Research Efforts Abound as the Role of BTK Inhibitors Continues to Evolve in CLL

BTK inhibitors have shifted the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to Erlene  Seymour, MD, and now, several studies are examining these agents in combination with venetoclax (Venclexta) and in those with BTK resistance mutations.

Research efforts have indicated the superiority of BTK inhibitors with regard to progression-free survival (PFS) compared with other standards, such as chemoimmunotherapy. For example, a phase 3 trial (NCT01886872) showed that ibrutinib (Imbruvica) significantly improved PFS versus bendamustine plus rituximab (Rituxan) in older, treatment-naïve patients with CLL.¹

Other phase 3 trials, such as ELEVATE-TN and ASCEND, have demonstrated the superiority of newer-generation BTK inhibitors such as acalabrutinib (Calquence) with regard to PFS. In the former, at a median follow-up of 28.3 months, median PFS was significantly longer with acalabrutinib with or without obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil (HR, 0.1; 95% CI, 0.06-0.17; P <.0001).² Results from the latter demonstrated that acalabrutinib significantly prolonged investigator-assessed PFS versus standard idelalisib (Zydelig) plus rituximab or bendamustine plus rituximab (HR, 0.27; 95% CI, 0.18-0.40; P <.0001).³

“BTK inhibitors are changing how we treat patients with CLL. [Moreover], we're now going to have multiple different BTK inhibitors; some may even be efficacious in BTK-resistant patients,” said Seymour. “The 2 head-to-head studies of acalabrutinib versus ibrutinib and zanubrutinib (Brukinsa) versus ibrutinib, as well as [those examining BTK] combinations will let us know how to best treat this disease in the future. Many cooperative studies will answer a lot of those questions, too.”

Several clinical trials are now examining BTK inhibitors in combination with venetoclax in time-limited durations or treatment courses directed by minimal residual disease status, according to Seymour. Newer agents, such as tirabrutinib (Velexbru), are also under investigation. For patients who harbor BTK resistance mutations, LOXO-305, vecabrutinib, and ARQ-531 are under exploration.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Seymour, an assistant professor at the Wayne State University School of Medicine and hematologist/oncologist with the Barbara Ann Karmanos Cancer Institute, discussed the utility of BTK inhibitors following disease progression on venetoclax, the kinase selectivity of newer-generation agents, and the next steps for research.

OncLive®: Could you provide an overview of BTK inhibitors in CLL?

Seymour: BTK inhibitors are an oral modality that's relatively well tolerated. [These agents] target the B-cell receptor pathway; this means that they don’t target a specific mutation, but they shut down a pathway that's very important for CLL cell growth. [BTK inhibitors are] very effective in this disease. Some patients have been using [these agents] in the frontline and the relapsed/refractory settings and they have been on this treatment for several years.

What was learned from the evaluation of ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL?

[In this study], ibrutinib actually resulted in a longer PFS in patients [with CLL], particularly if they [did not harbor] IGHV mutations. We had already previously known that [BTK inhibitors] perform well in patients who are high risk, such as [those with] del(17p). However, [in this trial] we showed a head-to-head improvement in PFS [with ibrutinib] compared with bendamustine and rituximab, which is a very commonly used standard of care.

What is known about the efficacy of BTK inhibitors following progression on venetoclax?

We do know that [BTK inhibitors] work after progression on venetoclax. We're seeing that clinically, as well. What was nice about the MURANO study is that [investigators] specifically looked at patients prospectively to [examine] their responses after they had been on a second therapy when venetoclax was discontinued. If [a patient] hasn’t been on a BTK inhibitor before, was treated with venetoclax first, and progressed following venetoclax or discontinued venetoclax, [it would not be unreasonable] to consider [using a] BTK inhibitor.

Could you highlight the differences between the overall kinase selectivity of BTK inhibitors?

There is highly specific kinase receptor binding in newer BTK inhibitors. For example, acalabrutinib and zanubrutinib have less binding on EGFR, so the hypothesis is that we might see less gastrointestinal adverse effects (AEs) with those specific BTK inhibitors. Additionally, [with these agents], there's not as much binding on targets that are important for platelet inhibition. As such, there's a hypothesis that maybe we will see less bleeding. These BTK inhibitors are being developed [with the idea of improving] upon toxicity profiles. I hypothesize that many of them will have different safety profiles and we’ll get to know more about them in future studies.

What have recent trials, such as ELEVATE-TN and ASCEND, revealed about highly selective BTK inhibitors?

The ELEVATE-TN trial examined acalabrutinib plus or minus obinutuzumab versus obinutuzumab plus chlorambucil. [Acalabrutinib] outperformed obinutuzumab and chlorambucil with or without obinutuzumab. However, the trial was not exactly powered to find a difference between the 2 arms comparing acalabrutinib by itself with acalabrutinib and obinutuzumab. The main point of that trial was to show that acalabrutinib combinations [result in a] much better PFS [benefit when used as] frontline therapy compared with obinutuzumab plus chlorambucil.

ASCEND is 1 of the few trials that actually compare 2 novel therapies that are available for CLL head-to-head. [Investigators examined] acalabrutinib by itself versus investigator’s choice, but the investigator’s choice regimens included idelalisib plus rituximab or bendamustine and rituximab. The majority of those patients actually received idelalisib plus rituximab. In that study, we did see a significantly better PFS with acalabrutinib, so that helped us answer the question of whether BTK [inhibitors] can outperform PI3K inhibitors.

What are the next steps for BTK inhibitors?

Many cool BTK [inhibitors] are being developed in multiple pipelines, [including tirabrutinib]. Some BTK inhibitors are even efficacious when BTK resistance mutations are present, [such as LOXO-305 and vecabrutinib]. It is still a growing field in terms of these agents. Once we get to know [these drugs better], it will kind of be like the TKIs that we use for chronic myeloid leukemia. These inhibitors will have different toxicity profiles and that [information] will help us decide which treatment to use for our patients with CLL. 

References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
3. Ghia P, Pluta A, Wach M, et al. Acalabrutinib (acala) versus idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. J Clin Oncol. 2020;38(suppl 8015). doi:10.1200/JCO.2020.38.18_suppl.8015