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Biosimilars: ASCO 2019

Kelly Davio
Research on biosimilars presented at the 2019 Annual Meeting of the American Society of Clinical Oncology.

Researchers Report on 3 Bevacizumab Biosimilar Development Programs

The anti-vascular endothelial growth factor (anti-VEGF) agent bevacizumab (Avastin) carries indications for lung cancer, colorectal cancer, breast cancer (in Europe), and glioblastoma, and has been the target of multiple hopeful biosimilar challengers, 2 of which are approved. Three developers reported on their progress with developing biosimilars of this anticancer agent.


The first bevacizumab biosimilar to be approved by the FDA and authorized by the European Commission, ABP 215 (Amgen’s MVASI), earned the FDA’s clearance on the basis of data that included findings from the phase 3 MAPLE study, which compared the biosimilar to the reference in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).

During the meeting, researchers reported on the totality of the evidence on ABP 215 that led to approval.1

The researchers compared VEGF-A kinetic parameters for common isoforms: 121, 165, and 189. They determined that binding to all 3 isoforms was similar for the biosimilar and the reference product.

Patients were randomized to receive the biosimilar (n = 328) or the reference (n = 314) with carboplatin and paclitaxel for up to 6 cycles, and efficacy was based on objective tumor assessments. The primary efficacy end point was the risk ratio of objective response rate (ORR), and clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio (RR) was within the prespecified margin of 0.67 to 1.5.

Based on a central analysis, ORR was achieved in 39.0% of patients in the biosimilar arm and in 41.7% of patients in the reference arm (ORR risk ratio, 0.93; 90% CI, 0.80-1.09). Based on an investigator analysis, ORR was achieved in 47.9% of patients in the biosimilar arm and in 48.1% of patients in the reference arm (ORR risk ratio, 1.01; 90% CI, 0.88-1.16).

These results, wrote the authors, further confirm the similarity of ABP 215 to its reference, and support the extrapolation to all available indications for bevacizumab. 


Innovent provided greater detail on its phase 3 comparative study in patients with NSCLC after having announced positive topline results of the study

in December 2018.

In the newly reported data, Innovent said that 450 patients with NSCLC who were receiving first-line treatment with carboplatin and paclitaxel were randomized to receive either the proposed biosimilar (n = 224) or the reference bevacizumab (n = 226) until progression.2

The primary end point was ORR, evaluated by comparing the 2-sided 90% CI of the risk ratio between the study arms. The prespecified equivalence margin was 0.75 to 1.33.

ORR in the full analysis set was 44.3% in the biosimilar arm and 46.4% in the reference arm; the RR for ORR was 0.95 (90% CI, 0.803-1.135), which fell within the prespecified margin. 

Medium progression-free survival was 8.4 months in the biosimilar arm and 8.3 months in the reference arm. Treatment-emergent adverse events were balanced between arms and consistent with the known profile of bevacizumab.

The incidence of antidrug antibodies (ADAs) was 0.5% in the biosimilar arm and 0% in the reference arm, and no patients developed neutralizing antibodies. 


Finally, researchers reported that the STELLA trial of MB02—a proposed bevacizumab biosimilar being developed by mAbxience—is underway.3

The study is a multinational, double-blind, randomized, parallel-group, equivalence study to compare the efficacy and safety of the biosimilar versus its reference, both in combination with plus chemotherapy in patients with stage IIIB to IV NSCLC.

Patients will be randomized to the biosimilar or the reference along with chemotherapy, and after 6 cycles, they will receive bevacizumab monotherapy every 3 weeks until progression, intolerance, death, withdrawal, or the end of the study. The primary objective is to compare the ORR between arms at week 18. Progression-free survival and overall survival at weeks 18 and 52, safety, and immunogenicity will also be assessed.

A sample size of 600 was calculated to provide 89% power to show equivalence on a primary end point of RR based on ORR, and 596 individuals have been recruited, say the investigators. 


1. Thomas M, Thatcher N, Goldschmidt JH, et al. Totality of evidence in development of the bevacizumab biosimilar ABP 215: central and investigator evaluation of efficacy from the MAPLE study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e201708.

2. Zhang L, Wu B, Huang L, et al. Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 9095.

3. Shparyk YV, Bondarenko I, Paravisini A, et al. Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): design of a confirmatory, double-blind, randomized, controlled study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e20731.


No Significant Difference in EFS, OS Between Herceptin and Biosimilar, Ontruzant, at 3 Years

Samsung Bioepsis' SB3 (Ontruzant) has been approved in the United States and European Union as a biosimilar of the brand name trastuzumab, Herceptin. 

Approval relied in part on a phase 3 study comparing the biosimilar with the reference in women with HER2-positive early or locally advanced breast cancer in the neoadjuvant setting.1

Notably, some of the lots of the reference trastuzumab that were used in the study—with expiry dates from August 2018 to December 2019—had been impacted by a product shift that resulted in downward changes to antibodydependent cell-mediated cytotoxicity (ADCC).

At the time, ADCC was not fully understood to be key to the efficacy of trastuzumab. However, in results that were presented in late 2018 at the San Antonio Breast Cancer Symposium, the importance of this quality attribute and its impact on event-free survival (EFS) came into clearer focus.

According the 2018 study data, 126 patients had been exposed to at least 1 lot of reference trastuzumab that had lower ADCC activity.2 Another 55 patients given the reference therapy were not exposed to these lots. After a median of 30.1 months of treatment with the biosimilar—which was given to 186 patients—and 30.2 months of treatment with the reference which was administered to 181 patients, there was no statistically significant difference in EFS between the biosimilar arm (96.7%) and the patients who were not exposed to the lower-ADCC activity lots of the reference (98.2%). However, in the patients exposed to the lower-ADCC activity reference, 2-year EFS was lower (92.5%). Researchers presented the 3-year results of an evaluation of survival by ADCC status.2

At a median follow-up of 40.8 months in the biosimilar arm and 40.5 months in the reference arm, EFS rates were 92.5% in the biosimilar arm, 94.5% among patients treated with the reference who were not exposed to the lower-ADCC activity lots, and 82.5% among patients who were exposed. Overall survival (OS) rates were 97.0%, 100%, and 90.6% in the 3 groups, respectively.

Among those treated with the reference, exposure was associated with decreased EFS compared with no exposure (hazard ratio [HR], 0.14; 95% CI, 0.04-0.51; P = .003). Decreased OS was noticed as a trend in the exposed group compared with the unexposed group, but no significant difference emerged (HR, 0.14; 95% CI, 0.02-1.15; P = .068).

Between patients treated with the biosimilar and those treated with the reference product who were not exposed to the lower-ADCC lots, no difference was observed in EFS (HR, 1.06; 95% CI, 0.33-3.44; P = .923) or OS (HR, 0.54; 95% CI, 0.05-5.44; P = .600).

The investigators concluded that patients exposed to the lower-ADCC lots of the reference had significantly lower EFS than those who were not exposed, whereas the biosimilar-treated patients and those unexposed to the affected lots had no significant differences in EFS or OS. 


1. Pegram MD, Pivot X, Cortes J, et al. Event-free survival by ADCC status from a follow-up study comparing SB3 (trastuzumab biosimilar) with reference trastuzumab for HER2 positive breast cancer in neoadjuvant setting. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P6-17-09.

2. Pivot X, Pegram MD, Cortes J, et al. Evaluation of survival by ADCC status: subgroup analysis of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up. Presented at: the American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 580.


iosimilar Pegfilgrastim Can Increase Access, but Patient Perception Remains a Barrier

Biosimilar pegfilgrastim, of which 2 brands (Mylan’s Fulphila and Coherus BioScience’s Udencya) have become available in the United States recently, is listed at a discount of 33% to the reference product, Amgen’s Neulasta.

Researchers said that, for payers with large populations, the discounted biosimilar pegfilgrastim can produce substantial cost savings that “can be applied to offer increased access to supportive care.”

The research team, from biosimilar developer Sandoz, which is developing its own biosimilar pegfilgrastim, used a cost minimization model based on a hypothetical group of 20,000 patients.1 They used the average selling price, obtained from payment allowance limits in the first quarter of 2019, for prophylaxis of febrile neutropenia for 1 chemotherapy cycle.

The simulation included a calculation of cost minimization per cycle when patients were converted from the reference pegfilgrastim to a biosimilar oa ratio of 10% to 100% and at a discount of 15% to 35%. Expanded access to biosimilar pegfilgrastim was calculated based on budget neutrality.

Per-cycle per-patient cost minimization of converting from reference pegfilgrastim to the biosimilar ranged from $702.27, representing a 15% discount, to $1638.63, representing a 35% discount. For the total 20,000 patients, these savings totaled more than $14 million at a 15% discount to $32 million at a 35% discount for a 100% conversion rate. If half of patients were prescribed the biosimilar, it was estimated that savings could range from more than $7 million at the 15% discount to more than 16 million at the 35% discount.

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