BTK inhibitors have become perhaps one of the most important drug classes in the management of chronic lymphocytic leukaemia. These oral medications combine some of the highest efficacy rates that we’ve seen in the published literature in this disease and, at the same time, have considerably improved toxicity profile relative to the historical chemotherapy regimens that we used. There are several BTK inhibitors available, the first in class was ibrutinib and ibrutinib has been available for several years based upon the strength of various studies. However, with newer or second generation BTK inhibitors there’s the hope that these will have an improved safety and efficacy profile, even relative to the first in class BTK inhibitors. Ideally these will be best in class type agents.
This study was conducted amongst treatment naïve patients with CLL, patients previously untreated, and the purpose of the study was to demonstrate superiority relative to a commonly utilised chemoimmunotherapy regimen at the time and, in doing so, has led to the approval of acalabrutinib with or without obinutuzumab for patients with treatment naïve chronic lymphocytic leukaemia. At the same time another study was done in the relapsed setting, also a randomised study, for acalabrutinib leading to FDA approval of acalabrutinib for patients with relapsed refractory disease. So the two studies in combination lead to a broad indication for patients with chronic lymphocytic leukaemia to use acalabrutinib.
What was the methodology used in this study?
The study was a randomised clinical trial utilising a three arm study. The reference regimen was obinutuzumab chlorambucil based upon a prior German CLL study, CLL11, that led to the approval of obinutuzumab chlorambucil. So that was the reference regimen; that tends to be a regimen utilised in older individuals so this study was for those patients 65 and older or younger than 65 provided they had pre-specified medical comorbidities that allowed them to enrol. Patients were randomised to one of three arms and those included obinutuzumab chlorambucil in one arm, acalabrutinib monotherapy in another arm and acalabrutinib in combination with obinutuzumab in the third arm.
The study was designed to demonstrate superiority of the combination of acalabrutinib obinutuzumab relative to the reference arm and then the additional arm of acalabrutinib monotherapy was considered a secondary endpoint as to whether or not it would demonstrate superiority against the chemoimmunotherapy regimen, which it did in the study.
What were your findings?
What the study showed was that both acalabrutinib-containing arms of the study significantly outperformed the reference regimen of obinutuzumab chlorambucil. The hazard ratio for the combination of acalabrutinib obinutuzumab was 0.1 with a highly statistically significant p-value. What we demonstrated and reported at ASCO this year was that the rates of four year progression free survival clearly outperformed the reference regimen. As a secondary endpoint the hazard ratio for acalabrutinib monotherapy relative to obinutuzumab chlorambucil was 0.2, also highly statistically significant. So demonstrating that acalabrutinib treatment arms are superior to chemoimmunotherapy in this population and that you would have, as a treating physician, the freedom to determine whether or not to add obinutuzumab.
As a secondary analysis we looked at the benefit and risk of adding obinutuzumab to acalabrutinib and there were some interesting findings there. I think a fair bit of the field is looking at the difference between these two arms. We saw that the addition of obinutuzumab to acalabrutinib resulted in an improved progression free survival that was also statistically significant versus acalabrutinib monotherapy. In fact, when we looked at overall survival the fewest deaths were observed amongst patients who got acalabrutinib obinutuzumab although the difference between that and acalabrutinib monotherapy were not statistically significant.
With the addition of obinutuzumab there was some additional toxicity, primarily neutropenia and infusion related reactions but these were considered characteristic of the agent and no new safety signals were identified.
How can these results impact the future treatment of CLL?
CLL is changing quite rapidly and as a field we have a number of new treatment options including now second generation BTK inhibitors that are available in the form of acalabrutinib. What this study shows us is that this is a well-tolerated regimen or regimens for patients with chronic lymphocytic leukaemia and, for me personally, when selecting a BTK agent I end up utilising acalabrutinib preferentially based upon my experience in this study, the adverse events reported and what we’ve seen in other studies, including the study of acalabrutinib directly compared head-to-head against ibrutinib, also showing an improved safety profile and similar overall efficacy.
So in totality, using multiple different studies, acalabrutinib is an effective and safe option for patients with untreated as well as relapsed/refractory chronic lymphocytic leukaemia.
What is next for this study?
We will continue to follow these results with time. There’s definitely interest in seeing the difference between the acalabrutinib monotherapy and acalabrutinib obinutuzumab. We will continue to monitor that moving forward to see what additional differences emerge. But for this particular study, it achieved its goal which is the approval of acalabrutinib for patients with treatment naïve CLL as well as the relapsed/refractory study leading to approval amongst patients previously treated. So these studies have achieved their goals but what’s next for acalabrutinib will be a variety of studies looking at novel-novel agent comparisons. So, for instance, comparing it with venetoclax-based regimens, trying to figure out what might be the best partner for venetoclax – is it a BTK agent or anti-CD20? We’re going to see additional combinations of acalabrutinib venetoclax against chemoimmunotherapy with younger, more fit populations.
So this will continue to round out the knowledge basis for acalabrutinib and will continue to move the field forward for patients who need treatment.
Is there anything else important that you would like to mention?
This summer congress season has revealed a number of important studies for patients with CLL, a number of studies particularly important to BTK agents. We’ve now seen several studies in which second generation BTK inhibitors are compared directly to ibrutinib, demonstrating that they have similar or possibly improved efficacy with an improved safety profile relative to the first generation BTK inhibitors. So practising physicians need to gain some familiarity with these second generation BTK inhibitors and it will be exciting to see how future studies read out.