Obinutuzumab's Benefit in iNHL Unclear After GAUSS Results Published

Lauren H. Sehn, MD

The anti-CD20 agent obinutuzumab (Gazyva) improved overall response and had acceptable toxicity compared with rituximab (Rituxan) in patients with relapsed indolent non-Hodgkin Lymphoma (iNHL), according to the final results from the GAUSS study published in the Journal of Clinical Oncology. However, the higher response did not result in an improvement in progression-free survival (PFS), leaving the role of obinutuzumab unclear in this setting.

Contrary to the GAUSS data, the phase III CLL11 study showed a PFS benefit with obinutuzumab in iNHL. In CLL11, combination therapy with obinutuzumab (Gazyva) and chlorambucil lead to an unprecedented improvement in PFS compared with rituximab plus chlorambucil as a frontline treatment for patients with chronic lymphocytic leukemia (CLL). Obinutuzumab plus chlorambucil is approved by the FDA as a first-line treatment for patients with CLL, based on data from CLL11.

In their conclusion, the GAUSS authors suggested possible explanations for the PFS discrepancies between the trials, including the limited benefit of single-agent therapy in a heavily pretreated, relapsed population and the potential synergistic effect that may occur when including obinutuzumab in a chemoimmunotherapy regimen.

The authors are hoping to gain clarity from the ongoing GADOLIN and GALLIUM trials. Interim results from the GADOLIN trial presented at ASCO 2015 showed a doubling of PFS in patients with rituximab-refractory, relapsed indolent non-Hodgkin lymphoma treated with obinutuzumab plus bendamustine versus bendamustine alone. The GALLIUM trial is comparing obinutuzumab plus chemotherapy followed by maintenance obinutuzumab with rituximab plus chemotherapy followed by maintenance rituximab in treatment-naïve patients with iNHL.

The GAUSS study, which took place between July 2009 and August 2010, examined 175 patients with relapsed CD20-postive indolent lymphoma with previous response to a rituximab-containing regimen. Patients were accrued from 74 sites across 15 countries and were randomly assigned to receive four once-per-week infusions of either obinutuzumab (1000 mg) or rituximab (375 mg/m²). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years.

The primary endpoint was investigator-assessed ORR to induction treatment in the follicular lymphoma population. Secondary endpoints included ORR in the non-follicular lymphoma population, complete response (CR) and partial response rates, progression-free survival (PFS), and safety.

ORR in the 149 patients with follicular lymphoma included in the study was 44% in the obinutuzumab arm versus 33% in the rituximab arm (P = .08), when assessed by study investigators. In a blinded independent review panel, ORR was 44.6% for obinutuzumab compared with 26.7% for rituximab (P = .01). At the end of induction, 6 patients in the obinutuzumab arm and 3 in the rituximab arm had progressive disease.

A total of 12.2% of patients (n = 9) in the obinutuzumab arm achieved CR compared with 5.3% (n = 4) in the rituximab arm. These results were not statistically significant.

Among patients with follicular lymphoma, the median follow-up period was 32 months (range, 0.1-43 months). No difference in PFS was observed between the two arms (HR, 0.93; 95% CI, 0.60-1.44). The 2-year PFS was 45.8% (95% CI, 33.5%-57.3%; median PFS, 17.6 months) for obinutuzumab and 50.3% (95% CI, 37.7%-61.6%; median PFS, 25.4 months) for rituximab.

Of the 26 patients without follicular lymphoma included in the study, ORR and CR rates were also higher for obinutuzumab versus rituximab. ORR was 43% (n = 6) in the obinutuzumab non-follicular indolent lymphoma patients who received obinutuzumab compared with 17% (n = 2) in the rituximab arm.

For the most part, toxicities were similar across both the rituximab and obinutuzumab arms. However, a higher rate of infusion-related reactions occurred in the obinutuzumab versus the rituximab arms, with 74% versus 51% of patients experiencing the reactions, respectively. There was also a higher rate of cough in the obinutuzumab arm, with 24% of patients experiencing cough after treatment with the drug versus 9% in the rituximab arm.

Twenty-six patients (15% in each arm) experienced serious adverse events (AEs). Eighteen patients in the obinutuzumab arm and 11 patients in the rituximab arm died during the study. Of these, 15 deaths were a result of disease progression (10 patients in the obinutuzumab arm and 5 patients in the rituximab arm).

Sehn L, Goy A, Offner F. Obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study [published online August 17, 2015]. J Clin Oncol. doi: 10.1200/JCO.2014.59.2139.