A presentation at the American Society of Clinical Oncology (ASCO) 2022 Annual meeting, which was held 3-7 June 2022, in Chicago, IL, featured the 5-year follow-up results of the phase 3 ELEVATE-TN trial (NCT02475681) in treatment-naïve patients with chronic lymphocytic leukemia (CLL) [1]. The long-term benefits of acalabrutinib plus obinutuzumab not only continued to outperform acalabrutinib monotherapy and obinutuzumab plus chlorambucil, but provided an overall survival (OS) benefit for acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil. While acalabrutinib monotherapy also seems promising, at this time point there is not yet an OS benefit. Physician’s Weekly interviews primary investigator Prof. Jeff Sharman (Willamette Valley Cancer Institute, Eugene, OR).

Bruton tyrosine kinase (BTK) inhibitors, either alone or with a CD20 antibody, have improved treatment-naïve (TN) CLL outcomes and offer a chemotherapy-free option [2,3]. However, long-term use of first-generation BTK inhibitors has been associated with cardiovascular toxicity, thus alternatives are needed.

Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia. Initial findings from the ELEVATE-TN trial in CLL demonstrated superior efficacy for acalabrutinib + obinutuzumab versus obinutuzumab + chlorambucil with acceptable tolerability [4].

Patients (total=535) were randomized (acalabrutinib + obinutuzumab, n=179; acalabrutinib monotherapy, n=179; obinutuzumab + chlorambucil, n=177). Median age was 70 years (range 41.0–91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene. Crossover from obinutuzumab + chlorambucil to acalabrutinib monotherapy was allowed upon disease progression (n=69).

At 5 years follow-up, the acalabrutinib arms continue to demonstrate a progression-free survival benefit vs obinutuzumab plus chlorambucil  (for acalabrutinib monotherapy median PFS not reached vs 27.8 months; HR 0.21; 95% CI 0.15-0.30; P<0.0001; for acalabrutinib plus Obinutuzumab median PFS was not reached vs 27.8 months; HR 0.11; 95% CI 0.07-0.16; P<0.0001). Importantly the PFS benefits were observed in all subgroups, even across high-risk genetic subgroups. Moreover, an overall survival OS benefit for acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil was observed with this longer follow-up (HR 0.55; 95% CI 0.30-0.99; P=0.0474).

With regard to safety, events of clinical interest including cardiovascular events at 5 years follow-up were consistent with previous analyses and similar between acalabrutinib-containing treatment arms. The investigators concluded that acalabrutinib showed tolerable safety in patients with TN CLL.

Physician’s Weekly spoke with Prof. Sharman to answer some of our questions.

Could you tell me a little bit about the 5-year update on the ELEVATE-TN follow-up? That is about twice as long as the initial interim analysis published in the Lancet…. So what have we learned?

What we’re learning from longer-term follow-up of the ELEVATE-TN is the ongoing safety and efficacy of acalabrutinib with, or without obinutuzumab. With greater follow-up, we’re seeing sustained benefit for both acalabrutinib containing arms and despite crossover from the control arm, we have an estimated five-year progression-free survival of 84% for the combination of acalabrutinib with obinutuzumab, 72% for acalabrutinib monotherapy, and 21% for the control arm of obinutuzumab chlorambucil.

Both acalabrutinib arms are highly statistically significant improvements over the control arm and the progression-free survival benefit for acalabrutinib obinutuzumab over acalabrutinib monotherapy actually has a hazard ratio of 0.51 with a P-value of 0.02 demonstrating improved progression-free survival with the addition of obinutuzumab. That addition of obinutuzumab is associated with some additional toxicity, infusion toxicity being the most notable, some increase in pneumonia, and other side effects consistent with anti-CD20  therapy. One of the interesting findings is we now, with this update, do have an overall survival benefit for the acalabrutinib obinutuzumab over the control arm, that’s statistically significant. The overall survival benefit for acalabrutinib obinutuzumab control arm has a hazard ratio of 0.55 with a P-value of 0.04.

Can we conclude that anti-CD20 antibodies add value on to BTK inhibition?

I think that there’s a big question at this point. Within the field, there’s been a longer-term question as to whether or not anti-CD20 antibodies add any value to BTK inhibitors. We’ve seen in several studies where the addition of rituximab to BTK provides no benefit.

My impression has been that the field has mostly felt as though there is no reason to add an anti-CD20 antibody. There was a subsequent study of ibrutinib with obinutuzumab, but it didn’t study the impact of obinutuzumab, so it didn’t really move the needle all that much. To date, this is really the only study where you can actually discriminate the added value of an anti-CD20 antibody with obinutuzumab rather than rituximab. And I think that you do get added bang for your buck, you get an improved progression-free survival, but because of the added toxicity, it might not necessarily be appropriate for everyone. And in current COVID environment where anti-CD20 antibodies seem to play a deleterious impact on outcomes for vaccination and COVID, I think, really there’s not necessarily a hard recommendation to add anti-CD20 antibody, but in a younger, more fit patient who might be considering a BTK-based strategy, who may already have had COVID or is already vaccinated, it might be reasonable to add the obinutuzumab in that setting.

In the 4-year update from last year’s ASCO, there was also a jump in the complete response percentage as well. Was that consistent with the 5-year data? Did that increase, it was 21% at 4 years, right?

That number continues to go up from last year’s data [5], so we now have an overall complete response rate of 32% with the combination therapy. That’s not really surprising. We can see depth of response improve with time with BTK inhibitors. It’s also not really a surprise that obinutuzumab leads to deeper responses because it is typical of BTK inhibitors to have residual lymphocytosis or a small volume of disease for long periods of time.

However, it is nice to see those responses continuing to deepen with time. But, with regards to BTK inhibitors, the depth of response doesn’t always correlate to the duration of disease control. So, whether that depth of response makes a huge difference or not, I think still remains to be seen.

Is this the final analysis of this data set?

No, we will have ongoing follow-up due to regulatory interest in long-term outcomes of the study. So I anticipate that we will continue to be able to provide further updates with time.

What are the next steps?

There’s a lot going on in CLL right now and I think we’re seeing early outputs of BTK in combination with venetoclax. Most of those are ibrutinib based BTK studies, but I think we will soon have acalabrutinib in combination with venetoclax readouts coming as well. And so I think that we have BTK inhibitor with anti-CD20, I think we’ll have BTK inhibitors with BCL-2, we have BCL-2 with anti-CD20.

I’m very excited. The MAGIC study, which compares acalabrutinib + venetoclax to obinutuzumab +  venetoclax, is asking what is the more strategic partner with venetoclax, is it a BTK inhibitor or an anti-CD20 antibody? And we’re getting additional outputs from German CLL13, the UK FLAIR study, and so forth.

I think that we’re continuing to see refinement of optimal first-line treatment strategies. And then in the salvage setting soon to have approval of third-generation BTK inhibitors, the non-covalent reversible inhibitors that can be appropriate salvage options for patients with prior BTK exposure, earlier on are the BTK degraders. We will soon going to be seeing additional Bcl-2 inhibitors, so there is a lot of progress still being made.