New Drug Combo Potentially 'Practice Changing' in CLL

Roxanne Nelson

December 08, 2013

NEW ORLEANS — More clinical details have been reported showing how the new monoclonal antibody obinutuzumab (Gazvya, Roche) was superior to the stadard therapy rituximab (Rituxan, Roche) when both were used in combination with chlorambucil in the treatment of chronic lymphocytic leukemia (CLL). Obinutuzumab was approved by the US Food and Drug Administration (FDA) last month for use in treatment-naive CLL.

New data presented here at the American Society of Hematology (ASH) 55th Annual Meeting come from a study of older CLL patients with comorbidities; they show that obinutuzumab with chlorambucil was associated with a higher complete response rate and longer progression-free survival as compared with rituximab and chlorambucil.

"I think this is a potential practice-changing treatment for this population," said study author Valentin Goede, MD, of University Hospital Cologne in Germany, during a press briefing. "While we will continue to evaluate these results through a longer follow-up period, these findings suggest that obinutuzumab has the potential to eventually replace rituximab for the care of CLL patients."

As a first-line therapy for older CLL patients with comorbidities, who are the typical CLL patients seen in daily clinical practice, this combination has an acceptable safety profile and prolonged overall survival, explained Dr. Goede. "It was superior to rituximab plus chlorambucil."

But as for whether or not obinutuzumab will replace rituximab in CLL, Dr. Goede noted that that is a "difficult question to address."

Importance of Study

An important aspect of this study is that it demonstrates the feasibility of enrolling patients into clinical trials who better represent the population that physicians are actually dealing with, said John Gribben, MD, DSc, from Barts Cancer Institute in London, United Kingdom. It also reflects the age group of patients with this disease.

"There was very rapid accrual of what everyone felt would be a very difficult population," noted Dr. Gribben, who introduced the study during the plenary session. "When we are looking to enroll patients in studies, very often elderly patients with comorbidities are exclude."

Thus, it can be difficult for physicians to extrapolate information from studies and apply it to the CLL patients they are seeing in their practice.

"It wasn't that important previously, because there were so few therapies in CLL," Dr. Gribben said. The paradigm has changed and exciting new agent are emerging, he noted.

There is a need for tools to assess comorbidities in these patients, so that the most appropriate treatment decisions can be made. "Treatment should not be withheld on the basis of age alone," he said.

This study establishes chemotherapy as the treatment of choice for all CLL patients, and established obinutuzumab and chlorambucil as the new control for the less fit patient population. "I also believe we can look forward to results of this newly approved monoclonal antibody in combination with targeted agents," said Dr. Gribben.

"We know that in this setting [ie, in older patients with comorbidities], it is superior to rituximab, and I think it will replace rituximab, but it is difficult to estimate that for younger patients," he said. In younger patients, rituximab is combined with much more aggressive chemotherapy backbones, "and we know that these treatment are very effective," he said.

"We don't know how much obinutuzumab adds to the efficacy when replacing rituximab in these patients," he continued, "so we can't say anything for these patients."

Prolonged Survival

Dr. Goede presented the results from the trial, known as CLL11, during the plenary session here. Top-line results have already been made public. A preplanned interim analysis showed that the primary endpoint was met early, and the results were released by the independent data monitoring board.

The trial was conducted in 781 patients with average age of 73 years. Patients were randomly assigned into 3 treatment arms: chlorambucil alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), obinutuzumab plus chlorambucil (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or rituximab plus chlorambucil (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Median follow-up was 19 months.

Almost 40% of the patients were older than 75 years, and they presented with a variety of comorbidities, said Dr. Goede. "They had typical comorbidities that a doctor would see in this population, such as hypertension, coronary artery disease, and pulmonary disease like COPD [chronic obstructive pulmonary disease], diabetes, and musculoskeletal disorders."

He added that the patients were also taking medications for these conditions.

The results showed that when combined with chlorambucil, obinutuzumab demonstrated more antileukemia activity than rituximab. Overall survival data is still maturing (hazard ratio [HR], 0.66; P = .0849), and there was a statistically significant and clinically meaningful prolongation of the median progression-free survival: 27 months with obinutuzumab vs 15 months with rituximab. There was also a higher overall response rate (78% vs 65% ).

When looking at minimum residual disease (MRD), the number of patients with negative blood samples at end of treatment was more than 10-fold higher with obinutuzumab compared with rituximab (MRD in bone marrow, 19.5% vs 2.6%; and in blood, 37.7% vs 3.3%).

There was a higher rate of grade 3-5 adverse events in the obinutuzumab arm (70% vs 55%), particularly for infusion-related reactions (20% vs 4%). However, the authors note that grade 3-4 infusion-related reactions with obinutuzumab occurred at first infusion only.

Need for Safer and More Effective Agents

"There are several new anti-CD20 monoclonal antibodies in development, to build on the success of rituximab," commented Saad Usmani, MD, who was approached by Medscape Medical News for independent commentary.

"The goal has always been to develop more effective and safer anti-CD20 monoclonal strategies, so this study is certainly encouraging in terms of its results," said Dr. Usmani, who is director of the plasma cell disorders program and director of clinical research in hematologic malignancies at the Levine Cancer Institute/Carolinas Healthcare System, Charlotte, North Carolina. "It may well be practice changing."

The issues of concern, he noted, would be cost, and it does take time for physicians to become more comfortable with new drugs. "So I think it would take a year or 2 before it starts to be used in clinical practice," Dr. Usmani said. "It would be important also to educate physicians on the difference between the monoclonal antibodies and why it would make sense to use one vs the other."

The study was funded by Roche.

American Society of Hematology (ASH) 55th Annual Meeting: Abstract 6, presented December 8, 2013.

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