GA101 Shows Gains in Pivotal CLL Trial

Valentin Goede, MD

Obinutuzumab (GA101), a novel antibody that targets CD20, demonstrated a dramatic advantage in response rates when added to chlorambucil compared with the chemotherapy agent alone in elderly patients with chronic lymphocytic leukemia (CLL), investigators reported at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

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.

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.

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.By contrast, the ORR among 106 patients in the chlorambucil monotherapy group was 30.2%, with no instances of CR. The MRD-negative rate was 0% for peripheral blood (80 patients) and bone marrow (30 patients).

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.

In the area of PFS, patients who took the rituximab combination achieved an investigator-assessed median PFS of 15.7 months, versus 10.8 months for chlorambucil alone (HR = 0.32; 95% CI, 0.24-0.44; P <.0001).

In terms of safety, patients in the GA101 group did experience more adverse events (AEs) than those who took either chlorambucil alone or the rituximab combination. The rates of those exhibiting ≥3 AEs were 66.7% in the GA101 arm, compared with 41.4% in the chlorambucil-alone arm and 45.8% in the rituximab group. Overall, 19.6% of those in the GA101 arm discontinued treatment due to AEs, compared with 14.7% in the chlorambucilalone group and 13.8% in the rituximab group.

The rates were higher in the GA101 arm compared with chlorambucil alone and rituximab for neutropenia and thrombocytopenia. By contrast, the rates were higher in the chlorambucil-alone group compared with GA101 and rituximab for infection and anemia.

Notably, infusion-related reactions (IRRs) were evidenced in 21.3% of those in the GA101 group, compared with no IRRs in the chlorambucil-alone group and 4.0% in the rituximab arm, said Goede. “Virtually all of these IRRs occurred with the first infusion of GA101,” said Goede, adding that patients who are infused for the first time should be watched, but that even if an IRR occurs, he would consider readministering the drug the next day.

Reference

1. Goede V, Fischer K, Humphrey K, et al. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol. 2013;31 (suppl; abstr 7004).