Increasing the Dose of Obinutuzumab Monotherapy Raised the Response Rate


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A randomized phase II study in symptomatic, untreated patients with chronic lymphocytic leukemia (CLL) found an increased overall response rate with obinutuzumab (Gazyva) at a 2,000 mg vs 1,000 dose. In addition, the “data demonstrate that obinutuzumab produces a higher response rate in symptomatic, previously untreated patients than previously observed in relapsed patients,” John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center, Columbus, and colleagues wrote in Blood.

Obinutuzumab injection was approved by the U.S. Food and Drug Administration in 2013 for use in combination with chlorambucil (Leukeran) in previously untreated CLL patients. A glycoengineered, type 2 anti-CD20 humanized antibody, obinutuzumab also has been shown to have single-agent activity in relapsed CLL. A dose-response relationship has been shown with other nonengineered anti-CD20 antibodies, and this study was designed to evaluate whether a dose-response relationship exists with obinutuzumab as well.

A total of 80 patients from 19 different study sites were randomized to receive either obinutuzumab at a dose of 1,000 mg (41 patients) or 2,000 mg (39 patients). One patient in each treatment group did not receive obinutuzumab. The median age of the study patients was 67 years; 41% had high-risk Rai disease, and 10% had del(17)(p13.1).

“Obinutuzumab was administered by IV infusion as an absolute (flat) dose of 1,000 mg or 2,000 mg,” the investigators reported. “Three doses of obinutuzumab were given during cycle 1, 1 each on days 1, 8, and 15. Splitting the first dose of obinutuzumab in cycle 1 was mandatory. For the 1,000-mg arm, the first dose was split over 2 consecutive days (100 mg on day 1 and 900 mg on day 2). For the 2,000-mg arm, the first dose could be split over 3 consecutive days (100 mg on day 1, 900 mg on day 2, and 1,000 mg on day 3). Alternatively, for the 2,000-mg arm, if the patient tolerated 100 mg on day 1, then the rest of the dose (1,900 mg) could be administered on day 2. The day 8 and day 15 doses could each be administered over 1 day (ie, not split). Thereafter, obinutuzumab was given on day 1 of each subsequent 21-day cycle, for up to 8 cycles.”

The median total cumulative dose of obinutuzumab was 10,000 mg in the 1000-mg treatment group and 20,000 mg in the 2,000-mg group. The median duration of treatment and the mean dose intensity received were the same in both treatment groups.

Response, Survival, and Toxicity

The overall response rate was 67% with 2,000 mg of obinutuzumab vs 49% with 1,000 mg of obinutuzumab (P = .08). Patients receiving 2,000 mg also had a higher complete response or complete response with incomplete cytopenic response, 20% vs 5% of patients receiving obinutuzumab at 1,000 mg (P < .05).

Four patients in each treatment group were considered high risk because they had del(17)(p13.1). All four of these patients in the 2,000-mg group achieved an objective partial response, but none in the 1,000-mg group did so.

Progression-free survival at 18 months was 83% in the 2,000-mg group vs 59% in the 1,000-mg group, but “the data show no difference in progression-free survival rates because the curves merge after month 18,” the researchers noted, and the confidence intervals overlap. “Further follow-up will be required to determine if dose response translates into improved progression-free survival.” The median overall survival had not been reached for each group at the time of the data analyses.

“Overall, therapy was well tolerated, and infusion events were manageable,” the investigators reported. Adverse events led to withdrawal of study medication in five patients (13%) in the 2,000-mg group and two patients (5%) in the 1,000-mg group.

Four deaths occurred. In the 1,000-mg group, two patients with del(17)(p.13.1) died due to disease progression after completion of treatment, and one patient died due to myocardial infarction, considered to be unrelated to the study treatment. One patient in the 2,000-mg group who had a history of chronic obstructive pulmonary disease died of emphysema.

“The overall response rate, complete response rate, and 18-month progression-free survival in the 2,000-mg obinutuzumab monotherapy arm very closely approximate that observed with the combination of obinutuzumab plus chlorambucil,” the researchers wrote. “In contrast, the 1,000-mg dose cohort of obinutuzumab monotherapy had a lower response and shorter 18-month progression-free survival than observed with the previously reported combination of obinutuzumab plus chlorambucil. Thus, these results suggest some benefit to the addition of chlorambucil for cytoreduction using the 1,000-mg dose of obinutuzumab.”

Further exploration of higher doses of obinutuzumab as part of combination therapy with chemotherapy or new targeted therapies should be considered, the authors suggested, as well as using higher doses of obinutuzumab earlier and then reducing dosing when there is significant tumor elimination. ■

Byrd JC, et al: Blood 127:79-86, 2016.


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