Obinutuzumab potentially practice-changing therapy
February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology - Leukemia
Wayne Kuznar

New Orleans, LA—The role of anti-CD20 antibodies in unfit patients with chronic lymphocytic leukemia (CLL) was discussed in several presentations at ASH 2013. Elderly and unfit patients constitute the majority of patients with CLL, but these groups have limited treatment options. Re­sults of 2 recent studies suggest that anti-CD20 antibodies provide promising alternatives to the current standard in this patient population.

Obinutuzumab Superior to Rituximab in Unfit Patients
In November 2013, the US Food and Drug Administration approved obinutuzumab (Gazyva), a novel, glycoengineered, type II CD20 antibody, for use in combination with chlorambucil (Leukeran) for the treatment of patients with previously untreated CLL.

Valentin Goede, MD, Hematologist/Oncologist, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Germany, presented up­dated results with this drug at the meeting. Obinutuzumab, in combination with chlorambucil, was superior to rituximab (Rituxan) plus chlorambucil in prolonging progression-­free survival (PFS) in previously untreated patients with CLL with comorbidities.

Treatment with obinutuzumab also led to a significantly higher objective response rate, and more patients treated with obinutuzumab were negative for minimal residual disease (MRD) in the bone marrow and blood, announced Dr Goede.

These findings “mean a significant and potentially practice-changing treatment advance for this large patient population,” said Dr Goede. “What we currently know is if we combine obinutuzumab or rituximab with a weaker chemotherapy backbone, obinutuzumab is obviously superior to rituximab, so in this setting I would say that it will substitute for rituximab…at least in the population of elderly patients.”

In the CLL11 trial, 781 patients with CLL complicated by comorbidities were randomized to 1 of 3 first-line regimens: chlorambucil alone, chlor­ambucil plus rituximab, or chlorambucil plus obinutuzumab. The results from the first stage of CLL11 were reported previously, and showed that obinutuzumab plus chlorambucil and rituximab plus chlorambucil were each associated with significantly better PFS than chlorambucil alone.

In the updated results presented at the meeting, compared with chlorambucil alone, the risk of disease progression or death was improved by 82% with obinutuzumab (P <.001). The median PFS was 26.7 months with the combination. Rituximab plus chlorambucil produced a 66% reduction in the risk of progression or death, and a 16.3-month median PFS. Overall survival (OS) was also superior with obinutuzumab, with a hazard ratio for death of 0.41 (P = .002).

The second-stage analysis was a head-to-head comparison of the 2 combination regimens. The median PFS with obinutuzumab plus chlor­ambucil was 26.7 months versus 15.2 months (P <.001) with rituximab plus chlorambucil, corresponding to a 61% (11.5 months) reduction in risk with the addition of obinutuzumab.

Complete responses were achieved in 21% of patients in the obinutuzumab arm versus 7% of patients in the rituximab arm. Each group had a partial response rate of 58%. The overall response rate was 78% with obinutuzumab and 65% with rituximab (P <.001).

Some 19.5% of patients in the obinutuzumab arm were MRD negative for bone marrow versus 2.6% of the rituximab group (P <.001). A total of 37.7% of patients in the obinutuzumab arm versus 3.3% of patients in the rituximab arm were MRD negative in blood.

After a median follow-up of approximately 19 months, survival still favors obinutuzumab in the head-to-head comparison with rituximab (P = .0849); however, the data for survival remain immature, with fewer than 15% of events included in the analysis, said Dr Goede.

More grade ≥3 adverse events (AEs) were reported with obinutuzumab plus chlorambucil than with rituximab plus chlorambucil (70% vs 55%, respectively). Infusion-related reactions (20% vs 4%, respectively) and thrombocytopenia (10% vs 3%, respectively) were more frequent in the obinutuzumab arm.

Ofatumumab Improves Outcomes, OS, in Elderly Patients When added to chlorambucil (Leukeran), ofatumumab (Arzerra), a second-generation fully humanized monoclonal antibody against the CD20 protein, improves clinical outcomes and is tolerable irrespective of age and fitness in patients with previously untreated CLL who are considered inappropriate for fludarabine (Fludara), according to the results of a phase 3 study.

In older patients with CLL who are unfit for the gold standard therapy with fludarabine/cyclophosphamide/ rituximab, chlorambucil, using various dosing schedules, remains a treatment option, said lead investigator Peter Hillmen, MB ChB, PhD, Honorary Consultant Hematologist, St James’s University Hospital, United Kingdom.

Ofatumumab has a discrete epitope that targets the small and large extracellular loops of CD20. In vitro, it displays more activity than rituximab through complement and through antibody-dependent cellular cytotoxicities.

In the phase 3 COMPLEMENT 1 study, 447 patients with previously untreated CLL who were considered inappropriate for fludarabine-based therapy because of advanced age and/or comorbidities were randomized to chlorambucil or ofatumumab plus chlorambucil until best response. Ofatumumab was given as an intravenous infusion for a maximum of 12 cycles. Chlorambucil was dosed orally at 10 mg/m2 on days 1 through 7 of each 28-day cycle.

Approximately 25% of the patients were aged >75 years. In each group, 87% of patients were aged ≥65 years or had ≥2 comorbidities or a creatinine clearance <70 mL/min, and were thus ineligible for fludarabine, said Dr Hillmen.

In each arm, 19% of the patients required a dose reduction of chlorambucil because of neutropenia. After a median follow-up of 28.9 months, PFS was 22.4 months in the arm receiving ofatumumab plus chlorambucil compared with 13.1 months in the arm receiving chlorambucil alone, corresponding to a 43% improvement with ofatumumab (P = .001).

OS was significantly superior in the ofatumumab arm versus the chlorambucil alone arm (82% vs 69%, respectively; P <.001), as was the rate of complete response (14% vs 1%, respectively). The median OS was not reached in either arm.

Of patients receiving ofatumumab plus chlorambucil, 12% showed no MRD compared with 4% of patients receiving chlorambucil alone.

There was a trend toward a shorter time to response with ofatumumab plus chlorambucil versus chlorambucil alone (P = .084). The median duration of response was longer in the ofatumumab plus chlorambucil arm at 22.1 months versus 13.1 months (P <.001) in the chlorambucil alone arm. The time to next treatment was also significantly longer in the patients receiving ofatumumab plus chlorambucil versus in the patients receiving chlorambucil alone (median, 39.8 months vs 24.7 months, respectively; P <.001).

More than 80% of the patients completed at least 6 cycles. Combination treatment was well tolerated. The rate of withdrawal as a result of AEs was 13% in each arm. The rate of grade ≥3 AEs was 50% with ofatumumab plus chlorambucil versus 43% with chlorambucil alone. In the ofatumumab plus chlorambucil arm, 10% of patients had grade ≥3 infusion reactions. There was a higher rate of grade ≥3 neutropenia in patients assigned to ofatumumab plus chlor­ambucil compared with chlorambucil alone (26% vs 14%, respectively), but this difference did not translate into a higher risk of infection, said Dr Hillmen.

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