Goy Lends Insight on Acalabrutinib and Ibrutinib in MCL

Andre Goy, MD

The FDA approval of ibrutinib (Imbruvica) in 2013 had a significant impact on the treatment landscape for patients with mantle cell lymphoma (MCL). However, the recent approval of acalabrutinib (Calquence) has similarly altered the field, as experts say it could be associated with slightly fewer adverse events (AEs) than ibrutinib, according to Andre Goy, MD.

The November 2017 approval for acalabrutinib was based on the findings from the phase II ACE-LY-004 trial, in which 124 patients with relapsed/refractory MCL received oral acalabrutinib at 100 mg twice daily. The investigator-assessed objective response rate was 81% (95% CI, 73%-87%). The complete response (CR) rate with acalabrutinib was 40% and the partial response (PR) rate was 41%.¹

The most common AEs of any grade were anemia (46%) thrombocytopenia (44%), headache (39%), fatigue (28%), myalgia (21%) and bruising (21%). The most common grade 3 or higher AEs included neutropenia (15%), thrombocytopenia (12%), anemia (10%), and diarrhea (3.2%). Comparatively, ibrutinib is associated with AEs of grade 3 or higher with neutropenia (16%), thrombocytopenia (11%), and anemia (10%), according to data from the phase II PCYC-1104 trial.²

“There is no head-to-head comparison yet with ibrutinib and acalabrutinib in MCL, but we are excited that there are now 2 BTK inhibitors approved for MCL,” said Goy.

OncLive: Please provide a comparison of acalabrutinib and ibrutinib.

In an interview with OncLive, Goy, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, discussed the excitement surrounding acalabrutinib, as well as emerging ibrutinib combination strategies for the treatment of patients with MCL.Goy: This is an exciting time in the field of hematologic malignancies, but particularly for patients with MCL in whom there are more options. We have the new second-generation BTK inhibitor acalabrutinib that was approved recently. This is in addition to ibrutinib, which was approved previously in 2013. Ibrutinib was investigated in a phase II study and was associated with a response rate of 67% and with a CR rate of 20% which goes up to 40% after 1 year of treatment. The median duration of response is around 17 months.

There were some interesting long-term follow-up data at the 2017 ASH Annual Meeting from grouping trials that stated that 1 group of patients is doing well and are progression free with ibrutinib as a single agent after 3 years. However, it is interesting that there are some AEs associated with ibrutinib even though it is a well-tolerated drug overall. There are issues with atrial fibrillation in approximately 5% to 7% of patients in the studies. This is a particular issue for patients with cardiac history. There are also concerns of off-target effects, such as rash, gastrointestinal (GI) symptoms, fatigue, and some bleeding. Overall, the toxicity profile with ibrutinib gets better over time.

Can you please discuss the efficacy of ibrutinib in combination with venetoclax (Venclexta)?

Acalabrutinib has a response rate of 80%, with half of that percentage being CRs. We do not yet have the median duration of response, as it is too early to tell. However, the toxicity profile was very impressive. We had no cardiac toxicity at all, which is due to the fact that this is a cleaner kinase with much less off-target AEs. There was no indication of tec, which is responsible for the cardiac toxicity and atrial fibrillation. There was also no indication of EGFR, which would be responsible for rash or GI toxicities. This is something that is important, as it might offer an alternative option for patients needing treatment for MCL.This is a logical next step because our experience is with ibrutinib as a single agent but when a patient progresses, they progress quickly with a short median overall survival of a couple of months. Therefore, it is important that we build upon this. With rituximab (Rituxan), the CR rate is much higher, and we have built upon that with R-squared [rituximab plus lenalidomide (Revlimid)] with ibrutinib, which demonstrated a CR rate of 67% to 80% in the relapsed/refractory, heavily pretreated patient population.

Where do you envision the future of this field headed?

The combination of venetoclax and ibrutinib is interesting. Venetoclax is the first BCL-2 inhibitor that has shown activity as a single agent in MCL and chronic lymphocytic leukemia (CLL), as well as in other lymphomas. This combination is impressive with a CR rate that is over 60% and potentially highly durable. That is where the field is heading in the relapsed/refractory setting that offers an option to control the disease if a patient is typically chemoresistant after failing chemoimmunotherapy. In the treatment of patients with MCL, we do not yet have a comparison of ibrutinib with acalabrutinib. However, in CLL, even though acalabrutinib is not yet approved, there was an interesting presentation at the 2017 ASH Annual Meeting last year. In this presentation, a patient who did not tolerate ibrutinib was switched to acalabrutinib where the response rate was 67% to 70%, which is very good. These patients did not progress on ibrutinib, but they just could not tolerate it.

References

1. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial [published online ahead of print December 11, 2017]. Lancet Oncol. doi: 10.1016/S0140-6736(17)33108-2.
2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.