Expert Highlights Evolution of BTK Inhibitors in CLL

Alexey V. Danilov, MD, PhD

Alexey V. Danilov, MD, PhD

In chronic lymphocytic leukemia (CLL), BTK inhibitors as monotherapy and in combination have expanded the armamentarium in both the frontline and relapsed/refractory settings, said Alexey V. Danilov, MD, PhD.

Most recently, the BTK inhibitor acalabrutinib (Calquence) received FDA approval for the treatment of adult patients with CLL or small lymphocytic lymphoma, based on findings from the randomized phase III ELEVATE-TN and ASCEND trials.

Updated data from the ELEVATE-TN trial, which were presented at the 2019 ASH Annual Meeting, reported that the median progression-free survival (PFS) was not reached with acalabrutinib monotherapy (HR, 0.20; 95% CI, 0.13-0.30; P <.0001) or acalabrutinib in combination with obinutuzumab (Gazyva; HR, 0.10; 95% CI, 0.06-0.17; P <.0001) compared with 22.6 months with chlorambucil/obinutuzumab (95% CI, 20-28). The overall response rates were 85.5%, 93.9%, and 78.5%, respectively.

Beyond ELEVATE-TN, additional trials have shown intriguing activity with combinations comprising ibrutinib and venetoclax, as well as acalabrutinib, venetoclax, and obinutuzumab, Danilov explained.

In an interview with OncLive, Danilov, an associate professor of medicine at Oregon Health and Science University, discussed the ELEVATE-TN trial and other potentially practice-changing BTK inhibitor combinations expected to emerge in CLL.

OncLive: What are the implications of the ELEVATE-TN trial?

&#8232; Danilov: Several important studies were presented at the 2019 ASH Annual Meeting with regard to CLL. One highlight was the ELEVATE-TN data, which randomized patients to acalabrutinib in combination with obinutuzumab, single-agent acalabrutinib, or chlorambucil in combination with obinutuzumab for treatment-naïve patients with CLL.

&#8232;The study demonstrated a PFS advantage in both acalabrutinib arms. Interestingly, this was one of the first studies to demonstrate a slight advantage to acalabrutinib in combination with obinutuzumab compared with acalabrutinib alone. However, the study was not powered to assess that difference.

&#8232;Responses were up to 94% in patients who received acalabrutinib. Importantly, toxicities were very low, and less than 10% of patients discontinued acalabrutinib due to adverse events. Although atrial fibrillation is certainly a concern with BTK inhibitors, the prevalence of it in this study was around 3%.

&#8232;What role does venetoclax (Venclexta) have in combination with BTK inhibitors?

&#8232;Multiple studies presented at the 2019 ASH Annual Meeting [explored] the combination of venetoclax with novel BTK inhibitors. We are heading into a new era where chemoimmunotherapy is fading.

&#8232;We are also trying to determine if we can achieve deep responses with fixed-duration regimens for patients with CLL.

&#8232;Studies of ibrutinib (Imbruvica) and venetoclax, as well as acalabrutinib and venetoclax with or without a CD20-directed antibody, were presented at the 2019 ASH Annual Meeting. For example, a phase II study demonstrated high efficacy with 60% bone marrow minimal residual disease (MRD) negativity after 6 months with the combination of acalabrutinib, venetoclax, and obinutuzumab. Additionally, the response rates [appeared to be very] durable.

&#8232;The combination of venetoclax and ibrutinib for patients with both treatment-naïve and relapsed/refractory CLL was also associated with high response rates.

&#8232;The question remains whether we need to use combination therapy for every patient, or whether combinations with novel agents ultimately results in prolonged PFS or overall survival (OS) compared with single-agent therapy. We need longer follow-up on those studies.

&#8232;Many patients with CLL may do very well with single-agent therapy, as many of them are older. [With single-agent treatment], we can minimize the toxicities.

Could you discuss the updated data from the MURANO trial?

&#8232;We also saw the 4-year follow-up of the MURANO trial, which randomized patients with relapsed/refractory CLL to venetoclax and rituximab (Rituxan) or bendamustine/rituximab (BR). We already knew that the novel therapy arm was associated with improved PFS and OS, as well as high MRD-negativity rate. In the longer follow-up, patients were off venetoclax/rituximab for 2 years. The advantage continues to show [benefit] with venetoclax/rituximab, as the PFS rate was close to 60%, where nearly all patients who received BR had progressed by this time. Again, there were no new toxicities associated with venetoclax/rituximab.

&#8232;Importantly, there was some response to subsequent therapies. [The data suggest that] patients who received venetoclax/rituximab can respond to BTK inhibitors upon progression; although longer follow-up is needed to understand the duration of response.

&#8232;This was echoed by a presentation given by Anthony R. Mato, MD, MSCE, of Memorial Sloan Kettering Cancer Center, who reported the results of a large retrospective dataset of patients treated with venetoclax/rituximab and the analysis of subsequent salvage therapies.

&#8232;In this set, patients who progressed following = venetoclax/rituximab discontinuation responded to treatment with BTK inhibitors. It did depend on whether patients were [previously] exposed to BTK inhibitors, and what their reason for discontinuing BTK inhibitor therapy was if they were [previously] exposed.

Patients who had not received prior BTK inhibitors had the best response to BTK inhibitors following progression on venetoclax/rituximab. Conversely, patients who developed resistance to ibrutinib in the past did not have as good response. However, even among those patients, responses indicated that treatment with venetoclax/rituximab may lead to eradication of BTK inhibitor—resistant clones in some patients. Longer follow-up is needed to assess the duration of those responses.

&#8232;Where does zanubrutinib (Brukinsa) fit into the treatment paradigm in CLL?

&#8232;Zanubrutinib is a second-generation BTK inhibitor that was recently approved [for the treatment] of patients with mantle cell lymphoma (MCL).

&#8232;In CLL, a large dataset of patients with 17p deletion del(17p) were treated with zanubrutinib in the frontline setting. These were certainly very encouraging data with high response rates. [Additionally], it appears to be a well-tolerated regimen as very few patients discontinued [treatment with zanubrutinib] while on study. Zanubrutinib provides another excellent option for patients with CLL, regardless of their deletion 17p status.

What can we expect in the CLL paradigm within the next year?

CAR T-cell therapy is one area to watch for, as it has made a big impact in therapy for lymphomas, such as diffuse large B-cell lymphoma and MCL. The TRANSCEND CLL 004 trial data are exciting. Results showed good responses in patients who were double refractory to BTK inhibition and venetoclax, and these responses appear to be durable so far.

Sharman JP, Banerji V, Fogliatto LM, 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-naïve chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1). doi: 10.1182/blood-2019-128404.