Carlson, Robert H.
NEW ORLEANS—The question in the chronic lymphocytic leukemia (CLL) arena today is not whether rituximab will be replaced, experts say, but rather when, and with what.
One contender certainly will be obinutuzumab (GA101), the subject of a plenary session report here at the American Society of Hematology Annual Meeting (Abstract 6). Valentin Goede, MD, Clinical Scientist in the Department of Internal Medicine and Center of Integrated Oncology at the University of Cologne in Germany, reported for the German CLL Study Group the final stage 2 analysis of CLL11, a Phase III study comparing the anti-CD20 antibody rituximab used with chlorambucil versus the anti-CD20 antibody obinutuzumab used with chlorambucil.
The median age for the 781 previously untreated patients in the study, all of whom had comorbidities, was 73, their median Cumulative Illness Rating Scale (CIRS) score was 8; and median creatinine clearance (CrCl) at baseline was 63 mL/min, thus reflecting the typical CLL patient population, Goede said.
He reported that the combination of obinutuzumab-chlorambucil demonstrated a statistically significant and clinically meaningful prolongation of progression-free survival (PFS), and higher complete response rate, and minimal residual disease (MRD) negativity rate compared with rituximab-chlorambucil.
An earlier stage 1 analysis of CLL11 showed that obinutuzumab-chlorambucil prolonged overall survival compared with use of chlorambucil alone.
There were more adverse events in the chlorambucil-obinutuzumab arm, due mainly to an increased rate of infusion-related reactions, 20 percent versus four percent for rituximab-chlorambucil, but there was no increase in infections, he reported.
“Importantly, these reactions occurred exclusively in the first infusion of the antibody and not during subsequent infusions,” he said, adding that vigilance appeared to be the key to increasing safety.
The trial was sponsored by Hoffmann-La Roche.
Responses Favor Obinutuzumab
The overall response rates were 78 percent for the 333 patients in the obinutuzumab-containing arm and 65 percent for the 329 patients in the rituximab-containing arm; complete remission rates were 21 percent vs. seven percent, respectively; and partial remission rates were the same, at 58 percent in each arm.
Negative MRD rates were significantly higher in the obinutuzumab arm—19.5 vs. 2.6 percent in the bone marrow; and 38 vs. 3.3 percent in blood.
Median progression-free survival was 26.7 months vs. 15.2 months, respectively.
While overall survival has not been reached for either monoclonal antibody arm, both were reported as being superior to chlorambucil alone, in a presentation of CLL11 stage 1 data a few months earlier at the ASCO Annual Meeting.
“The new data presented here demonstrate the feasibility of enrolling patients into clinical trials that better reflect the age group of patients with this disease,” Goede said.
The results of the CLL11 trial along with other data led to the FDA approval in November of obinutuzumab (Gazyva), used in combination with chlorambucil, in patients with previously untreated CLL—which was the first approved drug that had previously received the agency's Breakthrough Therapy designation (OT 12/10/13 issue).
VALENTIN GOEDE, MD
Results Translate to Clinic
Asked for his opinion, John C. Byrd, MD, Chair of Leukemia Research, Director of the Division of Hematology, and Professor of Medicine and Medical Chemistry at Ohio State University Comprehensive Cancer Center, called CLL11 “a phenomenal effort, a paradigm-changing study.”
Byrd, who was not involved in the study, said CLL11 “shows for the first time in a randomized trial that by adding a therapeutic antibody, obinutuzumab, to low-dose chlorambucil, there is improvement in response and progression-free survival. But most importantly, the trial demonstrated a survival advantage in elderly, unfit patients where no therapy before this has demonstrated a survival advantage. For a person in practice, this will immediately translate to use of chlorambucil combined with obinutuzumab versus rituximab.”
This is the first trial with any agent that's been shown to extend survival in CLL, Byrd said, and while the follow-up is still short, he thought it likely the difference over time will increase.
“We gain something—survival, response—but what are we giving up, what about the toxicity?,” he continued. “We do see more neutropenia with obinutuzumab, although it doesn't equate to infections like with chemotherapy, and the frequency between the different arms of the study was similar.” There were also more infusion reactions that can sometimes be severe with the first administration of obinutuzumab.
“It's going to be important in that first dose to watch the patient more carefully—the infusion side effects with obinutuzumab are different than with rituximab or other antibodies,” he continued. “They occur relatively quickly—they can occur within the first 30 minutes, whereas with the regular antibodies they occur after two hours.”
If obinutuzumab is being used in a small community practice with no opportunity for very close monitoring, Byrd advised administering the drug in an ambulatory care setting.
Goede, in a news conference at the meeting before his formal presentation of the data, was asked whether obinutuzumab would replace rituximab. He said that in the CLL11 setting of patients who are older or frail, obinutuzumab combined with a weaker chemotherapy such as chlorambucil could replace rituximab—“But it is not known whether this would be true in younger patients, who could tolerate a stronger chemotherapy regimen.”
The moderator of the news conference, Jennifer Brown, MD, PhD, Director of the CLL Center at Dana-Farber Cancer Institute, agreed with Goede. But she added that until CLL11, there had been skepticism that any CD-20 antibody could beat rituximab in a head-to-head study, “so the CLL11 data were very important in expectations for new anti-CD-20 agents.”
Byrd, in his interview, said that the clinical data for ofatumumab do suggest it is superior to rituximab, but the driving question in the field will be whether obinutuzumab is better than yet another monoclonal CD-20 antibody, ofatumumab.
Ofatumumab has been approved by the FDA for the treatment of CLL refractory to fludarabine and alemtuzumab.
“Obinutuzumab is going be a game changer for the CD-20 antibodies,” Byrd said, “but the real question will be which new agent will replace rituximab.”
Byrd said trials of ofatumumab had very similar results to the CLL11 study in response rates and progression-free survival, compared with chlorambucil alone. The ofatumumab study was not powered to identify a survival advantage, however, and one has not emerged. “So you have two antibodies, obinutuzumab and ofatumumab, that both look better for CLL when combined with chlorambucil than chlorambucil alone, and the question is, which one is better?”
A comparative trial would answer that, but Byrd speculated that with obinutuzumab and ofatumumab—as with the big debate with decitabine and 5-azacytidine in myelodysplastic syndromes—there likely won't be a randomized trial.
“People will probably more often go with the therapy that prolongs survival, so we'll have to see how that unfolds. But who would have thought three to five years ago at ASH we'd be talking about shelving rituximab for two new antibodies, and that we'd have the pleasure of debating which is going to be a better therapy than rituximab for CLL?”
He added that, hopefully, new studies coming forward are going to “dial chlorambucil out.” He said, “There are a lot of oral agents that could replace chlorambucil, like the BTK inhibitor ibrutinib, or PI3 kinase inhibitors like idelalisib. And ABT199 is already in a Phase I/II study combined with obinutuzumab.”
Treatment of Choice for Elderly
The speaker invited to introduce Goede in the plenary session, John G. Gribben, MD, Consultant Medical Oncologist and Professor of Experimental Cancer Medicine at Barts and the London School of Medicine, said the CLL11 results establish chlorambucilobinutuzumab as the new standard for the older and less fit CLL patient population.
“In studies of CLL, as in many other maladies, patients are often excluded on the basis of being more elderly and/or suffering from comorbidities. “This makes it difficult for the practicing oncologist to extrapolate from clinical trials the knowledge to apply to all the patients they face.”
“This has not mattered for many years before, when we had so few new therapies.”
Gribben applauded the German CLL Study Group for using the Systemic Inflammatory Response Syndrome score and the Cumulative Illness Rating Score as objective measures for assessing patients who would not be considered fit for standard chemotherapy.
“It's particularly appropriate that Dr. Goede is not only an oncologist but also a geriatrician, making him extremely qualified to be thinking about ways in which we can address these very issues,” Gribben said.
He noted that even though the CLL11 researchers selected clinical trial features that might make it more difficult for patients to travel to centers to take part in the study, they were able to demonstrate a very rapid accrual “to what everyone felt would be a very difficult-to-enroll population.”
The results have defined chemo-immunotherapy as the treatment of choice for all patients with CLL, and not just those who are fit to receive cytarabine and cyclophosphamide.
“The data have also suggested that the achievement of complete remission and the eradication of residual disease may be an appropriate goal of therapy for this patient population, rather than simply palliation, as in the past.”
In a video on the iPad edition of this issue, Valentin Goede, MD, also spoke to OT reporter Dan Keller, elaborating on the clinical implications of his research.
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