The U.S. Food and Drug Administration (FDA) today confirmed that it has granted accelerated approval of polatuzumab vedotin-piiq (Polivy™; Genentech; previously known as DCDS4501A and RG-7596), a first in class antibody-drug conjugate (ADC) targeting CD79b using a proprietary technology developed by Seattle Genetics.

“Antibody-drug conjugates are an emerging class of targeted immunotherapies for cancer. This type of therapy, unlike traditional chemotherapy, is intended to target specific cells,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Target protein
The target protein, CD79b, is highly specific and expressed in the majority of types of B-cell non-Hodgkin lymphoma (NHL), making it a promising target for the development of new therapies. [1][2] Polatuzumab vedotin binds to CD79b and destroys these B-cells (a type of white blood cell) through a targeted approach, which is thought to minimize the effects on normal cells while maximizing tumor cell death.[3][4]

The new, conditionally approved, agent was originally developed and will be commercialized by Genentech, a member of the Roche Group. The drug was conditionally approved in combination with bendamustine + rituximab (Rituxan®; Genentech/Roche) for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma that develops from the B-cells in the lymphatic system, who have received at least two prior therapies.

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Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of the disease. [5] DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline. [6] However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short. [1][4] Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year. [7]

The FDA’s Accelerated Approval Program allows conditional approval of this new agent based on the unmet medical need for this serious condition. However, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“Today’s approval of polatuzumab vedotin provides an alternative option for patients in whom multiple treatments have not worked,” the FDA’s Richard Pazdur added.

The accelerated approval was based on a multicenter, open-label study of polatuzumab vedotin (DCDS4501A or RG-7596) administered by intravenous (IV) infusion in combination with standard doses of bendamustine (B) and rituximab (R) or obinutuzumab (G) in patients with relapsed or refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). The study comprises two stages: a Phase Ib dose-escalation stage and a Phase II stage. The anticipated time on treatment is 18-24 weeks.

Clinical trial
The accelerated approval of polatuzumab vedotin was based on the results from the Phase Ib/II GO29365 study, a global, phase Ib/II randomised study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with bendamustine and rituximab or obinutuzumab (Gazyva®; Genentech/Roche) in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). (NCT02257567).

This study is the first and only randomized pivotal clinical trial to show higher response rates over bendamustine + rituximab in people with R/R DLBCL who are ineligible for a hematopoietic stem cell transplant.

The results of the study showed that 40% of people treated with polatuzumab vedotin plus bendamustine + rituximab achieved a complete response (n=16/40; 95% CI: 25-57), meaning no cancer could be detected at the time of assessment, compared to 18% with bendamustine + rituximab alone (n=7/40; 95% CI: 7-33).

Complete response rates were assessed by independent review committee. The study also showed that 45% of people on polatuzumab vedotin plus bendamustine + rituximab achieved an objective response at the end of treatment (n=18/40; 95% CI: 29-62), compared to 18% of people treated with bendamustine + rituximab alone (n=7/40; 95% CI: 7-33).

Of the people treated with polatuzumab vedotin plus bendamustine + rituximab who achieved a complete or partial response, 64% (n=16/25) had a duration of response (DOR) lasting at least six months as compared to 30% (n=3/10) of people treated with bendamustine + rituximab alone.

Additionally, 48% (n=12/25) of people treated with polatuzumab vedotin plus bendamustine + rituximab had a DOR lasting at least a year as compared to 20% (n=2/10) of people treated with bendamustine + rituximab alone.

Adverse reactions occurring in at least 20% of patients, and at least five percent more frequently in patients treated with polatuzumab vedotin plus bendamustine + rituximab compared to bendamustine + rituximab alone, included low white blood cell count, low platelet levels, low red blood cell count, numbness, tingling or pain in the hands and feet, diarrhea, fever, decreased appetite and pneumonia.

Breakthrough Therapy Designation
Polatuzumab vedotin previously received FDA Breakthrough Therapy Designation, and was approved more than two months ahead of the Prescription Drug User Fee Act (PDUFA) action date of August 19, 2019.

“Despite meaningful progress in the treatment of diffuse large B-cell lymphoma, treatment options are very limited when the disease is refractory to or recurrent after multiple regimens,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development.

“Today’s approval of this polatuzumab vedotin combination will provide a novel treatment that is both immediately available and very much needed for people with this aggressive disease,” Horning added.

Lymphoma Research Foundation
“The approval [..] offers patients with relapsed or refractory diffuse large B-cell lymphoma a new treatment option and new hope for improving patient outcomes,” added Meghan Gutierrez, chief executive officer at the Lymphoma Research Foundation, America’s largest nonprofit organization devoted exclusively to funding lymphoma research and serving patients impacted by this hematological cancer.

“New medicines can transform the way healthcare providers approach this type of blood cancer and we commend those who contribute to accelerating research for the benefit of patients.” Gutierrez said.

Innovative technology
Polatuzumab vedotin uses a specifc technology developed by Seattle Genetics that combines the specificity of monoclonal antibodies, innovative linker systems and potent cell-killing agents to treat cancer. The technology has been licensed to multiple companies, including Genentech and GlaxoSmithKline.

“The approval of polatuzumab vedotin under our collaboration with Genentech is an important milestone for Seattle Genetics as it extends the reach of our technology to more patients with significant unmet medical needs,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“This approval, along with our own internal ADCs in development and those of other collaborators, such as GlaxoSmithKline, highlights that antibody-drug conjugates continue to grow as an important therapeutic approach to treating both hematologic malignancies and solid tumors,” Siegall concluded.

European Approval
Polatuzumab vedotin was granted PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA) for the treatment of patients with R/R DLBCL. PRIME is a designation implemented by the EMA to support data generation and development plans for promising medicines, providing a pathway for accelerated evaluation by the agency. Polatuzumab vedotin is also being investigated by Genentech in several ongoing clinical trials for the treatment of non-Hodgkin lymphoma (NHL), including frontline DLBCL.

Clinical trial
A Study of Polatuzumab Vedotin (DCDS4501A) in Combination With Rituximab or Obinutuzumab Plus Bendamustine in Participants With Relapsed or Refractory Follicular or Diffuse Large B-Cell Lymphoma – NCT02257567

[1] Dornan D, Bennett F, Chen Y, Dennis M, Eaton D, Elkins K, French D, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009 Sep 24;114(13):2721-9. doi: 10.1182/blood-2009-02-205500. Epub 2009 Jul 24. [PubMed][Article]

[2] Pfeifer M, Zheng B, Erdmann T, Koeppen H, McCord R, Grau M, Staiger A, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia. 2015 Jul;29(7):1578-86. doi: 10.1038/leu.2015.48. Epub 2015 Feb 24. [PubMed][Article]

[3] Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010 Jan;21(1):5-13. doi: 10.1021/bc9002019.[PubMed]

[4] Mehr. S. ADC Review. What are antibody-drug conjugates? Online. Last accessed June 10, 2019. [Article]

[5] World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. IARC Press – Lyon, France (2008).

[6] Maurer MJ, Ghesquières H, Jais JP, Witzig TE, Haioun C, Thompson CA, Delarue R, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014 Apr 1;32(10):1066-73. doi: 10.1200/JCO.2013.51.5866. Epub 2014 Feb 18. [PubMed][Article]

[7] Data from GLOBOCAN 2018: Estimated cancer incidence, mortality and prevalence worldwide in 2018. Online. Last Accesses June 10, 2019 [Article]

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