Positive results from the randomized Phase II GO29365-study (NCT02257567) that compared polatuzumab vedotin (RG7596) in combination with bendamustine plus rituximab (Rituxan®; Genentech/Roche) against bendamustine plus rituximab alone in people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for hematopoietic stem cell transplant, were presented in a poster session on Sunday, December 10 at the 59th American Society of Hematology (ASH) Annual Meeting, held in Atlanta, December 9 – 12, 2017, by Laurie Sehn, M.D., British Columbia Cancer Agency/University of British Columbia. 
The data led to U.S. Food and Drug Administration (FDA) Breakthrough Therapy and PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA).
The promising efficacy observed for polatuzumab vedotin in this study supports its potential as a new treatment option for people previously treated for this aggressive blood cancer…
Diffuse large B-cell lymphoma or DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL). The disease accounting for about one in three cases of NHL. DLBCL is also an aggressive type of NHL. As many as 40% of patients will relapse, at which point their prognosis is poor. In the United States, it is estimated that more than 21,000 new cases of DLBCL will be diagnosed in 2017. This represents a major unmet medical need.
The investigational agent polatuzumab vedotin is a first-in-class anti-CD79b antibody-drug conjugate or ADC currently being investigated for the treatment of several types of non-Hodgkin’s lymphoma (NHL).
The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies. Polatuzumab vedotin binds to CD79b and destroys these B-cells via a targeted approach, which is thought to minimize the effects on normal cells while maximizing tumor cell death.
Once internalized, the stable linker of polatuzumab vedotin is cleaved, releasing the cytotoxic monomethyl auristatin E (MMAE). In this way, MMAE inhibits microtubule polymerization, disrupts cell division, and triggers apoptosis in vitro by binding to microtubules, rigid hollow rods approximately 25 nm in diameter which are a principal component of the cytoskeleton.
Polatuzumab vedotin is being developed by Genentech, a member of the Roche Group, and includes proprietary ADC-technology developed by Seattle Genetics.
The GO29365-study (NCT02257567) is a global, Phase Ib/II randomized study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with rituximab or obinutuzumab plus bendamustine in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). 
The Phase II stage randomized 80 patients with heavily pre-treated R/R DLBCL to receive either bendamustine plus rituximab, or bendamustine plus rituximab in combination with polatuzumab vedotin. Patients enrolled had received a median of two prior therapies (a range of 1-7 prior therapies in the polatuzumab vedotin arm and range of 1-5 prior therapies in the bendamustine plus rituximab alone arm).
The primary endpoint was complete response (CR) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). Secondary endpoints included objective response (OR; CR and partial response, PR) by investigator assessment and best objective response at the end of treatment by investigator and IRC assessment. Exploratory endpoints included duration of response (DOR), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS).
The study met its primary endpoint, demonstrating that the addition of polatuzumab vedotin to bendamustine plus rituximab increased Complete Response rates from 15% to 40% (p=0.012) at the end of treatment, which means means no cancer could be detected at that time, as measured by positron emission tomography (PET) and assessed by an Independent Review Committee (IRC). The researchers did not observe any unexpected safety signals with the addition of polatuzumab vedotin to bendamustine plus rituximab.
“As many as 40% of people with diffuse large B-cell lymphoma do not respond to initial therapy or experience the return of their disease, at which point their treatment options are limited and the prognosis is very poor,” noted Sandra Horning, M.D., chief medical officer and head of Global Product Development.
“The promising efficacy observed for polatuzumab vedotin in this study supports its potential as a new treatment option for people previously treated for this aggressive blood cancer, and we look forward to discussing the results with health authorities,” she added.
The trial data showed:
- Polatuzumab vedotin plus bendamustine plus rituximab significantly improved CR rates from 15% with bendamustine plus rituximab alone to 40% (p=0.012), as measured by PET and assessed by IRC.
- The benefit observed was consistent across secondary endpoints, including improvements in investigator-assessed best Objective Response (OR; CR and Partial Response, PR) and CR with polatuzumab vedotin plus bendamustine plus rituximab (70.0% OR, 57.5% CR) compared to bendamustine plus rituximab alone (32.5% OR, 20.0% CR).
- Exploratory endpoints also improved with the addition of polatuzumab vedotin to bendamustine plus rituximab:
- Patients treated with polatuzumab vedotin plus bendamustine plus rituximab lived longer than those receiving bendamustine plus rituximab alone (median overall survival; 11.8 months vs. 4.7 months; HR=0.35; 95% CI 0.19-0.67; p=0.0008).
- The addition of polatuzumab vedotin also increased the time until disease worsening or death (median progression-free survival: 6.7 months vs. 2.0 months; HR=0.31; 95% CI 0.18-0.55; p<0.0001), and the time between first response to treatment and disease worsening (duration of response: 8.8 months vs. 3.7 months).
- No unexpected safety signals were observed with the addition of polatuzumab vedotin to bendamustine plus rituximab. The most common Grade 3-4 adverse events with polatuzumab vedotin plus bendamustine plus rituximab compared to bendamustine plus rituximab alone, respectively, were low white blood cell count (46.2% vs. 35.9%), low white blood cell count with fever (10.3% vs. 5.1%), low platelet count (33.3% vs. 20.5%), anemia (25.6% vs. 12.8%) and infections (17.9% vs. 17.9%).
Breakthrough Therapy Designation
Based on results from this study, polatuzumab vedotin was recently granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) and PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA) for the treatment of people with relapsed or refractory DLBCL.
There are a number of ongoing studies evaluating the efficacy and safety of polatuzumab vedotin for several types of non-Hodgkin’s lymphoma, including combinations with obinutuzumab (Gazyva® ; Genentech/Roche), a humanized type II anti-CD20 monoclonal antibody that binds to the CD20 antigen ( a proven target for CD20+ CLL) engineered for reduced fucose content, rituximab (Rituxan® ; Genentech/Roche), venetoclax (Venclexta™ ; AbbVie and Genentech/Roche) and atezolizumab (Tecentriq®; Genentech/Roche), the first FDA-approved Anti-PDL1 Cancer immunotherapy.