In an interview with InFo ONCOLOGY & HEMATOLOGY, Michael Gregor, MD, of Lucerne Cantonal Hospital, talks about the CLL11 trial. It addresses the study population, the most relevant results, and the safety profile of the drugs studied.
Dr. Gregor, how does the CLL11 study differ from other chronic lymphocytic leukemia studies (e.g., in terms of study population)?
Dr. Gregor:
The CLL11 trial is the largest randomized phase III trial to date for CLL patients with comorbidities. The median age of the 780 patients studied was 73 years. The patient population of the CLL11 study is more similar to the typical CLL patient in practice than most previous studies, which predominantly considered younger “fit” patients.
Which results of the CLL11 study do you personally consider to be the most relevant?
The benefit of adding a CD20 antibody to previously used chemotherapy with chlorambucil was impressive in terms of response and progression-free survival. The difference between the two chemoimmunotherapy arms was surprisingly large. Progression-free survival with the combination of chlorambucil and rituximab was 15.2 months, compared with 26.7 months with the combination of chlorambucil and obinutuzumab. A surprising effect was the prolongation of overall survival with the combination of chlorambucil and obinutuzumab compared with the previous standard chemotherapy with chlorambucil in this early analysis after an observation period of almost two years.
What concrete value could the results have for clinical practice in Switzerland in the longer term, or for which patients could obinutuzumab be considered as a supplement to chlorambucil (GClb) in the future in your opinion?
I expect the combination of chlorambucil and a CD20 antibody to become the new standard for CLL patients with more severe comorbidities as early as 2014. To date, only a difference in progression-free survival has been demonstrated between the combination with rituximab and obinutuzumab. If in future analyses the advantage for obinutuzumab continues to increase or if there is even a better overall survival, the combination of chlorambucil and obinutuzumab will very soon become the preferred therapy for most CLL patients with comorbidities.
How do you assess the safety profile of the two compared combinations (obinutuzumab plus chlorambucil/rituximab plus chlorambucil)?
Grade ≥3 adverse events were observed more frequently with the combination of chlorambucil and obinutuzumab than with chlorambucil and rituximab (70% vs. 55%). These were most commonly infusion reactions, which usually occurred only on the first infusion, and neutropenias and thrombocytopenias. In contrast, the infection rate was the same in both study arms with chemoimmunotherapy as with chlorambucil monotherapy. Prophylaxis and therapy of common infusion reactions will be important for use in clinical practice.
What can be said about the dosage, did the GClb dosage chosen in the study prove appropriate, and what contribution did it make to the results?
The infusion regimen and dosing of obinutuzumab were derived from pharmacologic studies. With the regimen used and the significantly higher antibody dose compared with rituximab, the combination of chlorambucil and obinutuzumab was clearly superior to chlorambucil and rituximab. I think, however, that the large difference between the study arms cannot be explained by this alone. Obinutuzumab has significantly increased antigen-mediated cellular toxicity in vitro and greater direct cytotoxicity than rituximab, both of which may lead to the higher efficacy observed in the study.
Interview: Andreas Grossmann
InFo Oncology & Hematology 2014; 2(3): 2-3.
