GA101 Shows Gains in Pivotal CLL Trial
Published Online: Friday, July 26, 2013
Valentin Goede, MD
The agent also delivered higher response rates than rituximab (Rituxan) plus chlorambucil did in the same population, although full data comparing the two antibodies in a head-to-head stage of the phase III study are not yet mature, researchers indicated.
The FDA has designated GA101 as a breakthrough therapy and has granted the drug priority review status in CLL, with an action date of December 20, according to Genentech, a member of the Roche Group. A new drug application also is pending in Europe.
Overall, the GA101 combination regimen more than doubled median progression-free survival (PFS), the primary endpoint of the trial, to 23.0 months compared with 10.9 months for chlorambucil alone, resulting in an 86% reduction in the risk of progression (hazard ratio [HR] = 0.14; 95% confidence interval [CI], 0.09-0.21; P <.0001).
The PFS for the GA101 arm is likely to increase with longer follow-up time, said lead investigator Valentin Goede, MD, of the Department of Internal Medicine I, Center of Integrated Oncology Cologne- Bonn, University Hospital Cologne, Germany.
In addition to the results, the CLL11 study is noteworthy because it is the first pivotal trial conducted in a large population of previously untreated older adults with comorbidities typically seen in practice, said Goede. He said the median age ranged from 72 to 74, with up to 45% of patients ≥75 years, depending on the cohort. Participants had a median ≥3 comorbidities, which typically included hypertension, coronary heart disease, diabetes, and renal impairment.
“In real life, many of your CLL patients are elderly and have concurrent health problems,” Goede told attendees during his presentation at the ASCO meeting in June.
GA101 targets CD20 proteins commonly expressed on the surface of B cells, as does rituximab. However, GA101 is a type II anti-CD20 monoclonal antibody with a glycoengineered Fc region that has demonstrated in preclinical studies increased cell-killing capacity with a lower complement cytotoxicity than rituximab, said Goede.
In the international CLL11 study, approximately 780 patients are being randomized 1:2:2 to receive six cycles every 28 days of chlorambucil, chlorambucil plus GA101, or chlorambucil plus rituximab (Figure).
Goede reported PFS results based on the number of enrolled patients: 118 in the chlorambucil group, 238 in the GA101 arm, and 233 in the rituximab group. An additional 190 patients will be included in the stage II results.
In stage IA of the two-stage study at the cutoff time, the overall response rate (ORR) among 212 patients in the GA101 arm was 75.5%, including 22.2% who exhibited a complete response (CR). Moreover, the minimal residual disease (MRD)-negative rate among patients assessed in that area was 31.1% (41 of 132 patients) in peripheral blood and 17.0% (15 of 88 patients) in bone marrow.
Figure. CLL11 Study Design and Stage I Results1
aBased on number of enrolled patients
CIRS indicates Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; PFS, progression-free survival.
Results for stage IA were reported after a median observation time of 14.5 months for the GA101 arm and 13.6 months for the chlorambucil-only group, and a data cutoff of July 11, 2012. In stage IB at cutoff, the same patients who took chlorambucil alone were compared with 230 patients who took rituximab plus chlorambucil. (Three enrolled patients were not treated). The observation times were six months longer than in state IA for the chlorambucil arm and eight months longer in the rituximab arm, with a data cutoff of August 10, 2012.
In the rituximab group at cutoff, the ORR was 65.9% among 217 patients, with a CR of 8.3%. The MRD-negative rate was 2.0% (3 of 150 patients) for peripheral blood and 2.8% (2 of 72 patients) for bone marrow. By contrast, the response rate for 110 patients who took chlorambucil was 30.0%, with no MRD-negative patients.
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