Significantly improves PFS compared to chemoimmunotherapy

The Bruton tyrosine-kinase (BTK) inhibitor acalabrutinib — as either a monotherapy or in combination with obinutuzumab — is an effective first-line therapy for the treatment of patients with chronic lymphocytic leukemia, researchers found.

A randomized, controlled, phase III trial reported that treatment with acalabrutinib significantly improved progression-free survival in these patients compared to treatment with chemoimmunotherapy.

Thus, Jeff P. Sharman, MD, Willamette Valley Cancer Institute, Eugene, Oregon, and colleagues suggested acalabrutinib can provide CLL patients with a chemotherapy-free treatment option with an acceptable safety profile.

Acalabrutinib received FDA approval for adults with CLL in November 2019.

Their study was published in The Lancet.

CLL is a B-cell malignancy that typically occurs in older patients and is usually considered to be incurable. While chemoimmunotherapy has been the standard first-line therapy for treating CLL, Sharman and colleagues pointed out that recent evidence suggests some non-chemotherapeutic approaches, such as targeting BTK, can be beneficial in these patients.

In a commentary accompanying the study, Matthew S. Davids, MD, MMSc, Dana-Farber Cancer Institute, Boston, noted that the first drug targeting BTK, ibrutinib, proved superior to chemoimmunotherapy in untreated patients with CLL. However, ibrutinib is associated with toxic effects such as cardiovascular and bleeding risks, arthralgias, and rash, and, according to Davids, “efforts to augment the efficacy of ibrutinib with the addition of anti-CD20 monoclonal antibodies have been challenging.”

The ELEVATE-TN phase III, randomized, multicenter, open-label trial was designed to evaluate the efficacy and safety of another BTK inhibitor, acalabrutinib — as a monotherapy or combined with the anti-CD20 monoclonal antibody obinutuzumab — compared with chemoimmunotherapy in treatment-naive CLL patients.

The trial took place across 142 centers in 18 countries and involved 535 patients. These patients had untreated CLL and were aged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30–69 mL/min, or a Cumulative Illness Rating Scale for Geriatrics score greater than 6. They were also required to have an Eastern Cooperative Oncology Group performance status score of 2 or less, as well as adequate hematologic, hepatic, and renal function.

Patients were randomly assigned to receive either acalabrutinib and obinutuzumab (179 patients), acalabrutinib alone (179 patients), or obinutuzumab and the oral chemotherapy chlorambucil (177 patients). The primary endpoint of the trial was progression-free survival (PFS).

Sharman and colleagues found PFS was longer with acalabrutinib-obinutuzumab and acalabrutinib monotherapy, compared with obinutuzumab-chlorambucil.

Specifically, at a median of 28.3 months median progression-free survival was significantly longer with acalabrutinib-obinutuzumab (the median was not reached) compared to obinutuzumab-chlorambucil (22.6 months) — a 90% reduction in relative risk of progression or death with acalabrutinib-obinutuzumab.

The same held true with acalabrutinib monotherapy (median PFS not reached) compared with acalabrutinib (22.6 months).

Estimated progression-free survival at 24 months was 93% with acalabrutinib-obinutuzumab (95% CI 87–96%) and 87% with acalabrutinib monotherapy (81%-92%), compared with 47% with obinutuzumab-chlorambucil (39%-55%).

Regarding safety, the authors noted that BTK inhibitors are administered until disease progression, and therefore “tolerability and long-term safety are crucial, especially in chronic lymphocytic leukemia, which tends to affect an older population with comorbidities.”

They found that the most common adverse event across all 3 groups was neutropenia (30% of acalabrutinib-obinutuzumab patients, 9% of acalabrutinib monotherapy patients, and 41% of obinutuzumab-chlorambucil patients).

Grade 3 or higher infection occurred in 21% patients given acalabrutinib-obinutuzumab, 14% of patients given acalabrutinib monotherapy, and 8% of patients given obinutuzumab-chlorambucil. In addition, there were low rates of significant cardiovascular and bleeding events, and low discontinuation rates in both the acalabrutinib combination (11%) and monotherapy (9%) groups.

“The phase III ELEVATE-TN study substantiates that acalabrutinib with or without obinutuzumab is an efficacious and well tolerated treatment for patients with treatment-naive chronic lymphocytic leukemia,” Sharman and colleagues concluded.

In his commentary, Davids pointed out that while acalabrutinib was more efficacious than a chemoimmunotherapy approach that included chlorambucil, it is unknown how it will compare with more potent chemoimmunotherapy combinations used for younger, healthier patients with CLL.

He also noted that the apparent benefit of the acalabrutinib-obinutuzumab combination should be “weighed against the risk of increased toxic effects by the addition of obinutuzumab, including infusion reactions and infections, and the inconvenience of infusions and additional costs.”

While the ELEVATE TN trial confirms acalabrutinib as a safe and effective initial treatment option for patients with CLL, Davids wrote, “[f]uture studies will be crucial to further define its role in the treatment paradigm.”

  1. The Bruton tyrosine-kinase (BTK) inhibitor acalabrutinib — as either a monotherapy or in combination with obinutuzumab — is an effective first-line therapy for the treatment of patients with chronic lymphocytic leukemia. Treatment with acalabrutinib significantly improved progression-free survival in these patients compared to treatment with chemoimmunotherapy.

  2. Acalabrutinib had an acceptable safety profile that was consistent with previous studies.

Michael Bassett, Contributing Writer, BreakingMED™

Sharman reports personal fees from AbbVie, Acerta Pharma (a member of the AstraZeneca Group), AstraZeneca, Genentech, Pharmacyclics, Sunesis, and TG Therapeutics, during the conduct of this study.

Davids revealed relevant relationships with AbbVie, Adaptive Biosciences, AstraZeneca, BeiGene, Celgene, Genentech, Janssen, TG Therapeutics, and others.

Cat ID: 466

Topic ID: 78,466,282,494,730,466,192,255,60,925