Chicago, IL—In the phase 3 CLL14 trial, fixed-duration therapy with the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) was superior to the combination of chemotherapy with chlorambucil plus obinutuzumab as front-line therapy in older patients with chronic lymphocytic leukemia (CLL) and comorbidities. Kirsten Fischer, MD, Center for Integrated Oncology Cologne-Bonn, University Hospital, Germany, presented the study results at ASCO 2019 and were published simultaneously (Fischer K, et al. N Engl J Med. 2019;380:2225-2236).
Based on these results, on May 15, 2019, the FDA approved the combination of venetoclax plus obinutuzumab as first-line treatment for a fixed duration for patients with CLL.
The fixed-duration regimen significantly improved progression-free survival (PFS), complete response rate, and minimal residual disease (MRD)-negativity versus chemotherapy plus obinutuzumab, and was superior in patients with poor prognostic factors, such as IGHV and TP53 mutations. This fixed-duration combination was hailed as a new standard of care by experts at the ASCO meeting.
“This study is practice-changing in the front-line setting. For most patients, we should be considering venetoclax plus obinutuzumab for front-line therapy,” commented Matthew S. Davids, MD, MMSc, Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute, Boston, MA. He emphasized the fixed-duration treatment and the high rates of MRD-negativity achieved in the trial as the feature that distinguishes this regimen from other combinations in CLL, including front-line combination ibrutinib (Imbruvica) plus obinutuzumab, which was approved by the FDA in January 2019 but is given as a continuing therapy.
“Fixed-duration targeted therapy combining venetoclax and obinutuzumab can be applied safely to elderly CLL patients with comorbidities. Our study showed it is superior to fixed-duration chlorambucil and obinutuzumab. Venetoclax plus obinutuzumab achieves the highest rates of MRD-negative response so far observed in a randomized prospective trial” of patients with CLL, stated Dr Fischer.
The median follow-up is 28 months, and thus far no survival difference has been seen between the 2 regimens. “It might be too early to see an effect on survival,” Dr Fischer said.
The open-label, randomized, phase 3 CLL14 clinical trial enrolled 432 treatment-naïve patients (median age, 72 years) with CD20-positive CLL. Patients had to have clinically significant comorbidities, indicated by a score of >6 on the Cumulative Illness Rating Scale or a creatinine clearance of <70 mL/min. Patients were randomized in a 1:1 ratio to venetoclax plus obinutuzumab or to chlorambucil plus obinutuzumab for twelve 28-day cycles.
Treatment arms were well-balanced for demographic and disease characteristics. In total, 13.8% of the patients had TP53 deletion, mutation, or both, and 59.8% had IGHV mutation.
With a median follow-up of 28 months, the median PFS was not reached in either group. The estimated 24-month PFS was 88.2% in the venetoclax-obinutuzumab group versus 64.1% in the chlorambucil-obinutuzumab arm (P <.0001).
“MRD-negativity was achieved early with venetoclax and stayed that way over time,” Dr Fischer told listeners.
Three months after treatment ended, an intent-to-treat analysis showed an MRD-negativity in peripheral blood rate of 75.5% with the targeted combination versus 35.2% with chemotherapy plus obinutuzumab (P <.001); the rates of MRD in bone marrow were 56.9% versus 17.1%, respectively (P <.001).
The overall response rates were 84.7% versus 71.3%, respectively (P <.001) and the complete response rates were 49.5% versus 23.1%, respectively (P <.001).
The rates of patients with complete response and MRD-negativity in peripheral blood were significantly higher in the venetoclax plus obinutuzumab arm—42.1% versus 14.4%, respectively (P <.001); the rates in bone marrow were 33.8% versus 10.6%, respectively (P <.001).
Safety and Tolerability
At least 1 adverse event of any grade was reported in 94.5% of the patients in the venetoclax plus obinutuzumab arm and in 99.5% of those in the chlorambucil-obinutuzumab arm (total safety population, 426 patients). Adverse events leading to treatment discontinuation occurred in 16% and 15.4% of patients, respectively.
The most common grade 3 or 4 event was neutropenia. The rates of grade 3 or 4 febrile neutropenia were 5.2% and 3.7%, respectively, and rates of grade 3 or 4 infections were 17.5% and 15%, respectively. No patient had symptoms that met clinical criteria for tumor lysis syndrome. The rate of grades 3 and 4 infusion reactions was similar in both arms (9% and 10.3%, respectively). The rate of second cancers was not significantly different between the 2 treatment arms.