Treatment that includes acalabrutinib can improve progression-free survival in treatment-naïve patients with chronic lymphocytic leukemia.
A 6-year follow-up study of the randomized, controlled ELEVATE-TN trial (NCT02475681) presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition found that regimens containing acalabrutinib can improve progression-free survival (PFS) in treatment-naïve patients with chronic lymphocytic leukemia (CLL).1 Compared with obinutuzumab plus chlorambucil, researchers discovered that regimens containing acalabrutinib were more effective in improving the response rate and reducing risk of death. Physician’s Weekly (PW) interviewed lead investigator and presenter Jeff Sharman, MD.
The study team randomized patients with CLL 1:1:1 to receive either 100 mg acalabrutinib twice daily plus a fixed duration of obinutuzumab for 6 cycles, 100 mg acalabrutinib monotherapy twice daily, or a fixed duration of obinutuzumab for 6 cycles plus a fixed duration of chlorambucil. The primary endpoint was comparing the PFS of both combination regimens. Secondary endpoints included comparing the PFS of acalabrutinib monotherapy versus obinutuzumab plus chlorambucil, investigator-assessed PFS, objective response rate, time to next treatment, undetected minimal residual disease, and safety.
Previous long-term follow-ups at 28.3 months, 46.9 months, and 58.2 months also demonstrated superior efficacy and acceptable tolerability with acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil. In the 6-year follow-up, the median study follow-up in the acalabrutinib-obinutuzumab, acalabrutinib monotherapy, and obinutuzumab-chlorambucil arms was 74.6 months (range, 1.7-89.0), 74.5 months (range, 0.1-88.8), and 73.3 months (range, 0.0-88.8), respectively. Treatment is ongoing for 96 patients in the acalabrutinib-obinutuzumab group (53.6%) and 84 patients in the acalabrutinib monotherapy group (46.9%), while no patients are receiving the obinutuzumab-chlorambucil regimen. In total, 79 participants (44.6%) crossed over from the obinutuzumab-chlorambucil arm to the acalabrutinib-obinutuzumab arm.
“Acalabrutinib-containing regimens led to improved PFS over controlled obinutuzumab plus chlorambucil. The addition of obinutuzumab to acalabrutinib resulted in improved response rates and PFS compared to acalabrutinib monotherapy,” said Dr. Sharman during his presentation. “Obtaining a complete response with acalabrutinib-containing regimens leads to improved PFS, and the safety of acalabrutinib regimens in treatment-naïve CLL remains consistent with prior reports.”
Compared with the obinutuzumab-chlorambucil regimen, acalabrutinib plus obinutuzumab (median PFS, not reached [NR]); HR 0.14; 95% CI 0.10-0.20; P<0.001) and acalabrutinib monotherapy (median PFS, NR; HR 0.24; 95% CI 0.17-0.32; P<0.001) demonstrated superior PFS. Overall response rates with acalabrutinib, in combination and monotherapy, were also significantly higher (difference 6.1%; 95% CI 0.9-11.4; P=0.022) and complete response (CR) rates (difference, 17.9%; 95% CI 8.8-27.0; P=0.022). Patients treated with acalabrutinib who experienced CR or complete remission had reduced risk for disease progression by 77% (HR 0.23; 95% CI 0.12-0.42; P<0.001).
PFS of patients with unmutated IGHV was similar to that of patients with mutated IGHV; the addition of acalabrutinib either as monotherapy or with obunutuzumab continued to demonstrate superior benefit regardless of IGHV status. In patients with del(17p)/TP53 mutations, typically associated with poor prognosis, the 6-year PFS rates were 56% for both the acalabrutinib-obinutuzumab (HR 0.28, 95% CI 0.13-0.59; P<0.001) and acalabrutinib monotherapy arms (HR 0.23; 95% CI 0.10-0.52; P<0.001), compared with only 18% in the obinutuzumab-chlorambucil arm.
Crossover from the obinutuzumab-plus-chlorambucil arm was allowed after independent review committee-confirmed progression. Those who went on to receive acalabrutinib monotherapy after crossover demonstrated a 6-year PFS rate of 62% (median PFS was not reached), while the obinutuzumab-chlorambucil arm who crossed overachieved a 6-year PFS rate of 54% (median PFS was not reached).
Overall survival was not reached in any treatment arm; however, the combination use of acalabrutinib plus obinutuzumab reduced the risk for death by 38% compared with obinutuzumab plus chlorambucil (HR 0.62; 95% CI 0.39-0.97; P=0.0349).
The most common grade 3 or higher adverse events in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms were diarrhea (6.2% vs 0.6%, respectively), headache (1.1% vs 1.1%), arthralgia (2.2% vs 1.1%), neutropenia (30.9% vs 11.7%), fatigue (2.2% vs 1.1%), cough (0.6% vs 0.6%), thrombocytopenia (8.4% vs 3.4%), hypertension (4.5% vs 5.0%), and syncope (5.1% vs 2.2%).
PW interviewed Dr. Sharman following his presentation at the 65th ASH Annual Meeting.
PW: What are the key findings of the study?
Dr. Sharman: The ELEVATE-TN trial demonstrated that acalabrutinib, either as monotherapy or in combination with obinutuzumab, is a highly effective and well-tolerated treatment option for patients with CLL. The 6-year follow-up data showed that acalabrutinib-obinutuzumab and acalabrutinib monotherapy significantly improved PFS compared with obinutuzumab and chlorambucil. Adding obinutuzumab to acalabrutinib further improved PFS and response rates.
What are the implications of these findings for the treatment of CLL?
The ELEVATE-TN trial results further solidify the position of acalabrutinib as a leading treatment option for patients with CLL. The study showed that acalabrutinib can provide durable benefits for patients, regardless of their genomic marker status. The long-term safety profile of acalabrutinib is also reassuring.
What are the most important takeaways for oncologists from this study?
The ELEVATE-TN trial has provided valuable data that oncologists can use to make informed treatment decisions for patients with CLL. The study results show that acalabrutinib is a highly effective and well-tolerated treatment that can provide long-term benefits for patients. In addition to the key findings mentioned above, the trial also demonstrated that acalabrutinib can provide significant benefits for patients with CLL, regardless of their age or performance status. However, the trial allowed performance status 0-2, so we cannot necessarily generalize to all performance statuses.
The study also found an association between acalabrutinib and a low incidence of adverse events, including cardiac-related adverse events.
Overall, the ELEVATE-TN trial results provide strong evidence that acalabrutinib is a highly effective and well-tolerated treatment option for patients with CLL. The study results also suggest that acalabrutinib can provide durable benefits for patients, regardless of their genomic marker status or other patient factors.
