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Biosimilar demonstrates similar safety, efficacy as rituximab for follicular lymphoma

Rituximab biosimilar GP2013 demonstrated similar safety and efficacy as its reference agent in patients with previously untreated, advanced follicular lymphoma, according to results from the ASSIST-FL trial.

Rituximab (Rituxan; Genentech, Biogen) — a monoclonal antibody that targets the CD20 molecule expressed on B lymphocytes — is the standard of care in the frontline setting for patients with advanced-stage follicular lymphoma.

GP2013 (Sandoz) has demonstrated an identical amino acid sequence, matched protein structures and modifications, and indistinguishable biological and functional properties as rituximab.

“The introduction of biosimilars has the potential to make biological therapies more widely accessible and provide savings to health care systems,” Wojciech Jurczak, PhD, assistant professor in the department of hematology at Jagiellonian University in Krakow, Poland, and colleagues wrote.

Researchers conducted the multinational, double-blind, randomized, controlled confirmatory phase 3 study to compare the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of GP2013 with reference rituximab for untreated, advanced follicular lymphoma.

The researchers randomly assigned 629 patients 1:1 to receive eight cycles of GP2013 (n = 314) or rituximab (n = 315) in combination with cyclophosphamide, vincristine and prednisone over 24 weeks, or until disease progression, intolerable toxicity, treatment discontinuation or withdrawal.

Treatment responders followed the initial combination therapy with monotherapy maintenance for a 2-year period.

Equivalence of overall response served as the primary endpoint.

Median follow-up was 11.6 months.

Most patients in both arms (n = 274 each) completed the combination phase. Researchers included 254 patients from the GP2013 group and 252 patients from the reference rituximab group in the maintenance phase, all of whom received at least one dose of maintenance treatment.

Early treatment discontinuation occurred in both groups due to disease progression during the combination phase (n = 10 in each group) and the maintenance phase (GP2013, n = 37; rituximab, n = 25). Dose change during the combination phase (5% vs. 5%) and dose delays or interruptions (41% vs. 41%) were similar between both arms.

Overall response occurred in 87% of patients treated with GP2013 and 88% of patients treated with rituximab, for a difference between groups of –0.4% (95% CI, –5.94 to 5.14), which fell within the predefined equivalence CI interval of –12% to 12.

At data cutoff (median follow-up, 23.8 months), estimated median PFS and OS had not been reached in either treatment group. At that time, 30% of patients in the GP2013 group and 24% in the rituximab group experienced a PFS event (HR = 1.31; 95% CI, 0.97-1.78).

Twenty-three patients (7%) in the GP2013 group and 29 patients (9%) in the reference rituximab group died during the study (HR = 0.77; 95% CI, 0.45-1.33).

The researchers noted these results must be interpreted with caution, because the study was not powered to show similarity in PFS and OS.

At the end of the combination phase, 55 patients in the GP2013 group and 59 patients in the rituximab group achieved complete response (difference, –1.1%; 90% CI, –7.46 to 5.25), which further increased during the maintenance phase.

The difference in complete response between groups was 2.3% (90% CI, –8 to 3.29) at 15 months, 0.6% (90% CI, –5.59 to 6.75) at 27 months and 0.4% (90% CI, –6.61 to 5.88) at 33 months.

The clinical pharmacokinetic profile of GP2013 appeared similar to that of reference rituximab.

A similar proportion of patients in the GP2013 group and rituximab group experienced any adverse event (93% vs. 91%) and serious adverse events (23% vs. 20%). In the combination phase, the most common adverse events included neutropenia (26% vs. 30%), constipation (22% vs. 20%) and nausea (16% vs. 13%), and the most common grade 3 or 4 event was neutropenia (18% vs. 21%).

In the maintenance phase, the most common adverse events included neutropenia (10% vs. 6%), cough (9% vs. 6%) and upper respiratory tract infection (3% vs. 6%), and the most common grade 3 or 4 adverse event was neutropenia (7% vs. 4%).

In total, five patients in the GP2013 group and three patients in the reference rituximab group developed antidrug antibodies.

“Biological treatments, including monoclonal antibodies, such as rituximab, have greatly improved outcomes of several types of cancers and now form an integral part of treatment,” Jurczak and colleagues wrote. “However, access to biologicals can be limited by high treatment costs, which pose a challenge to patients, families, providers and insurers. Development and introduction of biosimilars that are similar in structure, function, immunogenicity, efficacy and safety to the reference biological agent has the potential to provide savings for health care systems, broaden patient access to biological therapies and support the sustainability of cancer care.”

Competitors to the rituximab reference product exist, such as subcutaneous rituximab and the next-generation anit-CD20 antibody obinutuzumab (Gazyva, Genentech), which is more effective than rituximab when combined with chemotherapy, Shinichi Makita, MD, PhD, and Kensei Tobinai, MD, PhD, from the department of hematology at the National Cancer Center Hospital in Tokyo, wrote in an accompanying editorial.

“However, rituximab is expected to remain an important drug in the treatment of B-cell malignancies for the time being,” they added. “Rituximab biosimilars have potential cost-saving benefits for health care, and can also improve the accessibility of rituximab-containing treatment worldwide. The results ... will certainly promote the introduction of rituximab biosimilar into daily, clinical practice in the immediate future.” – by Kristie L. Kahl

Disclosure s : Hexal, a Sandoz company, funded the study. Jurczak reports he received research funding and lecture honoraria from Sandoz. Please see the full study for a list of all other researchers’ relevant financial disclosures. Makita reports honoraria from Celgene and Chugai. Tobinai reports he has received honoraria from HUYA Bioscience International and Zenyaku Kogyo; grants and honoraria from Celgene, Chugai, Eisai, Janssen, Kyowa Hakko Kirin, Mundipharma, Ono Pharmaceutical and Takeda; and grants from AbbVie, GlaxoSmithKline and Servier.

Rituximab biosimilar GP2013 demonstrated similar safety and efficacy as its reference agent in patients with previously untreated, advanced follicular lymphoma, according to results from the ASSIST-FL trial.

Rituximab (Rituxan; Genentech, Biogen) — a monoclonal antibody that targets the CD20 molecule expressed on B lymphocytes — is the standard of care in the frontline setting for patients with advanced-stage follicular lymphoma.

GP2013 (Sandoz) has demonstrated an identical amino acid sequence, matched protein structures and modifications, and indistinguishable biological and functional properties as rituximab.

“The introduction of biosimilars has the potential to make biological therapies more widely accessible and provide savings to health care systems,” Wojciech Jurczak, PhD, assistant professor in the department of hematology at Jagiellonian University in Krakow, Poland, and colleagues wrote.

Researchers conducted the multinational, double-blind, randomized, controlled confirmatory phase 3 study to compare the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of GP2013 with reference rituximab for untreated, advanced follicular lymphoma.

The researchers randomly assigned 629 patients 1:1 to receive eight cycles of GP2013 (n = 314) or rituximab (n = 315) in combination with cyclophosphamide, vincristine and prednisone over 24 weeks, or until disease progression, intolerable toxicity, treatment discontinuation or withdrawal.

Treatment responders followed the initial combination therapy with monotherapy maintenance for a 2-year period.

Equivalence of overall response served as the primary endpoint.

Median follow-up was 11.6 months.

Most patients in both arms (n = 274 each) completed the combination phase. Researchers included 254 patients from the GP2013 group and 252 patients from the reference rituximab group in the maintenance phase, all of whom received at least one dose of maintenance treatment.

Early treatment discontinuation occurred in both groups due to disease progression during the combination phase (n = 10 in each group) and the maintenance phase (GP2013, n = 37; rituximab, n = 25). Dose change during the combination phase (5% vs. 5%) and dose delays or interruptions (41% vs. 41%) were similar between both arms.

Overall response occurred in 87% of patients treated with GP2013 and 88% of patients treated with rituximab, for a difference between groups of –0.4% (95% CI, –5.94 to 5.14), which fell within the predefined equivalence CI interval of –12% to 12.

At data cutoff (median follow-up, 23.8 months), estimated median PFS and OS had not been reached in either treatment group. At that time, 30% of patients in the GP2013 group and 24% in the rituximab group experienced a PFS event (HR = 1.31; 95% CI, 0.97-1.78).

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Twenty-three patients (7%) in the GP2013 group and 29 patients (9%) in the reference rituximab group died during the study (HR = 0.77; 95% CI, 0.45-1.33).

The researchers noted these results must be interpreted with caution, because the study was not powered to show similarity in PFS and OS.

At the end of the combination phase, 55 patients in the GP2013 group and 59 patients in the rituximab group achieved complete response (difference, –1.1%; 90% CI, –7.46 to 5.25), which further increased during the maintenance phase.

The difference in complete response between groups was 2.3% (90% CI, –8 to 3.29) at 15 months, 0.6% (90% CI, –5.59 to 6.75) at 27 months and 0.4% (90% CI, –6.61 to 5.88) at 33 months.

The clinical pharmacokinetic profile of GP2013 appeared similar to that of reference rituximab.

A similar proportion of patients in the GP2013 group and rituximab group experienced any adverse event (93% vs. 91%) and serious adverse events (23% vs. 20%). In the combination phase, the most common adverse events included neutropenia (26% vs. 30%), constipation (22% vs. 20%) and nausea (16% vs. 13%), and the most common grade 3 or 4 event was neutropenia (18% vs. 21%).

In the maintenance phase, the most common adverse events included neutropenia (10% vs. 6%), cough (9% vs. 6%) and upper respiratory tract infection (3% vs. 6%), and the most common grade 3 or 4 adverse event was neutropenia (7% vs. 4%).

In total, five patients in the GP2013 group and three patients in the reference rituximab group developed antidrug antibodies.

“Biological treatments, including monoclonal antibodies, such as rituximab, have greatly improved outcomes of several types of cancers and now form an integral part of treatment,” Jurczak and colleagues wrote. “However, access to biologicals can be limited by high treatment costs, which pose a challenge to patients, families, providers and insurers. Development and introduction of biosimilars that are similar in structure, function, immunogenicity, efficacy and safety to the reference biological agent has the potential to provide savings for health care systems, broaden patient access to biological therapies and support the sustainability of cancer care.”

Competitors to the rituximab reference product exist, such as subcutaneous rituximab and the next-generation anit-CD20 antibody obinutuzumab (Gazyva, Genentech), which is more effective than rituximab when combined with chemotherapy, Shinichi Makita, MD, PhD, and Kensei Tobinai, MD, PhD, from the department of hematology at the National Cancer Center Hospital in Tokyo, wrote in an accompanying editorial.

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“However, rituximab is expected to remain an important drug in the treatment of B-cell malignancies for the time being,” they added. “Rituximab biosimilars have potential cost-saving benefits for health care, and can also improve the accessibility of rituximab-containing treatment worldwide. The results ... will certainly promote the introduction of rituximab biosimilar into daily, clinical practice in the immediate future.” – by Kristie L. Kahl

Disclosure s : Hexal, a Sandoz company, funded the study. Jurczak reports he received research funding and lecture honoraria from Sandoz. Please see the full study for a list of all other researchers’ relevant financial disclosures. Makita reports honoraria from Celgene and Chugai. Tobinai reports he has received honoraria from HUYA Bioscience International and Zenyaku Kogyo; grants and honoraria from Celgene, Chugai, Eisai, Janssen, Kyowa Hakko Kirin, Mundipharma, Ono Pharmaceutical and Takeda; and grants from AbbVie, GlaxoSmithKline and Servier.

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