ASCEND final results: Acalabrutinib compared with idelalisib + R or Bendamustine + R in R/R CLL

Bruton’s tyrosine kinase (BTK) inhibitors are recommended for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), even for patients with high-risk disease. Ibrutinib has been used previously but its safety profile is not ideal. As a next-generation BTK inhibitor with increased specificity, acalabrutinib has the potential to cause fewer off-target effects. The efficacy and safety of acalabrutinib was compared with the PI3K inhibitor idelalisib plus rituximab (IdR) or bendamustine and rituximab (BR) in the ASCEND phase III trial (NCT02970318).

During the eighth annual meeting of the Society of Hematologic Oncology (SOHO), Paolo Ghia presented the final results of the ASCEND trial with 6 months of follow-up.¹

Study design

To be included in the study, patients had to meet the following conditions:

• ≥ 18 years
• Diagnosed with CLL (according to the criteria defined by the International Workshop on Chronic Lymphocytic Leukemia)
• Eastern Cooperative Oncology Group performance status of 2
• Treated with at least one line of prior therapy

Exclusion criteria: Diagnosed central nervous system leukemia or lymphoma, cardiovascular disease, or prior treatment with a BCL2 or B-cell receptor inhibitor.

Overall, 310 patients with R/R CLL were included and randomly split between treatment groups:

1. Acalabrutinib (n = 155), 100 mg twice a day, orally
2. Investigator’s choice of:
   1. IdR (n = 119). Id, 150 mg orally, twice daily + R 375 mg/m² intravenous (IV) on Day 1 of first cycle, then 500 mg/m² every 2 weeks for four infusions then reducing to three infusions every 4 weeks; or
   2. BR (n = 36). B, 70 mg/m² IV on the first and second day of Cycles 1−6, + R, 375 mg/m² IV on Day 1 of first cycle then 500 mg/m² on Day 1 of Cycles 2−6.

The primary endpoint of the study was progression free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival (OS), and safety.

Key points

Patient characteristics were consistent between the different groups (Table 1). The majority of patients were male, over 60 years of age, and the median number of prior lines of therapy was two (range, 1−10). The most common high-risk factor was an unmutated immunoglobulin heavy chain variable (IGHV) region, identified in > 75% of the population, while del(17p) was the rarest at 15.8%.

Table 1. Patient baseline characteristics¹

B, bendamustine; Id, idelalisib; IGHV, immunoglobulin heavy chain variable; mAb, monoclonal antibody; R, rituximab; SCT stem cell transplant.
Characteristic		Acalabrutinib (n = 155)	IdR/BR (n =155)	Total (N = 310)
Median age (range), years		68 (32−89)	67 (34−90)	67 (32−90)
Men, %		69.7	64.5	67.1
Bulky disease ≥ 5 cm, %		49.0	48.4	48.7
Number of prior therapies, %	1	52.9	43.2	48.1
2	25.8	29.7	27.7
3	11.0	15.5	13.2
4	10.3	11.6	11.0
Prior therapy type, %	Purine analogues	70.3	67.1	48.1
Alkylators (other than B)	85.8	84.5	85.2
B	30.3	31.0	30.6
Anti CD20 mAbs	83.9	76.8	80.3
SCT	0.6	0.6	0.6
Other	5.8	3.9	4.8
Cytogenetic status, %	Unmutated IGHV	76.1	80.6	78.4
Del(17p)	18.1	13.5	15.8
Del(11q)	25.2	28.4	26.8
≥ 3 abnormalities	32.3	29.7	31.0

 

The ASCEND trial met its primary endpoint. Estimated PFS after 18 months was 82% for the acalabrutinib group compared with 48% for investigator’s choice therapy. The median PFS was 16.8 months for IdR/BR and not reached for acalabrutinib (HR, 0.27; 95% CI, 0.18–0.40; p < 0.0001).

Similar results were seen when looking at IdR and BR patients separately. For BR alone, median PFS was 18.6 months, and for IdR it was 16.2 months. Compared with acalabrutinib, IdR produced an HR of 0.27 (95% CI, 0.18–0.41; p < 0.0001), and for BR the HR was 0.29 (95% CI, 0.17–0.50; p < 0.0001). In a sub-analysis of patients with del(17p) and TP53 mutations, acalabrutinib was still found to prolong PFS compared with IdR/BR (HR, 0.11; 95% CI, 0.04–0.34). Patients with unmutated IGHV regions similarly showed improved PFS compared with investigator’s choice-treated patients.

The median OS was not reached in either treatment arm. OS was not significantly different between groups – acalabrutinib compared with IdR/BR resulted in a HR of 0.78 (95% CI, 0.44–1.40; p = 0.41). It should be noted, however, that patient crossover was permitted from the IdR/BR arm following confirmed disease progression, which may have impacted OS comparisons. ORR was similar between the two treatment groups (80% vs 84% for acalabrutinib vs IdR/BR).

The median duration of response was 18 months for IdR/BR and not reached for acalabrutinib. Estimated 18-month duration of response rates were 85.4% (95% CI, 77–91) and 49.4% (95% CI, 40–58) for acalabrutinib and IdR/BR, respectively.

Table 2. Exposure and compliance¹

BR, bendamustine + rituximab; IdR, idelalisib + rituximab.
Characteristic		Acalabrutinib (n = 154)	IdR (n = 118)	BR (n = 35)
Median duration of exposure (range), months		21.9 (1.1−27.9)	11.5 (0.1−27.2)	5.6 (1.0−7.1)
Median relative dose intensity (range), %		99.3 (48.3−100)	90.0 (46.6−100.0)	96.4 (14.5−102.5)
Discontinued treatment, %		27	77	19
Reasons for discontinuation, %	Adverse event	16	56	17
Progressive disease	10	14	3
Death	1	0	0
Investigator discretion	0	4	0
Withdrawal of consent	0	1	0
Other	1	3	0

As shown in Table 2, exposure was longest for patients in the acalabrutinib group (median 21.9 months). Patients treated with BR had the shortest duration of exposure (median 5.6 months). Discontinuation of treatment was highest for IdR (77%); 56% of these patients ceased treatment due to an adverse event (AE).

Table 3. Adverse events¹

BR, bendamustine + rituximab; IdR, idelalisib + rituximab.
	Acalabrutinib	IdR	BR
Any AE, %	96	99	80
Grade ≥ 3, %	55	90	49
Serious AEs, %	33	56	6
Treatment-related AEs, %	70	95	69
AEs leading to dose withholding, %	38	66	20
AEs leading to drug discontinuation, %	14	59	17

While AEs were recorded for all treatments, serious AEs and Grade ≥ 3 AEs were more common in the IdR group than in the acalabrutinib or BR groups (Table 3). Treatment-related AEs were 95% for IdR vs 70% for acalabrutinib. The most common AEs were neutropenia, diarrhea, and upper respiratory tract infection. Serious AEs in ≥ 5 patients included pneumonia, pyrexia, and diarrhea and were most frequent in the IdR group.

In terms of events of clinical interest, hemorrhage of any grade was observed more frequently with acalabrutinib than the other treatment groups (29% vs 8%, for acalabrutinib vs IdR/BR) but incidence of major hemorrhage was low and similar between groups.

Conclusion

The final results of the ASCEND trial indicate the increased efficacy of acalabrutinib compared with current standard of care treatments for treating patients with R/R CLL irrespective of high-risk characteristics. In addition, acalabrutinib seems to be better tolerated than IdR, with fewer AEs leading to treatment discontinuation. This supports the postulation that the increased specificity of acalabrutinib results in fewer off-target effects. Together, these results support the use of acalabrutinib for the treatment of patients regardless of their cytogenetic status.