Sandra Horning, MD

According to the pivotal phase III CLL14 study presented during the 2019 American Society of Clinical Oncology Annual Meeting, venetoclax (Venclexta) plus obinutuzumab (Gazyva) demonstrated a lengthening in progression-free survival (PFS) time for patients with previously untreated chronic lymphocytic leukemia (CLL) compared with obinutuzumab plus chlorambucil. Trial results show that the chemotherapy-free combination reduced the risk for disease worsening or death by 65% compared with obinutuzumab plus chlorambucil.1,2

The trial met its primary endpoint of investigator-assessed progression-free survival (PFS; HR, 0.35; 95% CI, 0.23-0.53;P<.001). Moreover, nearly 9 of 10 patients (88.2%) in the venetoclax arm remained progression free at 2 years, 1 year after stopping treatment, compared with 64.1% in the obinutuzumab plus chlorambucil arm.

“The results of our phase III CLL14 trial…represent a major advance in improving outcomes in chronic lymphocytic leukemia,” said Sandra Horning, MD, chief medical officer and head of Global Product Development for Roche, Basel, Switzerland. “We are pleased this fixed-duration, chemotherapy-free regimen of Venclexta plus Gazyva was approved by the FDA [on May 15, 2019] and look forward to providing an important treatment option to even more adults with the most common form of adult leukemia.”

In the multinational, open-label, phase III trial (NCT02242942), investigators evaluated a fixed-duration treatment using venetoclax plus obinutuzumab in 432 patients with previously untreated CLL and coexisting conditions, which included reduced kidney function or comorbidities assessed by the Cumulative Illness Rating Scale, which ranges from 0 to 56, with higher scores indicating more impaired function of organ systems.

Eligibility included a score of greater than 6 on the Cumulative Illness Rating Scale or a calculated creatinine clearance of less than 70 ml per minute.

Patients were randomly assigned to receive either a 12-month duration of venetoclax plus a 6-month duration of obinutuzumab (Arm A; n = 216) or a 6-month duration of obinutuzumab plus a 12-month duration of chlorambucil (Arm B; n = 216). Arm A started with an initial dosing of obinutuzumab followed by a 5-week venetoclax dosage ramp-up to help reduce the risk of tumor lysis syndrome.

In addition to investigator-assessed PFS, secondary endpoints included PFS assessed by independent review committee (IRC), minimal residual disease (MRD) status, overall response rate (ORR), complete response (CR) with at least partial blood count recovery, overall survival (OS), duration of response, event-free survival, time to next CLL treatment, and safety.

Patients were a median age of 72 and had a median Cumulative Illness Rating Scale score of 8 and median creatinine clearance of 66.4 ml per minute.

After a median follow-up of 28.1 months, 30 patients experienced disease progression or death in the venetoclax-obinutuzumab group and 77 in the chlorambucil-obinutuzumab group. Meanwhile, the percentage of patients with PFS at 2 years was significantly higher with the addition of venetoclax to obinutuzumab, compared with chlorambucil (88.2% [95% CI, 83.7-92.6] vs 64.1% [95% CI, 57.4-70.8]). Median PFS reported by investigators was not yet reached in either arm; however, IRC assessment of PFS was consistent (HR, 0.33; 95% CI, 0.22-0.51;P<.001).

Similarly, the investigators observed this benefit among those with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes.

The venetoclaxobinutuzumab group also demonstrated clinical benefit across secondary endpoints, including ORR (84.7% vs 71.3%;P<.001); CR including incomplete marrow recovery (49.5% vs. 23.1%; P< .001); and higher rates of MRD-negativity (56.9% vs. 17.1%; P<.001) and peripheral blood (75.5% vs. 35.2%; P<.001) 3 months after treatment.

The safety profile of both treatments showed no new safety signals or higher incidences of known toxic effects. The most common grade 3 or higher adverse events (AEs) in the venetoclaxobinutuzumab group and chlorambucil–obinutuzumab group were neutropenia (52.8% vs 48.1%, respectively) and infections (17.5% vs 15.0%). All-cause mortality occurred in 9.3% and 7.9% of patients, respectively; however, these differences were not significant.

“Fixed-duration, targeted treatment with venetoclaxobinutuzumab was effective in previously untreated patients with CLL, and coexisting conditions and resulted in a significantly higher percentage of patients with progression-free survival than standard treatment with chlorambucil–obinutuzumab,” the investigators concluded. “Longer follow-up is necessary to assess the durability of the responses.”

Results of the study were simultaneously published in theNew England Journal of Medicine.3

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