In Relapsed NHL, Time to Progression Doubles when Gazyva is Added to Rituxan

Patients with relapsed indolent non-Hodgkin lymphoma who took the anti-CD20 agent Gazyva with Treanda, rather than Treanda alone, doubled their time until further disease progression during the phase 3 GADOLIN study.

Patients with relapsed indolent non-Hodgkin lymphoma (iNHL) who took the anti-CD20 agent Gazyva (obinutuzumab) with Treanda (bendamustine), rather than Treanda alone, doubled their time until further disease progression during the phase 3 GADOLIN study.

Treanda is a chemotherapy, and Gazyva is a drug that recognizes the protein CD20 expressed on the outsides of abnormal B cells that are associated with NHL, helping the immune system to kill them.

The interim Gazyva results in the GADOLIN study were so positive that the trial closed early, noted lead study author Laurie Helen Sehn, a medical oncologist at the BC Cancer Agency in Vancouver, Canada, who reported the late-breaking data at the 2015 annual meeting of the American Society of Clinical Oncology, a gathering of nearly 30,000 oncology professionals in Chicago.

The study involved patients whose disease had become resistant to Rituxan (rituximab), another anti-CD20 drug. Data showed that after a median follow-up of just over 20 months, median progression-free survival (PFS) as assessed by an independent radiology facility (IRF) — the study’s primary endpoint — was 14.9 months for patients in the Treanda-only cohort, whereas for patients in the Gazyva combination arm, median PFS had not yet been reached (hazard ratio (HR) = 0.55; P < .0001), a result indicative of a 45 percent reduction in the rate of progression with the dual therapy, Sehn reported.

“The fact that this new approach doubled average remission time marks a major step forward for our patients. Obinutuzumab may offer patients the chance to stay well for a significantly longer period of time, putting off the need for chemotherapy.”

Currently, the standard initial treatment for iNHL is a combination of chemotherapy and Rituxan, but most patients become Rituxan-resistant, leaving them few options for further treatment. Treanda is effective in these patients, but remission duration is only approximately seven to nine months.

Gazyva, which is currently approved by the U.S. Food and Drug Administration in combination with chemotherapy for patients with chronic lymphocytic leukemia, is a novel glycoengineered antibody that targets the CD20 protein located on the surface of all B cells, including B-cell lymphoma cells. Preclinical studies have suggested that when monoclonal antibodies attach to this protein, some lymphoma cells die, and others appear to become more responsive to chemotherapy.

The multicenter, open-label GADOLIN study involved 413 patients with Rituxan-refractory iNHL. Patients in the trial had various forms of NHL, the most common being follicular lymphoma.

Those randomly assigned to the experimental arm (n = 194) received Treanda (90 mg/m2 on days one and two of cycles one through six) plus six cycles of Gazyva (1,000 mg on days one, eight and 15 of cycle one, and day one of cycles two through six). Patients showing benefit from this regimen followed it with maintenance Gazyva at the same 1,000-mg dose administered once every two months for two years or until progression.

In the comparator group (n= 202), patients received six cycles of Treanda monotherapy (120 mg/m2 on days one and two of cycles one through six). The cycle length for both treatment arms was 28 days.

Patients were considered Rituxan-refractory if they did not respond to either Rituxan monotherapy or Rituxan in combination with chemotherapy, or had relapsed within six months of completion of the last dose of a Rituxan-based regimen (Rituxan monotherapy or Rituxan + chemotherapy).

Clinical characteristics across both arms of the study were comparable: Median patient age was 63 years, with a median two prior lines of therapy; approximately four months had elapsed since their last treatment. More than 90 percent of patients in each arm were refractory to their last treatment, Sehn added.

Investigator-assessed PFS was a secondary endpoint, and results were similar to those assessed through IRF: a median PFS of 29.2 months was seen with the combination versus 14.0 months in the control arm (HR = 0.52; P < .0001).

Safety was another important secondary endpoint of the study, Sehn said. Side effects of all grades and withdrawals from therapy were similar in both arms, and no new safety signals were observed.

In the Gazyva-Treanda and Treanda-only arms, the most common hematologic side effects were neutropenia (35 percent vs 29 percent) and thrombocytopenia (15 percent vs 24 percent). The most common nonhematologic side effects were infusion-related reactions (69 percent vs 63 percent), nausea (54 percent vs 61 percent), fatigue (39 percent vs 33 percent) and diarrhea (27 percent vs 30 percent).

Sehn said that the trial findings were not only statistically significant but clinically meaningful:

“This study is remarkable, because it demonstrates the first randomized evidence of a clinical benefit of a novel anti-CD20 monoclonal antibody for patients who are Rituxan-refractory.”

“It’s encouraging to see such impressive results for a novel anti-CD20 monoclonal antibody in a difficult-to-treat population …” concurred Merry-Jennifer Markham, an ASCO expert on the targeted therapies press briefing panel that announced the findings. “That this approach stalled cancer progression by more than a year will be good news for patients who urgently need additional treatment options.”

The drug’s manufacturer, Genentech, announced that it will be submitting data from this study to the FDA, the European Medicines Agency and other international health authorities for approval of Gazyva in this setting.

Gazyva also is being studied in a large clinical program, the manufacturer said, including two phase 3 studies: the GOYA trial is comparing Gazyva with Rituxan plus chemotherapy as first-line treatment for diffuse large B-cell lymphoma, and the GALLIUM trial is comparing Gazyva with Rituxan plus chemotherapy as first-line treatment in iNHL.

Genentech noted that additional combination studies are planned or underway investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, across a range of blood cancers.

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Sehn LH, Chua N, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;(suppl; abstr LBA8502).