During the annual meeting of the American Society of Clinical Oncology (ASCO), held virtually June 4-8, 2021, representatives from Genentech/Roche presented new data on the company’s investigational CD20xCD3 T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab (RG6026), and its first-in-class anti-CD79b antibody-drug conjugate, polatuzumab vedotin (Polivy®; Genentech/Roche) in non-Hodgkin’s lymphoma (NHL).
The two investigational agents, mosunetuzumab and glofitamab, are designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual-targeting approach activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells.
The two agents differ in their structures but are designed to maximize potential clinical benefits for patients.
Mosunetuzumab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions, but is different from naturally-occurring antibodies in that one ‘Fab’ region targets CD20 and the other ‘Fab’ region targets CD3.
Glofitamab is based on a novel structural format, which, based on the structure of the antibody, is referred to as ‘2:1.’ The drug is engineered to have two ‘Fab’ regions that bind to CD20, and one ‘Fab’ region which binds to CD3.
Polatuzumab vedotin is a first-in-class anti-CD79b ADC. The CD79b protein is expressed specifically in the majority of B-cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. The drug binds to CD79b and destroys these B-cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells.
Polatuzumab vedotin is an antibody-drug conjugate or ADCs, a highly targeted biopharmaceutical drug that combines monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker. With ten approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
More options to improve outcomes
“People with difficult-to-treat blood cancers such as non-Hodgkin’s lymphoma still need more options to help improve outcomes,” noted Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development at Genentech.
“We are encouraged by promising data from our emerging T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab, and the antibody-drug conjugate, polatuzumab vedotin, that demonstrate the potential of these novel immunotherapeutic approaches for various groups of patients,” Garraway added.
Limited treatment options
While approximately 500,000 people worldwide are diagnosed with NHL each year, treatment options are currently limited and resistance to existing therapies or relapse following treatment is common. The most prevalent form of NHL, accounting for about 40% of newly diagnosed NHL cases, is an aggressive form called diffuse large B-cell lymphoma (DLBCL), which comes with a life expectancy of weeks or months if left untreated.
In clinical trials to date, the investigational CD20xCD3 T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab, have shown promising responses across multiple types of NHL, including relapsed or refractory (R/R) DLBCL and follicular lymphoma (FL).
Pivotal data for these medicines are expected this year and Genentech is targeting a regulatory filing for mosunetuzumab in FL by the end of 2021, following its U.S. Food and Drug Administration Breakthrough Therapy designation granted in June 2020. Key data on mosunetuzumab and glofitamab to be presented at the meeting include:
- Phase I NP30179 study investigating step-up dosing of glofitamab in heavily pre-treated R/R NHL showed high, ongoing complete responses (CRs) and an acceptable safety profile. After a median follow-up of 6.3 months, results showed that glofitamab achieved a complete metabolic response rate, defined as the disappearance of metabolic tumor activity, of 71.4% in patients with aggressive (fast-growing) NHL. The most common adverse events (AEs) were cytokine release syndrome (CRS) (63.5%), neutropenia (38.5%), and pyrexia (32.7%); CRS events were mostly low grade and confined to the first cycle of treatment. 
- Phase I/II GO40516 study of mosunetuzumab in combination with polatuzumab vedotin in R/R NHL showed promising efficacy and an acceptable safety profile. The regimen achieved a CR of 54.5% in all patients. Eighty-six percent of patients evaluated had aggressive NHL, and these patients achieved a CR rate of 47.4%. The most frequent treatment-related AEs were neutropenia (45.4%), fatigue, nausea, and diarrhea (all 36.4%), and CRS (9.1%; all Grade 1). 
Broad development programs are ongoing for mosunetuzumab and glofitamab, including the Phase III GO42909 trial investigating mosunetuzumab plus lenalidomide versus rituximab (Rituxan®; Genentech/Roche) plus lenalidomide (Revlimid®; Bristol-Myers Squibb) in R/R FL, which will soon be enrolling patients.
For glofitamab, the Phase III GO41944 open-label, randomized trial designed to evaluate the safety and efficacy of glofitamab plus gemcitabine (Gemzar®; Eli Lilly and Company) and oxaliplatin (Eloxatin®; Sanofi Genzyme), a combination referred to as glofit-GemOx, versus rituximab plus GemOx in patients with R/R DLBCL, is also ongoing.
Researchers at Genentech/Roche are pursuing treatment solutions that can be tailored to meet the various needs of both people living with NHL and healthcare professionals.
Polatuzumab vedotin is already a treatment option for people with R/R DLBCL and continues to show potential in multiple combinations. Key data at the meeting include:
- New triplet combination of polatuzumab vedotin with rituximab and lenalidomide, which demonstrated promising activity in difficult-to-treat R/R DLBCL, based on results from the Phase Ib/II GO29834 study. With a median follow-up of 9.7 months, median overall survival was 10.9 months (95% CI: 7.4–NE) and median progression-free survival was 6.3 months (95% CI: 4.5–9.7) in patients treated with the triplet. The most commonly reported Grade 3-4 AEs were neutropenia (58.0%), thrombocytopenia (14.0%), infections (14.0%) and anemia (11.0%). 
A Study to Evaluate the Safety and Efficacy of Mosunetuzumab (BTCT4465A) in Combination With Polatuzumab Vedotin in B-Cell Non-Hodgkin Lymphoma – NCT03671018
A Dose Escalation Study of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab, Administered After a Fixed, Single Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma (NP30179 study) – NCT03075696
A Study of Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide in Relapsed or Refractory Follicular Lymphoma (FL) and Rituximab in Combination With Polatuzumab Vedotin and Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (GO29834 study) – NCT02600897
Highlights of prescribing information
Polatuzumab vedotin (Polivy®; Genentech/Roche)[Perscription Information]
Rituximab (Rituxan®; Genentech/Roche)[Perscription Information]
Lenalidomide (Revlimid®; Bristol-Myers Squibb)[Perscription Information]
Gemcitabine (Gemzar®; Eli Lilly and Company)[Perscription Information]
Oxaliplatin (Eloxatin®; Sanofi Genzyme)[Perscription Information]
 Polatuzumab vedotin (Drug Description) | ADC Review, Journal of Antibody-drug Conjugates. Online. Last accessed on June 4, 2021.
 Carmelo Carlo-Stella, Martin Hutchings, Fritz C. Offner, Franck Morschhauser, Emmanuel Bachy, Michael Crump, Anna Sureda Balari, Gloria Iacoboni, et al. Glofitamab step-up dosing (SUD): Complete response rates in updated efficacy data in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts). Abstract #7519. Presented at: American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021. J Clin Oncol 39, 2021 (suppl 15; abstr 7519)
 Budde LE, Ghosh N, Chavez JC, Lossos IS, Mehta A, Dorritie KA, Kamdar MK, Negricea R, et al. Promising tolerability and efficacy results from dose-escalation in an ongoing phase Ib/II study of mosunetuzumab (M) with polatuzumab vedotin (Pola) in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin’s lymphoma (B-NHL). Abstract #7520. Presented at: American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021. J Clin Oncol 39, 2021 (suppl 15; abstr 7519)
 Diefenbach CSM, Abrisqueta P, Gonzalez-Barca E, Panizo C, Arguinano Perez JM, Miall F, Bastos-Oreiro M, Lopez-Guillermo A, et al. Polatuzumab vedotin (Pola) + rituximab (R) + lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Primary analysis of a phase 1b/2 trial. Abstract #7512. Presented at: American Society of Clinical Oncology (ASCO), held June 4 – 8, 2021. J Clin Oncol 39, 2021 (suppl 15; abstr 7512)