Biosimilars: ASCO 2019

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.

ABP 215 (MVASI)

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.

IBI305

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.

MB02

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.

References

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. https://abstracts.asco.org/239/AbstView_239_270387.html.

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. https://abstracts.asco.org/239/AbstView_239_267151.html.

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. https://abstracts.asco.org/239/AbstView_239_258561.html.

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.

References

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. http://cancerres.aacrjournals.org/content/79/4_Supplement/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. https://abstracts.asco.org/239/AbstView_239_262069.html.

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.

If 100% of patients were prescribed the biosimilar at the 15% discount, an additional 3529 patients could be treated with the savings generated. If half of the patients were prescribed the biosimilar, the savings could be applied to treat 1765 patients at the same discount. Assuming a 35% discount, 50% biosimilar use would produce savings that could allow 5385 patients to be treated.

For payers with sizable populations, biosimilar pegfilgrastim offers an opportunity to provide increased access on a budget-neutral basis, according to the researchers.

Despite the budgetary benefits of biosimilar pegfilgrastim being clear from the payer perspective, patients may continue to have concerns about receiving a biosimilar rather than its reference. Also during the meeting, another research team published findings that, although a majority of patients with cancer do not believe that more costly drugs work better than cheaper alternatives, they may have residual concerns about cost-saving drugs when used in cancer care.²

The researchers surveyed a sample of 75 patients with cancer in clinics and an infusion center, asking questions about cost and patient participation in decision making about treatment options. In total, 66% of respondents said they did not believe that more costly medicines were more effective than less costly ones for the same disease. However, just 60% of that group, and 44% of the overall group, said they preferred that their doctor prescribe a cheaper drug for them.

Among respondents who expressed a belief that more expensive drugs are not more effective but wanted to receive a more expensive drug anyway, 8 respondents indicated that they believed cancer to be too serious to take chances, 5 wanted the most expensive drug covered by insurance, and 2 said they wanted the best possible medication available.

Additionally, 90.67% said they wanted to be informed if their physician was prescribing a less expensive version of their therapy. According to the authors, patients have lingering concerns that cost savings may be a proxy for quality, particularly in cancer indications. Overcoming these perceptions will be crucial, they indicate, if cost savings are to be possible.

References

1. Wang W, Balu S, Campbell K. Cost-minimization analysis for biosimilar pegfilgrastim in the prophylaxis of chemotherapy induced (febrile) neutropenia and expanded access based on budget neutral basis. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 6645. https://abstracts.asco.org/239/AbstView_239_268565.html.

2. Harvey RD, McGrath M, Cook JW, Dixon MD, Pentz RD. How will the cost of biosimilars affect patients’ willingness to receive them? Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e18338. https://abstracts.asco.org/239/AbstView_239_249465.html.

Phase 3 and Postmarketing Data Support the Efficacy and Safety of Biosimilar Trastuzumab, Ogivri

Myland and Biocon's trastuzumab biosimilar, Ogivri, was the first biosimilar referencing Herceptin to be approved by the FDA. Approval of Ogivri was based in part on data from the phase 3 HERITAGE trial, a double-blind, randomized clinical trial that evaluated the biosimilar in patients with HER2-positive metastatic breast cancer without prior chemotherapy or trastuzumab for metastatic disease.

Data from the HERITAGE study, reported elsewhere, show that the biosimilar was equivalent to the reference trastuzumab when given in combination with a taxane as first-line therapy, as measured by 24-week overall response. The safety profile of the biosimilar was also comparable to that of the reference Herceptin.¹ Researchers presented the final overall survival (OS) results from HERITAGE.²

After 24 weeks, the 343 patients who had responding or stable disease continued to receive trastuzumab as monotherapy according to their initial randomization to either the biosimilar (n = 179) or the reference (n = 164).

Also included in the results were safety and OS during maintenance, through 36 months of follow-up from the last patient on the study. The mean time to discontinuation was 19 months in both the biosimilar arm and the reference arm. Treatment-emergent adverse events (AEs) during monotherapy were similar in the biosimilar arm (69%) and the reference arm (73%). Serious AEs occurred in 6% of patients in both groups.

At 36 months, 169 patients had received additional lines of therapy, with a similar distribution of HER2 treatments, endocrine therapies, and chemotherapies.

Final median progression-free survival was 11.1 months in both of the arms. The median duration of response was 9.9 months in the biosimilar arm and 9.8 months in the reference arm. OS was 35.0 months and 30.2 months in the 2 arms, respectively.

In addition to these data from HERITAGE, separately, another research group shared its research on postmarketing surveillance of Ogivri: their results show that the safety of the biosimilar is consistent with that of the reference.³

The biosimilar, although not yet launched in the United States, is available in other markets, including Brazil, where it is subject to inclusion in the manufacturer’s patient support program to monitor AEs. The authors of a prospective observational study used data from the program, which covered 21 patients with HER2-positive breast cancer who enrolled in the program between May 2018 and January 2019.

In total, 16 patients reported 101 AEs, 7 of which were serious. The most frequently reported AEs were general disorders and administration-site conditions, followed by nervous system disorders and gastrointestinal disorders. The most-reported symptoms were nausea, asthenia, infusionsite

reactions, paresthesia, and pain.

According to the investigators, these safety data are consistent with the profile of the reference trastuzumab, and no new safety signals were detected.

References

1. Rugo H, Barve A, Waller C, et al. HERITAGE: a phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus herceptin. Eur J Cancer. 2017;72(1):S41. doi: 10.1016/S0959-8049(17)30216-2.

2. Waller CF, Manikhas A, Penella EJ, et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: final overall survival (OS) from the phase III HERITAGE Trial.

Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 1021. https://abstracts.asco.org/239/AbstView_239_268475.html.

3. da Silva AM, Dib GVC, Saraiva ELF, Watanabe TT, de Paulo JA. Active postmarketing surveillance: results from a manufacturer’s patient support program for patients under treatment with the first biosimilar trastuzumab (MYL-1401O) approved in Brazil. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e14000. https://abstracts.asco.org/239/

AbstView_239_264009.html.

Real-World Data Underscore the Safety and Highlight the Acceptance of Biosimilar Rituximab

Although no biosimilar rituximab products have become available in the United States—despite the recent approval of Celltrion and Teva’s Truxima—

biosimilar rituximab products are available in the European Union. Data on their use (published concurrently with the 2019 Annual Meeting of the American Society of Clinical Oncology [ASCO]) highlight not only their safety, but also their growing acceptance among prescribers in Europe.

First, researchers reported interim safety results from a real-world study of Sandoz’s biosimilar rituximab, Rixathon, as curative therapy for CD20-positive

diffuse large B-cell lymphoma (DLBCL).1 The study, REFLECT, is the first postapproval real-world study of the biosimilar in DLBCL.

REFLECT includes adult patients with DLBCL who are eligible for treatment with rituximab and cyclophosphamide, doxorubicin, vincristine, or prednisone

(R-CHOP). The study’s primary end point is complete response rate at the end of treatment.

In an interim analysis, with a cutoff of early September 2018 and with approximately 50% enrollment, the full analysis set comprised 80 patients. In

total, adverse events (AEs) were reported in 53 and 13 patients, respectively.

There were 19 patients with serious AEs, 2 of which were deemed to be treatment-related. Six AEs led to discontinuation, 6 led to dose interruption, and none led to death. According to the investigators, these interim data from this ongoing study are as expected for rituximab-based treatment.

Also published alongside the ASCO meeting were data concerning the prescribing of biosimilar rituximab in the European Union.²

The study used data from the Ipsos Global Oncology Monitor, which provided deidentified data on 3239 patients with non-Hodgkin lymphoma treated with anticancer drugs in France, Germany, Italy, Spain, and the United Kingdom between July 2017 and September 2018. Data on patients treated with and without a rituximab biosimilar were compared using descriptive statistics.

Although the prescribing of the reference rituximab was stable during the study period, the prescribing of biosimilar rituximab increased significantly, from 7% to 35% (P <.01). The uptake of the biosimilar was particularly strong in Germany and the United Kingdom; by the third quarter of 2018, for those patients who had rituximab prescribed as part of a regimen, prescribing of a biosimilar was 72% in Germany and 63% in the United Kingdom.

Additionally, physicians were more likely in 2018 than in 2017 to state “proven efficacy” and “well tolerated” as their reasons for prescribing the biosimilar. France, Italy, and Spain had 47%, 32%, and 30% rates of biosimilar prescribing, respectively, which the study suggests may be driven by skepticism about subsequent-entry products that has been observed with generics in some European countries.

Prescribing of the brand name rituximab may also be driven, in part, by the availability of a subcutaneously administered formulation, which is not available for biosimilar versions at this time, the study author noted.

References

1. Welslau M, Marschner N, Wolff T, et al. Sandoz rituximab (GP2013; SDZ-RTX) for the treatment of diffuse large B-cell lymphoma (DLBCL): interim safety results of the non-interventional, observational, multicenter, open-label REFLECT study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e19020. https://abstracts.asco.org/239/AbstView_239_248911.html.

2. Franceschetti A. NHL and rituximab biosimilar: how have prescribing behaviours changed in EU5 in 15 months? Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e19054. https://abstracts.asco.org/239/AbstView_239_267249.html.

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