Acalabrutinib Triplet Impresses in Frontline CLL, Advances to Phase III Study

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Partner | Cancer Centers | <b>Dana-Farber Cancer Institute</b>

The addition of acalabrutinib (Calquence) to venetoclax (Venclexta) and obinutuzumab (Gazyva) was shown to be highly active in patients with newly diagnosed chronic lymphocytic leukemia, eliciting deep and durable responses.

Benjamin L. Lampson, MD, PhD

The addition of acalabrutinib (Calquence) to the combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) was shown to be highly active in patients with newly diagnosed chronic lymphocytic leukemia (CLL), eliciting deep and durable responses that improved over time, according to data from a phase II trial (NCT03580928).

In the trial, 48% of patients achieved undetectable minimal residual disease (uMRD) in the bone marrow after 8 cycles of therapy, which increased to 75% after 16 cycles. Moreover, 16.7% of patients achieved a complete response (CR) with uMRD in the bone marrow after 8 cycles and was 12.5% after 16 cycles.

The objective response rate (ORR) was 97.3% after cycle 4, and was 100% after cycle 8 and cycle 16. Responses were also observed, regardless of IGHV or TP53 mutation status.

Patients received a 28-day lead-in with acalabrutinib at 100 mg twice daily and 6 cycles of obinutuzumab at the standard dose. Venetoclax was introduced on day 1 of cycle 4 and continued for 15 cycles.

Patients who achieved uMRD in the bone marrow after cycle 15 were allowed to discontinue therapy. All other patients continued on the combination until cycle 24, at which point they were reevaluated for uMRD in the bone marrow.

Furthermore, the triplet demonstrated a toxicity profile that was consistent with each agent alone. The most common hematologic toxicity was neutropenia (68% all-grade; 32% grade ≥3). The most common nonhematologic toxicities were fatigue (84% all-grade; 3% grade ≥3), headache (76% all-grade; 3% grade ≥3), and bruising (46% all-grade; 0% grade ≥3).

Notably, pretreatment with acalabrutinib and obinutuzumab reduced the rate of venetoclax-associated tumor lysis syndrome.

“The first finding is that the triplet can be safely administered in combination,” said lead study author Benjamin L. Lampson, MD, PhD. “The second finding is that the triplet is highly active in frontline CLL and thus merits further investigation in the phase III setting.”

The phase II trial will enroll an additional 35 patients with TP53-aberrant disease. Meanwhile, a phase III study (NCT03836261), which launched in February 2019, will compare the combination of acalabrutinib and venetoclax with or without obinutuzumab versus chemoimmunotherapy in treatment-naïve patients without 17p deletion or TP53 aberrations.

In an interview with OncLive, Lampson, a medical oncologist at Dana-Farber Cancer Institute, discussed the primary efficacy and safety findings from the ongoing phase II trial with acalabrutinib, venetoclax, and obinutuzumab in frontline CLL.

OncLive: Could you provide a rationale for studying the triplet in this space?

Lampson: We already know that frontline therapy with the BTK inhibitor, either ibrutinib (Imbruvica) or acalabrutinib, is very effective in CLL. We also know that the combination of venetoclax and obinutuzumab as fixed-duration therapy is very effective in CLL. The idea is by combining these 2 therapies, we can achieve deeper and more durable remissions, and perhaps allow patients to discontinue treatment.

What was the design of the trial?

Treatment began with 1, 28-day cycle of acalabrutinib followed by 6 monthly cycles of obinutuzumab. On cycle 4, we ramped up with venetoclax. We continued therapy for 15 total cycles, at which point we assessed the primary endpoint, which was the rate of CR with uMRD in the bone marrow at this time. MRD was measured by flow cytometry with a sensitivity of 10-4.

What were the results of this trial?

[At the 2019 ASH Annual Meeting], we only had response data from cycle 8 and a few responses from cycle 16. However, even at cycle 8, we saw high rates of uMRD. Approximately 48% of patients achieved uMRD in the bone marrow, and 68% of patients achieved uMRD in the peripheral blood. We also saw a high ORR; 100% of patients had a response to therapy by cycle 8, and about 25% of those were CRs.

Could you discuss the safety profile of the triplet?

The safety profile of the triplet is similar to what we would expect from each of the agents individually. For example, the rate of grade 3/4 neutropenia was about 32%. The most common nonhematologic AE was fatigue. The second most common nonhematologic AE was headache, which is commonly seen with acalabrutinib. There were no grade 4 nonhematologic toxicities.

What are the immediate next steps for this research?

We're expanding this trial to include 35 more patients with TP53-aberrant disease. There's also a phase III trial that is now enrolling patients and is comparing the triplet therapy with acalabrutinib and venetoclax versus chemoimmunotherapy.

Pending positive phase III results, how could this regimen impact practice?

The hope is, if we can show that the combination of acalabrutinib, venetoclax, and obinutuzumab achieves deep, durable remissions as frontline therapy, then we have defined a new frontline treatment for patients with CLL.

Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1):32. doi: 10.1182/blood-2019-127506.