Jeff P. Sharman, MD
The phase III ASCEND trial is only one of the pivotal trials that have presented data to suggest that acalabrutinib (Calquence) could see an FDA approval for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), explained Jeff P. Sharman, MD.
“[CLL] is considerably more frequently diagnosed and managed [now], so there is a larger [patient] population. But, as of yet, we do not have an FDA approval for acalabrutinib for those patients. Now, that is going to change,” said Sharman, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network.
In the ASCEND trial, acalabrutinib monotherapy was found to significantly improve progression-free survival (PFS) at 12 months at a rate of 88% versus 68% with physicians’ choice of standard therapy. At a median follow-up of 16.1 months, median PFS was not reached in the acalabrutinib monotherapy arm compared with 16.5 months in the control arm (HR, 0.31; 95% CI, 0.20-0.49; P
Additionally, a phase II trial evaluating acalabrutinib found that the agent demonstrated efficacy in patients intolerant to ibrutinib (Imbruvica) and, as such, offers a viable strategy to continue BTK inhibitor therapy for patients with relapsed/refractory disease. Specifically, the overall response rate with the agent was 77%, with 70% of patients experiencing a partial response.2
In an interview with OncLive
, Sharman highlights a phase II study of acalabrutinib in ibrutinib-intolerant patients, the promising data that may lead to its approval in the frontline setting, and future treatment options for patients with relapsed indolent non-Hodgkin lymphoma (NHL).
OncLive: Could you provide some background on the study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory CLL?
: Ibrutinib has been a transformational agent in the management of CLL and many of the advances that we have seen in CLL over the last several years have been based on ibrutinib. However, ibrutinib does have some adverse events (AEs) that are challenging. We see arthralgias and we see bruising and bleeding. There’s also some infections, cardiac issues, and less frequent pneumonitis.
When you are clinician, if somebody is running into a problem with a BTK inhibitor, the question is: Can you continue with a BTK inhibitor that is a different drug or do you have to abandon BTK entirely? And, at least from early data, it appears you can switch those patients to acalabrutinib, and a good fraction of those patients do not experience a recurrence of the same AEs that they had before. Therefore, maybe as many as two-thirds to three-quarters of patients can stay on a BTK inhibitor and simply change from one BTK inhibitor to the next. Hopefully that preserves the opportunity to continue treating these patients with a very effective drug class.
To date, what are some of the key efficacy data seen with acalabrutinib?
Acalabrutinib received its first FDA approval in mantle cell lymphoma [MCL] and the overall efficacy comparing cross studies in MCL looked very similar to ibrutinib.
There are 3 pivotal studies out there. In the relapsed setting, we have just seen data at the 2019 European Hematology Association Annual Meeting, where acalabrutinib beat investigator’s choice of bendamustine or idelalisib (Zydelig) plus rituximab (Rituxan) and so that should lead to [an FDA] approval for [patients with] CLL in the relapsed setting. Then there is a press release available that states that a frontline study of acalabrutinib versus acalabrutinib [plus] obinutuzumab (Gazyva) versus chlorambucil [plus] obinutuzumab has also met its primary endpoint, but we don’t have data on that yet. Therefore, I do anticipate that we will get approval for acalabrutinib in the frontline setting [based on these data].
Whether or not [acalabrutinib] differentiates itself from ibrutinib will then be answered in the third pivotal study, which is actually a head-to-head study of acalabrutinib versus ibrutinib. That study probably won’t read out for quite some time, but it will be very important for the field.
Where does acalabrutinib stand among other BTK inhibitor options?
There are a handful of BTK inhibitors out there; ibrutinib, acalabrutinib, and zanubrutinib (BGB-311) are all what we call covalent inhibitors. I anticipate that we will get approval of zanubrutinib in certain settings as well so clinicians may soon have a choice of 3 different covalent BTK inhibitors.
What we’ve learned, however, is that resistance to ibrutinib is based upon, in many cases, a mutation at the binding site of one of those drugs. There is a family of noncovalent BTK inhibitors in earlier development [with which investigators are] looking to see if we can turn off the enzyme by binding at another location. It remains to be seen at this point; the data are still premature, but it could be that additional BTK inhibitors [will be] available down the road as well.
Could you provide an overview of the latest data from the phase IIIb MAGNIFY study?
In relapsed indolent lymphoma which consists of several different diseases, but most prominently follicular lymphoma and marginal zone lymphoma, there is no clear-cut standard [of care] for patients with relapsed disease. There have been a handful of studies utilizing PI3KI (phosphoinositide 3-kinase inhibitors) and by and large those studies have been designed for patients in the third-line and beyond. Some of the agents that are available in that family include idelalisib, duvelisib (Copiktra), and copanlisib (Aliqopa), and they all show approximately similar results with about a 50% overall response rate and a [PFS] of just shy of a year. In the third line, you see an increase of use of PI3KI [while] in the first line you have generally chemoimmunotherapy-based regimens with either rituximab or obinutuzumab in combination with either bendamustine or CHOP. However, there is really no clear standard of what to do in the second-line.
To that end, rituximab monotherapy versus lenalidomide (Revlimid) [plus] rituximab (R2
), has now been FDA approved to probably occupy a significant fraction of those patients in the second-line setting or potentially in the third-line setting if patients did not have prior lenalidomide. We saw in that study approximately a 3 to 3.5-year median [PFS] for those patients treated with the combination therapy.
The MAGNIFY study is a complimentary study to [the AUGMENT study] and had different enrollment criteria to allow patients who were rituximab-refractory, including more patients with marginal zone [lymphoma], those with double-refractory disease and early relapse, and so forth. In many ways it complements the AUGMENT study and expands the [use of the] combination.
In this study, all patients received R2
for 12 months and then there was a randomization to either maintenance rituximab or maintenance R2
. Ideally, the study is designed to answer the question of, what is the optimal duration of lenalidomide? We don’t know that yet. What we have and what we are reporting is the current efficacy of that 12-month run-in and we see very similar efficacy data to that which had been seen in the AUGMENT study, with a median PFS of around 36 months. We don’t yet know the contribution of maintenance therapy.
What does the safety profile look like for the combination?
With regards to safety for R2
, it’s a very well tolerated regimen. The predominance of grade 3/4 toxicity is hematologic with somewhat predictable neutropenia being the most common. There is also some thrombocytopenia, anemia, and fatigue, but overall, it’s a very well-tolerated regimen.
What does the future treatment landscape look like for NHL?
In indolent lymphoma, we’ve had positive studies looking at the substitution of obinutuzumab for rituximab. The magnitude of that benefit has been such that the field has not completely embraced the addition of obinutuzumab; there’s still some tension as to [which] is the right CD-20 antibody [to use]. However, the chemotherapy backbones remain steady.
Another study we haven’t talked about was the R2
versus chemoimmunotherapy, which showed very similar overall efficacy. For some selected patients, as is endorsed by the National Cancer Comprehensive Network guidelines, R2
might be suitable for some frontline patients for whom chemoimmunotherapy might otherwise be contraindicated.
In the relapsed setting, we are going to see R2
occupy a lot of more of the second-line space, but it will also serve as a platform for future drug studies because there hasn’t necessarily been an established second-line regimen from which to compare.
Now, you can envision a multitude of studies where R2
is either the control arm with the addition of a drug or the substitution of a CD-20 or the addition of R2
plus or minus a novel agent and so forth. I believe this is going to really help the field more than simply just the results of the study.
- Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib (iDR) or bendamustine (BR) by investigator choice in relapsed/refractory (RR) chronic lymphocytic leukemia: phase 3 ASCEND study. Presented at: 2019 International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 048. onlinelibrary.wiley.com/doi/10.1002/hon.54_2629.
- Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractor chronic lymphocytic leukemia. Presented at: 2019 International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 029. onlinelibrary.wiley.com/doi/10.1002/hon.29_2629.