Jeff P. Sharman, MD, discusses updated data from the ELEVATE-TN trial and ongoing research that is poised to define the optimal role of acalabrutinib in chronic lymphocytic leukemia.
Jeff P. Sharman, MD
The highly selective BTK inhibitor acalabrutinib (Calquence), either as a single agent or in combination with obinutuzumab (Gazyva), has proven to be a safe and effective treatment option for patients with previously untreated chronic lymphocytic leukemia (CLL), according to Jeff P. Sharman, MD.
In November 2019, acalabrutinib received regulatory approval for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL), based, in part, on data from the phase III ELEVATE-TN trial.
Updated data from the trial presented at the 2019 ASH Annual Meeting showed that at a median follow-up of 28.3 months, the combination of acalabrutinib and obinutuzumab (Gazyva) led to a 90% reduction in the risk of disease progression or death (HR, 0.10; 95% CI, 0.06-0.17; P <.0001). Furthermore, acalabrutinib monotherapy showed a statistically significant PFS benefit (HR, 0.20; 95% CI, 0.13-0.30; P <.0001) over chlorambucil plus obinutuzumab.
“The landmark 2-year PFS analysis showed that 93% of patients who received the combination of BTK and CD20 [inhibition] were alive [compared with] 87% with the BTK inhibitor alone, and 47% of those who were randomized to the control arm of chlorambucil/obinutuzumab,” said Sharman, who is the lead study author of ELEVATE-TN.
Common all-grade adverse events (AEs) in the acalabrutinib/obinutuzumab and acalabrutinib monotherapy arms included headache (39.9% vs 36.9%) and arthralgias (21.9% vs 15.6%). However, these events were generally short-lived, and the regimen was otherwise well-tolerated, Sharman explained.
In an interview with OncLive® at the 2019 ASH Annual Meeting, Sharman, director of research at Willamette Valley Cancer Institute and medical director of hematology research for The US Oncology Network, discussed the updated ELEVATE-TN data and ongoing research that is poised to define the optimal role of acalabrutinib in CLL.
OncLive: Could you discuss the design of the ELEVATE-TN trial?
Sharman: The ELEVATE-TN trial was done in patients with previously untreated CLL. Eligible patients were age 65 and older, or less than age 65 [if they had] medical comorbidities that made them suitable for a less intensive chemoimmunotherapy regimen. This was a 3-arm study in which investigators compared the effect of combination treatment with acalabrutinib and obinutuzumab, acalabrutinib monotherapy, and the combination of standard chemoimmunotherapy with chlorambucil and obinutuzumab. Subjects were randomized 1:1:1 to the 3 arms. If patients who were randomized to the control arm experienced disease progression that was confirmed by central review, they were allowed to cross over to the acalabrutinib monotherapy arm.
The primary end point of the study was PFS with a comparison between the acalabrutinib/obinutuzumab arm versus the chlorambucil/obinutuzumab arm. Key secondary endpoints included the comparison between acalabrutinib monotherapy versus standard chemoimmunotherapy, as well as safety, time to next treatment, and overall survival (OS).
What distinguishes acalabrutinib from other BTK inhibitors?
Two BTK inhibitors have been approved for the treatment of patients with CLL, and a third BTK inhibitor has been approved for the treatment of those with MCL. We tend to see less arthralgias with acalabrutinib [than ibrutinib (Imbruvica)]. Regarding bruising and bleeding, the rates appear to be the same numerically; it's hard to tell if a difference exists there. The cardiac AEs do appear to be lower with [acalabrutinib], with less hypertension and less atrial fibrillation. However, atrial fibrillation we weren't totally keyed into when ibrutinib first became available; it was only something we became aware of afterwards. Longer-term follow-up will help us determine whether or not those rates are genuinely different or not.
What did the data from the trial show?
With regard to the trial’s primary endpoint, the median PFS was not observed in either of the acalabrutinib arms, whereas it was observed in the obinutuzumab/chlorambucil arm. The HR was 0.10 with a P value of less than .0001 in favor of the experimental combination. For patients who received monotherapy, the HR was 0.20 compared with the control arm, [showing] a highly statistically significant P value. [Estimated 30-month] OS rates were relatively similar [between the combination, monotherapy, and control arms] at 95%, 95%, and 92%, respectively. A slightly higher incidence of deaths occurred in the control arm compared with the experimental arm; however, this was not statistically significant.
Key secondary endpoints included the comparison of acalabrutinib monotherapy versus the control arm, and that was the one for which the HR was 0.20. Other secondary endpoints were really defined by safety. We observed that approximately 30% of patients treated with acalabrutinib developed a headache. Those headaches generally tended to be a relatively short-term phenomenon lasting just a few days. Generally, this event was reasonably controlled with adequate oral hydration or caffeine. Some individuals needed acetaminophen or ibuprofen, but overall, this was a relatively short-lived [occurrence]. However, it's important to alert patients that this [AE] can happen and to let them know that it tends to pass.
Additional safety features included arthralgias, which appeared to be quite well tolerated. Bruising and bleeding occurred in about one-third of patients as well. Rates of severe bleeding tended to be only a few percentage points. AEs of special interest included acquisition of hypertension, which was seen in about 7% of acalabrutinib-treated patients, whereas it was observed in about 4% of those in the control arm; it was not a huge difference between the 2 arms. Lastly, atrial fibrillation was relatively infrequent. Overall, [we saw] a nice safety profile for acalabrutinib.
What are the implications of these data?
These findings, in combination with the data from the phase III ASCEND study in the relapsed/refractory setting, led to the FDA approval of acalabrutinib in the United States. [The agent is also approved in] Canada and Australia for use in patients with CLL and SLL. The big question in the field is which BTK agent to use. A randomized head-to-head study comparing the BTK inhibitors will provide us with a lot of important information [with regard to the] safety and efficacy [of these agents]. For the time being, all we have is the ability to compare across trials, which is an imperfect analysis. I would encourage physicians to become familiar with both medications, so they can determine how to choose [the right option] for patients in the future.
Where should future research focus?
The next steps for this research are to see how fixed-duration therapy with a BCL-2 inhibitor compares with continuous BTK inhibition. Additional steps would be to combine those agents and see how well they work together. Ongoing studies are combining acalabrutinib with venetoclax (Venclexta) compared with more intensive chemoimmunotherapy regimens; this could potentially lead to approval.
Sharman P, Banerji V, Fogliatto L, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):31. doi: 10.1182/blood-2019-128404.