Obinutuzumab is a type II, glycoengineered, humanized anti-CD20 monoclonal antibody. In the phase II GAUGUIN studies reported in the Journal of Clinical Oncology by Franck Andre Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille and Gilles A. Salles, MD, PhD, of Hospices Civils de Lyon–Université de Lyon and their colleagues, obinutuzumab exhibited encouraging clinical activity and an acceptable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma or mantle cell lymphoma and in patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL).

Study in Aggressive NHL

In the study by Dr. Morschhauser and colleagues,¹ 40 patients with relapsed/refractory diffuse large B-cell lymphoma (n = 25) or mantle cell lymphoma (n = 15) were randomly assigned to receive eight 21-day cycles of obinutuzumab infusion as a flat dose of 400 mg on days 1 and 8 of cycle 1 and day 1 of cycles 2 to 8 (400/400-mg group, n = 21) or 1,600 mg on days 1 and 8 of cycle 1 and 800 mg on day 1 of cycles 2 to 8 (1,600/800-mg group, n = 19). The 400/400-mg group consisted of 10 patients with diffuse large B-cell lymphoma and 11 with mantle cell lymphoma, and the 1,600/800-mg group consisted of 15 with diffuse large B-cell lymphoma and 4 with mantle cell lymphoma. Thirteen patients (62%) in the 400/400-mg group and 12 (63%) in the 1,600/800-mg group had rituximab (Rituxan)-refractory disease.

Responses

The response rate at the end of treatment was 28%, including 32% in the 1,600/800-mg group and 24% in 400/400-mg groups. Best overall response rates were 37% in the 1,600/800-mg group and 24% in the 400/400-mg group. Responses were observed in 32% of patients with diffuse large B-cell lymphoma and in 27% of patients with mantle cell lymphoma, including 2 of 4 with mantle cell lymphoma in the 1,600/800-mg group. Five of 25 rituximab-refractory patients exhibited response, including 4 of 12 in the 1,600/800-mg group.

Overall, the median response duration was 9.8 months and > 6 months in rituximab-refractory patients. Median progression-free survival was 2.7 months (range, 0.2–32.7 months) in the 1,600/800-mg group and 2.6 months (range, 0.3–32.7 months) in the 400/400-mg group.  

Toxicity

The most common adverse events were infusion-related reactions (75% of patients), which were considered manageable. The most common grade 3 or 4 adverse events were lymphopenia (15%; 14% in the 400/400-mg group and 16% in 1600/800-mg group), anemia (10%; 14% and 5%), infusion-related reactions (8%; 10% and 5%), and thrombocytopenia (8%; 10% and 0%). Grade 3 or 4 tumor lysis syndrome occurred in two patients in the 400/400-mg group. Grade 3 or 4 neutropenia occurred in one patient. There were no treatment-related deaths.

Study in Indolent NHL

In the second study by Dr. Salles and colleagues,² 40 patients with relapsed/refractory indolent NHL, including 34 with follicular lymphoma, were randomly assigned to the 1,600/800-mg (n = 22, 20 with follicular lymphoma) or 400/400-mg (n = 18, 14 with follicular lymphoma) obinutuzumab regimens described above. Rituximab-refractory disease was present in 12 (67%) of the 400/400-mg patients and 10 (45%) of the 1,600/800-mg patients. 

Responses

Response rates at the end of treatment were 55% in the 1,600/800-mg group and 17% in the 400/400-mg group, including response in 5 of 10 rituximab-refractory patients in the 1,600/800-mg group and 1 of 12 in the 400/400-mg group. Best overall response rates were 64% in the 1,600/800-mg group and 33% in the 400/400-mg group. Among patients with follicular lymphoma, response rates at the end of treatment were 50% in the 1,600/800-mg group and 21% in the 400/400-mg group, with best overall response rates of 60% and 36%, respectively.

The median response duration was 17.2 months (range, 0.8–31.3+ months) in all responders and 8.8 months in rituximab-refractory patients. Median progression-free survival was 11.9 months in the 1,600/800-mg group (range, 1.8–33.9+ months) and 6.0 months in the 400/400-mg group (range, 1.0–33.9+ months).

Toxicity

The most common adverse events were infusion-related reactions (73% of patients), with two patients (9%) in the 1600/800-mg group having grade 3 or 4 reactions. Overall, grade 3 or 4 adverse events occurred in four patients (22%) in the 400/400-mg group and nine patients (41%) in the 1,600/800-mg group. Other grade 3 or 4 adverse events occurring in more than one patient were infection, lymphopenia, and neutropenia. No deaths occurred during treatment. 

Based on the encouraging activity observed in these studies and pharmacokinetic modeling, a simplified schedule using obinutuzumab 1,000 mg for all cycles, with doses on days 1, 8, and 15 of cycle 1, has been moved forward to phase III studies in both aggressive and indolent NHL. ■

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

References

1. Morschhauser FA, Cartron G, Thieblemont C, et al: Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. July 8, 2013 (early release online).

2. Salles GA, Morschhauser F, Solal-Céligny P, et al: Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: Results from the phase II GAUGUIN study. J Clin Oncol. July 8, 2013 (early release online).