib plus rituximab with lower frequency of discontinuation.”

Moreover, adverse effects (AEs) were the most common reason for treatment discontinuation in all arms. However, more patients on the IdR arm discontinued treatment because of toxicities compared with those on the acalabrutinib or BR arms. The most common any-grade AEs reported with acalabrutinib included headache, neutropenia, diarrhea, and upper respiratory tract infection, and they were mostly grade 1 or 2 in severity.

In an interview with OncLive, Ghia, a professor of medical oncology and the director of the Strategic Research Program on CLL and the B-Cell Neoplasia Unit at Vita-Salute San Raffaele University, discussed the final results from the phase 3 ASCEND trial with acalabrutinib monotherapy in patients with relapsed/refractory CLL.

OncLive: Could you shed light on the design and objective of the ASCEND trial?

Ghia: In the phase 3 randomized trial, we compared acalabrutinib monotherapy with physician’s choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia. At the 2020 ASCO Virtual Scientific Program, we presented the final results of the trial, with a follow-up of 6 additional months.

Interim data with acalabrutinib were previously reported and showed favorable results. What were the longer-term follow-up data that read out at the meeting?

Most of the [previous] results, if not all, are confirmed; this means that we see an advantage in terms of PFS, which has not yet been reached with acalabrutinib when compared with the standard-arm [IdR or BR]. The median PFS in the control arm was already reached at 18 months. Eighty-two percent of patients who are receiving acalabrutinib are still responding at 18 months. In terms of safety, no unexpected AEs were reported compared with [what had been observed in the] interim analysis and the tolerability of the drug remains similar, as well.

Do you feel that treatment has shifted away from chemoimmunotherapy regimens to these novel therapies in recent years?

Chemoimmunotherapy is fading out of the treatment algorithm of CLL. We will see with the new updated ESMO guidelines whether chemoimmunotherapy remains an option only for patients who don't have access to novel drugs. We have to remember that in many countries, in many regions, not everyone will have the same accessibility to [these new drugs].

However, for the rest of the patients in the first-line setting, most appear to have benefited from the novel therapy. Again, even in the relapsed/refractory setting, the fraction of patients who can benefit from chemoimmunotherapy is reducing with time.

Is there anything else you want to add about this research?

In the moment, we don't see an OS advantage. Nowadays, it’s typically in the new trials because patients on the control arm, upon disease progression, had the opportunity to switch over to the acalabrutinib treatment. Of course, this affected the OS and showed the relevance of the treatment that we provide to our patients.

Reference

1. Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ASCEND final results. J Clin Oncol. 2020;38(suppl 15):8015. 10.1200/JCO.2020.38.15_suppl.8015