Roche's Obinutuzumab Gains NMPA Approval in China for Two Follicular Lymphoma Indications

Source: PharmaCube Info

On June 3, obinutuzumab, Roche's next-generation anti-CD20 monoclonal antibody, officially received marketing approval from the NMPA, with two indications approved simultaneously: ① obinutuzumab in combination with chemotherapy, followed by obinutuzumab maintenance therapy, for the treatment of treatment-naïve patients with follicular lymphoma; and ② obinutuzumab in combination with bendamustine, followed by obinutuzumab maintenance therapy, for patients with follicular lymphoma (FL) who are refractory to or experience disease progression during or after treatment with rituximab or a rituximab-containing regimen.

Follicular lymphoma (FL) is a classic indolent non-Hodgkin lymphoma (NHL) originating from B lymphocytes. It is the second most common form of NHL, accounting for approximately 17% of all NHL cases.

CD20 is a transmembrane phosphoprotein located on the surface of B lymphocytes. B lymphocytes differentiate from pluripotent stem cells in the bone marrow, and their development progresses through several stages: pro-B cells, pre-B cells, immature B cells, and mature B cells. Mature B cells are released into lymphoid tissues, where they can further differentiate into plasma cells. As a B cell surface antigen, CD20 is expressed from the pre-B cell stage through the mature B cell stage; however, CD20 is not expressed on hematopoietic stem cells, pro-B cells, or mature plasma cells.

In addition to its expression in normal B cells, CD20 is also expressed on tumor cells of B-cell-derived lymphomas and leukemias, as well as on B cells involved in immune and inflammatory diseases. Therefore, the CD20 antigen has become a therapeutic target for the treatment of lymphomas, leukemias, and certain autoimmune diseases.

CD20 monoclonal antibodies developed to date are classified into Type I or Type II based on their binding mode to CD20 and their primary mechanisms for killing CD20-positive cells. Type I CD20 mAbs primarily kill tumor cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), but do not induce direct cell death; whereas Type II CD20 mAbs primarily induce direct cell death by directly activating intracellular death signaling pathways, participate in ADCC or antibody-dependent cellular phagocytosis (ADCP), but do not mediate CDC.

Since their introduction, anti-CD20 monoclonal antibody drugs have undergone a series of optimizations and improvements. The first generation is represented by rituximab, a chimeric mouse-human monoclonal antibody. The second generation is represented by ofatumumab (brand name Arzerra), a fully human monoclonal antibody with reduced immunogenicity. Obinutuzumab (brand name Gazyva), recently approved for marketing in China, represents the third generation of type II anti-CD20 monoclonal antibodies featuring a modified Fc region. Compared with rituximab and ofatumumab, obinutuzumab exhibits weaker complement-dependent cytotoxicity (CDC) but stronger antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), along with a more potent direct B-cell killing effect.

The open-label, multicenter, Phase III clinical trial, codenamed GADOLIN, evaluated the efficacy of obinutuzumab in combination with bendamustine, followed by obinutuzumab maintenance therapy, in patients with follicular lymphoma (FL) who were refractory to rituximab or a rituximab-containing regimen, or who experienced disease progression during or after treatment with rituximab or a rituximab-containing regimen.

At the time of the initial analysis, the median follow-up time was 21.1 months. The study results showed that the median progression-free survival (PFS) was 13.8 months in the bendamustine group, while the median PFS was not reached in the obinutuzumab plus bendamustine group (PFS HR=0.48, 95% CI: 0.34-0.68; p< 0.0001).

The final analysis included 335 patients, with 171 randomized to receive bendamustine alone and 164 randomized to receive obinutuzumab plus bendamustine. The overall median follow-up was 52.2 months (range: 0–100.9 months). There were 66 deaths (40.2%) in the combination therapy group and 85 deaths (51.3%) in the bendamustine group (OS HR = 0.71, 95% CI: 0.51–0.98).

The multicenter, open-label, randomized phase III GALLIUM study evaluated the efficacy of obinutuzumab in treatment-naïve follicular lymphoma (FL), comparing obinutuzumab (G) plus chemotherapy with conventional rituximab (R) plus chemotherapy in previously untreated patients with CD20-positive FL. The study demonstrated that the 3-year progression-free survival (PFS) rates for the R-chemotherapy and G-chemotherapy regimens were 80.0% and 73.3%, respectively. Compared with the R-chemotherapy regimen, the G-chemotherapy regimen reduced the risk of progression, relapse, and death by 34% in patients with FL.

In terms of safety, the incidence of grade 3–5 adverse events was higher in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), and the incidence of serious adverse events was also higher (46.1% vs. 39.9%). Mortality rates were similar between the two groups, at 4.0% for the obinutuzumab group and 3.4% for the rituximab group. Currently, both the NCCN Guidelines and the CSCO Guidelines have included obinutuzumab plus chemotherapy in their first-line treatment recommendations for FL.