Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Biosimilars employed in clinical studies may reduce the costs of those studies, relative to using reference brand drugs. As clinical research tools, they may also provide answers to questions about appropriate therapy.

When it comes to treatment for breast cancer, investigators used biosimilar trastuzumab (Trazimera) to help understand whether a genetically targeted population of patients would benefit from a de-escalation of standard therapy by leaving out chemotherapy.

Improved outcomes have been derived from the addition of human epidermal growth factor receptor 2 (HER2)–targeted therapies to conventional chemotherapy, although patients sometimes are overtreated with combination therapies or suffer adverse events that might otherwise be avoided.

In KEYRICHED-1 (NCT03988036), a prospective phase 2 trial, investigators sought to determine whether comparable pathologic complete response (pCR) rates could be achieved in the neoadjuvant setting without a chemotherapy therapeutic component in patients with HER2-positive early breast cancer (EBC).

For this study, investigators enrolled patients with HER2-enriched (HER2-E) EBC, because this PAM50 molecular subtype of HER2-positive breast cancer is associated with higher pCR rates following anti–HER2-based treatment. In other words, this subgroup of patients was more likely to respond well to de-escalated treatment.

In this single-arm study, investigators enrolled pre- and postmenopausal patients (N = 48) with newly diagnosed HER2-postive stage I-III EBC with immunohistochemical (IHC) expression 2+ or 3+ and HER2-E subtype by PAM50.

Treatment consisted of 4 cycles (every 21 days) of the following:

Trastuzumab biosimilar (Trazimera, loading dose 8 mg/kg, maintenance dose 6 mg/kg)

Pertuzumab (loading dose 840 mg/kg, maintenance dose 420 mg/kg)

Pembrolizumab is an immunotherapy that blocks the programmed cell death receptor (PD-1) from binding with the PD-L1/L2 ligands, thereby preventing the tumor cell from “switching off” the immune system response against the cancer.

Pertuzumab mutes the tumor cell signaling process by locking onto HER2-expressing cancer cells, thereby arresting their growth and inducing apoptosis, or cell death.

Trastuzumab is complementary in action to pertuzumab. It attaches to HER2 receptors on breast cancer cells and prevents them from receiving growth signals.

Trial enrollment was conducted between May 2020 and March 2021. Investigators said that of 98 patients initially screened, 52 (55%) had the HER2-E subtype by PAM50, and of those, 48 entered the treatment phase.

The median age of patients was 57; 65% had tumors larger than 2 cm and 30% were positive for lymph node involvement.

Investigators said the centrally confirmed pCR rate was 52% in 46 evaluable patients (a minimum pCR rate of 50% was predetermined for recruitment continuation).

“Despite the HER2-E subtype, no pCR was observed in 4 patients with IHC HER2 2+/fluorescence-in-situ hybridization (

)–positive status in contrast with 20/39 (51.2%) pCRs in HER2 3+ tumors,” authors of the study wrote.

They said the confirmed pCR rate for HER2-positive/hormone receptor (HR)–positive tumors was 38.5% vs 58.5% for HER2-positive/HR-negative tumors. They observed no new safety signals.

The investigators said the findings were favorable in comparison with those from the 

, another de-escalation study, which compared trastuzumab and pertuzumab alone (dual blockade) with trastuzumab, pertuzumab, and paclitaxel in patients with HER2-positive/HR-negative EBC.

In WSG-ADAPT, investigators concluded that the addition of taxane therapy (paclitaxel/chemotherapy) to dual HER2 blockade over 3 months “substantially” increased pCR rates in HER2-postive/HR-negative EBC compared with dual blockade alone.

They said that in KEYRICHED-1, “The observed pCR rates compare favorably in HR-positive as well as HR-negative/ HER2-positive EBC. Moreover, KEYRICHED-1 demonstrates that with appropriate molecular patient selection, clinically meaningful pCR rates in the range of those obtained with longer, more toxic chemotherapy-containing regimens can be achieved.”

Kuemmel S, Gluz O, Reinisch M, et al. KEYRICHED-1 – a prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype. Presented at: 2021 SABCS; December 7-10, 2021. https://www.abstractsonline.com/pp8/#!/10462/presentation/1034

Articles

Investigators said pathologic complete response (pCR) improved in a trastuzumab biosimilar/pertuzumab trial when patients were preselected for a subtype of breast cancer. 

Molecular Selection Boosts pCR Rate in Early Breast Cancer Trial

A phase 1 study of the proposed eculizumab biosimilar (SB12) vs reference product (Soliris) has demonstrated pharmacokinetic (PK) bioequivalence and comparable pharmacodynamic (PD), safety, and immunogenicity characteristics in a population of healthy volunteers, investigators reported at the 2021 American Society of Hematology meeting.

Eculizumab is a humanized monoclonal antibody that binds to human C5 complement protein and blocks hemolysis, or the breakdown of red blood cells. Eculizumab is currently indicated for paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis, and neuromyelitis optica spectrum disorder.

Investigators sought to demonstrate comparable PK and PD in healthy individuals aged 18 to 55 years (N = 240) who were randomized in a 3-arm trial to a single 300-mg dose of SB12 or US- and EU-sourced reference product. Blood samples for analysis were collected over 64 days.

The primary end point was PK similarity between the various agents as determined by total drug exposure, or area under the concentration-time curve. Biosimilarity for the primary end point was confirmed, as the 90% CIs were within the predetermined equivalence margin of 80% to 125%, authors of the study wrote.

Investigators said there were no deaths or discontinuation of investigational products (IPs) due to treatment-emergent adverse events (TEAEs); they said there were 2 serious adverse events: renal colic in the SB12 cohort and back pain in the US-eculizumab group. “Both events were considered not related to the IP,” investigators wrote.

They said 70.0%, 65.0%, and 71.3% of patients in the SB12 and EU- and US-sourced eculizumab cohorts, respectively, experienced TEAEs, which investigators said was similar.

The number of participants who developed postdose antidrug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%), respectively, authors wrote. “There was no significant difference between treatment groups. None of the [participants] with post-dose ADA to eculizumab had a positive result for neutralizing antibodies.”

Lee HA, Jang H, Kim Y, et al. A randomized, double-blind, single-dose phase 1 comparative pharmacokinetic study comparing SB12 (eculizumab biosimilar) with reference eculizumab in healthy volunteers. Presented at: ASH 2021; December 11-14, 2021. Abstract 929.

In a pharmacokinetic (PK) and pharmacodynamic (PD) trial in healthy participants, Samsung Bioepis' SB12 eculizumab biosimilar candidate demonstrated equivalence to Soliris, the reference product. 

SB12 Eculizumab Biosimilar Candidate Demonstrates PK, PD Equivalence in Phase 1 Trial

Alvotech, the Icelandic biosimilars company, has won approval from the European Commission (EC) for the marketing of its adalimumab biosimilar, AVT02, which references Humira. The biosimilar product is cutting edge among approved adalimumab products, as it is high concentration (100 mg) and citrate-free, a formulation that has been capturing market share in the European Union (EU) and United States recently.

The EC approval was officially issued November 15, 2021 and publicized by Alvotech this week. Alvotech may yet face hurdles in commercializing AVT02 in the European Union, where competitive bidding in individual markets, partnership arrangements, and potential opposition from Humira's maker, AbbVie, may cause delays. Alvotech made no mention of a possible EU launch date in its announcement.

An FDA review for possible approval of AVT02 is underway, and Alvotech also must successfully resolve ongoing patent litigation with AbbVie before this product can launch in the United States.

The product received a recommendation for approval from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in September. The committee's recommendations are pivotal in EC final decisions about medicinal products. 

Adalimumab is used in the treatment of autoimmune and inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, Crohn disease, ulcerative colitis, hidradenitis suppurativa, and plaque psoriasis. Adalimumab is a tumor necrosis factor (TNF) inhibitor that in binding to TNF neutralizes its activity and induces apoptosis, or death, of TNF-expressing cells.

"We are thrilled by the EC’s approval of our high concentration biosimilar to Humira," said Róbert Wessman, founder and chairman of Alvotech.

The company has poised itself for rapid expansion of adalimumab biosimilar commercialization in multiple global markets via commercialization deals with multiple companies. Alvotech also has an ustekinumab biosimilar referencing Stelara under development. Clinical studies for the biosimilar candidate, AVT04, were begun in July 2021.

, Anil Okay, chief commercial officer for Alvotech, said the company had commercialization deals for its pending biosimilars for upwards of 90 countries.

If launched, AVT02 would become Alvotech’s first commercialized biosimilar. The company was founded in 2013 and has administrative and manufacturing facilities in Europe and under construction in China. The company recently announced a $450 investment from a business consortium and plans to take the company public with a stock offering at an undisclosed future date.

The value of the adalimumab market is sizeable. The product brought in roughly $20 billion in revenues in 2020 for AbbVie. Competitor biosimilars have entered the market in the European Union and in the United States there are 6 approved adalimumab biosimilars scheduled for launch in 2023 and as many as 4 others under development that could launch around that time or later.

Alvotech has received European Commission (EC) approval to begin marketing its adalimumab biosimliar AVT02, the company announced this week. 

Alvotech Gains EC Approval for Adalimumab Biosimilar 

Biosimilars are considered clinically equivalent to the biologic brand drugs they reference, but how about their equivalence, or lack thereof, to other biosimilars of the same brand drugs?

A group of researchers set out to answer that question with an 

of the clinical trials literature on cross comparisons of biosimilars. They noted that the FDA generally is concerned only with whether the biosimilars it approves are equivalent to reference products but not whether biosimilars are equivalent to one another. That equivalence is implied, but the FDA does not issue approvals stating that expressly.

“Similarity among biosimilars of a reference product is not a regulatory agency concern and therefore is unlikely to be investigated in randomized controlled trials in the foreseeable future,” they wrote.

Nevertheless, they noted providers and other clinicians would feel more comfortable having evidence or guidelines in support of switches from one biosimilar to another for the same drug type, such as trastuzumab, for which 5 biosimilars have been approved in the United States.

In their review, they concluded from the available evidence that biosimilars are essentially equivalent to one another.

“Comparative studies of biosimilars of the same reference product are not mandated, since the comprehensive biosimilarity exercises that each proposed biosimilar must undergo before regulatory approval is granted suggests that establishing clinical equivalence between the biosimilars ought to be achievable using educated inductive reasoning complemented by robust pharmacovigilance systems,” authors of the study wrote.

“This is supported by the emerging real-world evidence for switching between biosimilars, with no unexpected findings or concerns being raised from the initial data from cross-switching studies published thus far,” they concluded.

They cited numerous challenges to providers being able to accept cross-switches between biosimilars as producing no unwanted effects that would not accrue from remaining on a biosimilar and not making a switch.

Regulatory authorities don’t require that biosimilars be compared with one another in clinical trials.

There is a scarcity of clinical data supporting cross-switching between biosimilars.

Abbreviated approvals of biosimilars could make cross-switching appear more risky than it is.

Cross-switching can occur under many different scenarios.

Professional medical organizations largely have yet to issue guidance on cross-switching.

“Overall, the majority of evidence suggests that switching from a reference drug to a biosimilar, or between biosimilars, is not associated with increased immunogenicity, an escalated or clinically meaningful safety risk, or any appreciable loss of effectiveness,” the authors said.

Switches can occur in multiple ways: from the reference drug to a biosimilar, or via a reverse switch from a biosimilar to a reference product, or by a cross switch between biosimilars, or by multiple switches either between reference drugs and biosimilars or between biosimilars.

The authors provided examples of ex vivo immunogenicity studies that had a bearing on cross-switching. Immunogenicity is defined as the immune system’s response to the presence of a biologic in the body. Higher immunogenicity with a replacement or “switched” drug is a concern because it can reduce the effectiveness of the new biologic.

In a study cited by the authors, serum samples were collected from patients with inflammatory bowel disease who received infliximab reference product or 1 of 2 biosimilars: CT-P13 or SB2. Analysis of immunogenicity from these samples demonstrated “immunogenic similarity,” they said.

“This aspect of the study highlighted the futility of biosimilar cross-switching among infliximab biosimilars in the event of an immune response to (reference product) or an infliximab biosimilar,” they noted. This is because the same immune response or level of immunogenicity could be expected from the biosimilar as well.

In a retrospective study, investigators tested serum samples from adults with Crohn disease and ulcerative colitis. Assays to assess immunogenic cross-reactivity “revealed that patients’ antibodies recognized [reference infliximab] and infliximab biosimilars CT-P13 and SB2 equivalently,” the authors wrote. “The uniformity…suggests that cross-switching between CT-P13 and SB2 may not result in divergent immunogenicity.”

In an in vivo study of patients with chronic plaque psoriasis, safety and efficacy of cross-switching between CT-P13 and SB2 was evaluated. Investigators said Psoriasis Area and Severity Index scores taken at various intervals “did not change significantly” and “cross-switching in these patients was considered safe and effective.”

Current systems used to develop and approve biosimilars leave many gaps that could be plugged to improve confidence in these agents and satisfy clinical needs for more data, the authors wrote.

Comparisons of biosimilars are complicated by “heterogeneous single-switch study designs.”

Evolving medical scenarios in clinical practice are exposing evidence gaps.

Less long-term evidence exists for biosimilars than reference products.

Antidrug antibody development (immunogenicity) can take time to spot.

The investigators said one problem is that many surveillance studies are planned but never initiated or completed. They also stated that the nocebo effect—outcomes influenced by patients’ own levels of confidence—is also a factor of concern for cross-switching success.

“In the absence of clinical trial data, clinicians must attempt to objectively evaluate the emerging real-world cross-switching evidence within the context of the science of biosimilarity,” they said.

Mysler E, Azevedo EF, Danese S, et al. Biosimilar-to-biosimilar switching: What is the rationale and current experience? 2021;81(16):1859-1879. doi: 10.1007/s40265-021-01610-1 

Investigators said more evidence would help to convince clinicians of the safety of switching between biosimilar products.

Study: Data for Cross-Switching of Biosimilars Are Scarce but Supportive

Xbrane Biopharma, a 13-year-old startup, said it will initiate the development of biosimilar candidates referencing Keytruda (pembrolizumab) and Darzalex (daratumumab).

Pembrolizumab is a monoclonal antibody programmed death inhibitor (PD-1) used in the treatment of melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, and cervical cancer. It works by preventing tumor cells from shutting down the immune system attack on cancerous growth.

Daratumumab is used in the treatment of multiple myeloma (bone marrow cancer) and light chain amyloidosis (blood disease). It functions by binding to a glycoprotein on tumor cells (CD38) and causing apoptosis, or cell death.

Keytruda is one of Merck’s best-selling drugs, having generated $14.4 billion in 2020, up 30% from the previous year. Sales of Darzalex in 2020 totaled $4.19 billion. The product was developed by Genmab and is distributed under license by Johnson & Johnson.

Patent expirations on reference products are key to when biosimilar competition may enter the market, and the multiplicity of patents issued for individual drugs on a rolling basis makes it difficult to pinpoint those entry points on a timeline. However, the Generics and Biosimilars Initiative 

 in 2017 that the key US patents for Keytruda and Darzalex would expire in November 2036 and February 2025, respectively 

Xbrane has other biosimilars in development, though none on the market currently. These include Xlucane (ranibizumab), which references the blockbuster ophthalmology drug Lucentis for wet age-related macular degeneration, diabetic-related macular edema, and retinal vein occlusion. This biosimilar candidate is in phase 3 development.

Two others are Xcimzane (certolizumab pegol), referencing Cimzia, for rheumatoid arthritis, axial spondylarthrosis, psoriasis, and Crohn disease; and also Xdivane (nivolumab), referencing Opdivo, for melanoma, lung cancer, renal cell carcinoma, head and throat cancer, and bladder and urinary tract cancer. These biosimilar candidates are in preclinical development.

“With our high-yield platform technology, experienced team, and recently established development lab, we believe we are well positioned to accelerate the development of our portfolio,” said Martin Amark, CEO of Xbrane, in a statement.

Founded in 2008 at Stockholm University, the company has worked with MedImmune, Eli Lilly, and Daiichi Sankyo to develop cost-efficient production platforms for new drugs; but it decided the risk inherent in developing new drugs was too high and switched to a focus on biosimilars.

The company anticipated that the market for biosimilars would grow larger over time and that it could step in with its already-developed production platform and potentially compete successfully.

The company did develop 1 nonbiosimilar product: Spherotide (triptorelin), which is used in the treatment of prostate cancer, endometriosis, uterine fibroids, precocious puberty, and breast cancer. This product was first authorized for sale in Iran in 2017.

The company went public in 2016 with a listing on Nasdaq First North, a Nordic exchange, and later on Nasdaq Stockholm, in 2019.

In line with the theory that biosimilars are lower-risk products to develop than novel agents, the company states on its website that analysis of 108 biosimilar development programs in the Informa Pharma Biomedtracker database suggests an average probability for success of 78% for biosimilars, encompassing all progress from phase 1 development to marketing authorization from a regulatory authority.

“This stands in sharp contrast to the probability of success for novel drug development programs, estimated to be about 10% from entering phase 1 to marketing authorization,” the company says, basing this assumption on data from more than 10,000 novel drug development programs, also from the Informa Pharma Biomedtracker database.

“The probability of success of a biosimilar program entering phase 3 is about 95% compared with about 50% for a novel drug,” the company claims.

Development costs are also significantly lower for biosimilars, Xbrane officials state on their website. They estimate $56 million to $113 million for biosimilar development, vs roughly $1.13 billion for a novel drug.

The biosimilars estimate is low by industry standards. The Association for Accessible Medicines (AAM), a trade association of generics and biosimilars producers, has estimated between $100 million and $300 million on average for biosimilar development costs. Litigation costs, which are very much a fact of life in bringing biosimilars to market against reference company opposition, may add to that total, the AAM has stated.

Xbrane Biopharma of Stockholm, Sweden, said its next biosimilar candidates will target the demand for oncology and hematology therapeutics.

Xbrane Seeks to Bring Keytruda and Darzalex Biosimilars to Market

In midterm results for a phase 2 study presented at the the 2021 San Antonio Breast Cancer Symposium, a trastuzumab biosimilar (Herzuma) in conjunction with gedatolisib, a cell-signaling inhibitor, demonstrated an overall response rate of 58.8% with manageable toxicity in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (mBC) with a PIK3CA aberration.

The disease control rate achieved with this combination was 82.4%, investigators said. Median progression-free survival was 5.9 months.

Trastuzumab is a monoclonal antibody that targets HER2, which is overexpressed in cancers and contributes to excessive cell growth. Trastuzumab binds to the HER2/neu receptor and reduces HER2 expression and also reduces growth of blood vessels that support tumor growth.

Gedatolisib targets the mTOR/PIK3 signaling pathway, which plays a role in tumor growth and proliferation. mTOR is a protein whose signaling regulates cell metabolism, growth, proliferation and survival. And PI3K is a group of enzymes that also regulate cell growth and are implicated in the development of cancer.

In the trial, investigators sought to elucidate the value of trastuzumab in combination with gedatolisib in patients whose cancers had progressed after multiple lines of therapy.

Resistance to anti-HER2 agents with antibody-drug conjugates (ADCs) is common, especially along the mTOR/PI3K signaling pathway. ADCs combine an antigen-specific antibody with a cytotoxic payload. At least 2 anti-HER2 ADCS have been approved for HER2-positive breast cancer. One is ado-trastuzumab emtansine, which was initially approved in 2013. Another was trastuzumab deruxtecan, approved in 2020.

In this study, patients were enrolled who had HER2-positive mBC with a known PIK3CA pathologic mutation or amplification whose disease had progressed following ≥ 2 HER2-directed therapies. Patients were treated with the trastuzumab biosimilar plus gedatolisib until progression or intolerable toxicity.

Median age of patients (N = 17) was 54.5 years and premenopausal (11.8%) and menopausal (88.2%) patients were enrolled.

Following therapy, investigators said 3 patients had progressive disease, 4 had stable disease, and 10 showed a partial response. The trial will continue with enrollment up to a target 62 patients.

Kim JW, Ahn HK, Choi JG, et al. Phase II study of trastuzumab biosimilar (Herzuma) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy: KM-10A (KCSG BR 18-13) interim analysis. Presented at: 2021 SABCS; December 7-10, 2021. Poster PS16-03.

In metastatic breast cancer (mBC) resistant to multiple lines, Herzuma (a trastuzumab biosimilar) plus gedatolisib, an mTOR/PI3K signaling pathway inhibitor, demonstrated value. 

Biosimilar-Gedatolisib Combo Elicits Response in Resistant mBC

Researchers who surveyed patients and oncologists about biosimilars and switches to biosimilars from reference products said they found discrepancies between patients’ perceptions and physician perceptions of whether the information provided was adequate.

The study was presented at the 2021 San Antonio Breast Cancer Symposium. Oncologists and patients were asked the same questions following a switch to a trastuzumab biosimilar.

The widest discrepancies in perceptions were the following:

Oncologists tended more often than patients to report that information about the switch was presented in an easy-to-understand way: 58% vs 42%.

Oncologists were more likely to conclude that patents had ample opportunity to ask questions: 59% vs 35%.

Oncologists tended more often to conclude that patients were given adequate information resources about the switch: 33% vs 18%.

Patients were less likely than oncologists to have the impression that their cancer would be treated as effectively with a biosimilar rather than the reference drug (Herceptin): 43% vs 79%.

Oncologists agreed less of the time that patients understood the reason for the switch to a biosimilar: 39% vs 43%.

Oncologists were more likely than patients to conclude that patients were not worried about switching: 41% vs 24%.

Oncologists tended more often than patients to conclude that switching to a biosimilar was a “minor change” in a patient’s care: 67% vs 37%.

Investigators in this study noted that 5 trastuzumab biosimilars have been approved in the United States and with two 60-item questionnaires, they sought to elucidate patient and oncologist perspectives on switching to biosimilars and the relative levels of understanding between patients and their providers.

“Ours is the first survey comparing the experiences and perspectives of oncologists and patients,” they wrote.

In other findings, 55% of patients reported being given an option to switch from the reference drug, Herceptin, to a biosimilar. Investigators said 41% of patients surveyed said they received no prior notification of a switch. In addition, 44% of patients said they learned more about biosimilars through self-directed study than from their providers, and 41% said they had wanted more time to discuss switching to a biosimilar with their oncologist.

Areas where patients and their oncologists were in close agreement were as follows:

Patients felt involved in care decisions: 18% vs 18%.

Patients trusted their oncologists: 63% of patients vs 67% of oncologists.

Patients trusted their insurance companies: 9% of patients vs 12% of oncologists.

Patients understood reasons for switching: 43% of patients vs 39% of oncologists.

Patients emotionally adjusted to the switch: 41% of patients vs 42% of oncologists.

Patients were not worried about treatment success: 29% of patients vs 33% of oncologists.

The surveys included 33 oncologists and 143 patients. The median patient age was 50 years and for oncologists, 46 years. Patients were predominantly White (91%), but oncologists were not (39%). Investigators said 56% of patients had a bachelor’s degree and 56% had metastatic breast cancer.

Papautsky EL, Carlson M, Lustberg M. The patient-centered paradox: A US-based survey of oncologist- and patient-reported experiences with trastuzumab biosimilars. Presented at: SABCS 2021; December 7-10, 2021. Poster P2-13-13.

After a switch to a biosimilar, patients and their oncologists may not always agree on how well the switch was described or whether the patient felt involved. 

Patient-Provider Surveys Elucidate Biosimilar Switching Process in Oncology

Long-term survival findings for the trastuzumab biosimilar Ontruzant (SB3) demonstrated equivalence to the reference product (Herceptin) in a 

 of patients with human epidermal growth factor receptor 2 (HER2)–positive early or locally advanced breast cancer, investigators reported at the 2021 San Antonio Breast Cancer Symposium (SABCS).

Findings were analyzed following a medium of 68 months from patient randomization, constituting the longest monitored data to date for SB3, investigators said.

Previously, at the European Society for Medical Oncology meeting in September 2021, long-term cardiac safety and efficacy results were reported for patients (n = 367) from the same trial. The findings presented at SABCS reflect outcomes for those patients plus an additional 171, as well as stratified, comparative findings for patients exposed to reference drug lots whose quality “drifted,” or was not consistent with the standard, during the trial.

“Patients treated with reference drug ‘drifted’ lots were patients who were exposed to at least 1 vial from reference lots with a downward drift in antibody-dependent cellular cytotoxicity (ADCC) during the neoadjuvant treatment period,” authors of the study wrote.

Patients who were treated with nondrifted lots were those who received reference drug at the standard strength and formulation during the neoadjuvant treatment period.

Investigators said that the 5-year event-free survival (EFS) for patients treated with SB3 vs reference product (drifted or nondrifted) was 79.8% and 75.0%, respectively (HR 0.84; 95% CI, 0.58-1.20; 

 = .335). Investigators said this still demonstrated equivalence between the biosimilar and the reference product.

The 5-year overall survival (OS) between groups also was comparable: 92.5% for the SB3 group and 85.4% for the reference product group (HR 0.61; 95% CI, 0.36-1.05; 

“However, there was a meaningful difference within reference product arm depending on the ADCC-drift status,” authors of the study wrote.

In the comparison with nondrifted trastuzumab reference product, the event-free survival for SB3 was 79.8% vs 82.5% for the reference product (HR 1.28; 95% CI, 0.73-2.22; 

 = .391), and investigators said this demonstrated equivalence.

The OS for patients who received SB3 vs nondrifted reference product was 92.5% vs 91.4% respectively (HR 0.99; 95% CI, 0.42-2.31; 

They said 5-year EFS for reference drug patients who received drifted vs nondrifted product was 70.3% vs 82.5%, respectively (HR 2.57; 95% CI, 1.28-5.14; 

 = .008). OS for these 2 groups was 81.3% vs 91.4%, respectively (HR 3.87; 95% CI, 1.37-10.93; 

“For HER2-positive breast cancer treatment, monitoring long-term outcome is important, and we hope these five-year follow-up study results in a large group of patients provide meaningful value to the oncology society by demonstrating robust comparable long-term safety and efficacy profile of a trastuzumab biosimilar,” said Dong-hoon Shin, vice president and Medical and Lifecycle Safety Team leader for Samsung Bioepis, which developed the biosimilar SB3.

In the phase 3 study, patients were randomly assigned to receive 8 cycles of SB3 or reference drug with concurrent neoadjuvant chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide).Patients then underwent surgery and went on to receive 10 cycles of SB3 or reference drug based on previous treatment, completing 1 year of treatment.

Following the adjuvant treatment, patients were enrolled in the 5-year follow-up study.

Pivot X, Pegram MD, Cortes J, et al. Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. Poster P2-13-04.

The trial included "drifted" (nonstandard) reference product, forcing a stratified analysis to yield relevant data. 

Ontruzant Biosimilar Demonstrates Equivalence to Herceptin in 5-Year Study

Well known for aluminum, geothermal energy, and horses, Iceland may one day also be known for biosimilars, based on a mega-deal to take Reykjavic-based company Alvotech public with a $450 million investment. 

Alvotech has biosimilar candidates under development and regulatory review, but none so far on the market. The company has commercialization deals signed with multiple corporate partners and plans to market biosimilars in at least 90 countries.

The company has signed a merger deal that includes an infusion of cash and a plan to take the company public on the Nasdaq under the symbol ALVO. 

Most recently, Alvotech has been known for a

 with AbbVie, maker of the world’s best-selling drug adalimumab (Humira). Alvotech is hoping that through a legal struggle rather than a settlement, it can bring its adalimumab biosimilar (AVT02) to market earlier and on better terms than its competitors, many of whom have, in agreement with AbbVie, consented to delayed market entry.

AbbVie, however, is fighting back, contending Alvotech’s high-concentration, citrate-free formulation of adalimumab infringes its patents. Alvotech has also 

with AbbVie over the source of manufacturing information used to develop its adalimumab formulation.

Under the deal announced this week, a special purpose acquisition company (SPAC) based in the Cayman Islands, Oaktree Acquisition Corp., will merge with Alvotech, enabling a consolidation of investment funds from various corporate entities such as Suvretta Capital, Athos, CVC Capital Partners, Temasek, Farallon Capital Management, Arctica Finance, Arion Bank, and others.

“The combined company will have an implied initial enterprise value of approximately $2.25 billion and will be well positioned to continue investing in the growth of its biosimilar pipeline,” Alvotech said in a statement. Although an eventual listing on the Nasdaq is intended, a target date for the initial public offering was not announced.

Alvotech was founded in 2013. The company’s strategy so far has been to concentrate on developing biosimilar candidates and the manufacturing capacity to support commercialization of these agents once regulatory approvals have been secured. Rather than handle the marketing itself, the company has established multiple partnerships with companies better positioned to secure market share around the globe.

In this respect the company is pursuing a plan that is opposite to one announced by recent Merck spinoff 

, which is using its marketing expertise to sell biosimilars and is leaving the development of biosimilar candidates to its partner Samsung Bioepis.

Although 8 years old, Alvotech is very much a development-stage company. The company is funded largely by investor capital.

Biosimilars are highly similar in terms of safety and efficacy to the brand-name products they reference. In the United States there are 21 on the market, mostly in oncology treatment categories, but also in rheumatology, ophthalmology, and endocrinology. Newly launched biosimilars in the United States have been capturing market share at a faster rate than earlier ones, and the adalimumab market remains wide open for biosimilar competition, as the 6 FDA-approved biosimilars will not launch before 2023. The first, Amjevita (Amgen), will launch in January 2023.

The importance of the US market for adalimumab is illustrated by the revenues Humira earned in 2020: roughly $20 billion worldwide and $16 billion in the United States. The cost of a year’s treatment with adalimumab has been pegged at $77,000.

At the November 2021 Association for Accessible Medicines GRx+Biosims conference, Anil Okay, chief commercial officer for Alvotech, delivered an overview of the company's business model and plans for AVT02, which would likely be the first of the company's biosimilar candidates to come to maket, assuming a successful resolution of the litigation with AbbVie.

In September 2021, the product candidate received a positive opinion from the European Medicines Agency, whose recommendations for marketing approval are weighed by the European Commission for a final regulatory decision. The FDA also is reviewing AVT02 for possible approval.

Adalimumab products, for the treatment of autoimmune and inflammatory conditions, are on the market in the European Union, and it’s possible AVT02 could launch there much sooner than in the United States, where Alvotech must undergo a nearly year-long court process to resolve patent issues with AbbVie.

The company is banking on the high-concentration, citrate-free formulation of AVT02, but also the potential for interchangeable status in the United States, which would enable much freer substitution by pharmacists. Alvotech has subjected AVT02 to a clinical trial to demonstrate outcomes are the same if patients switch between Humira and AVT02. 

“We believe we are the first company to have demonstrated bioequivalence of repeated switches between a proposed high concentration adalimumab biosimilar and Humira,” Okay said at GRx+Biosims.

Various other companies hoping for a piece of the adalimumab pie in the United States are 

 even though market entry for most is a year off. In addition to the 6 FDA-approved adalimumab biosimilars, several more are under development.

Some companies are developing high concentration formulation products, some are going for the interchangeable designation, and some are also offering citrate-free formulations, which reduce pain upon injection. Cyltezo, a Boehringer Ingelheim adalimumab biosimilar, received an interchangeable designation in October 2021 and is citrate free, although its concentration is low (50 mg).

Okay said at GRx+Biosims that Alvotech is comfortable with its competitors’ maneuvering and remains confident in its strategy: “We have seen recent reports some competitors are just now trying to invest in interchangeability. It's great. Alvotech made this decision very early.”

To support its commercial growth, Alvotech has developed a research and development and manufacturing infrastructure that spans multiple geographic borders. “Beyond our Iceland facility, we also have very strong R&D capabilities in 2 locations in Germany. We also have our US base in Arlington, Virginia. On top of that, we are also building a second manufacturing site in China, which is going to help to ensure our medicines reach patients, not only in the European Union and US regions, but also in Asian countries,” Okay said.

Alvotech is also developing an ustekinumab (Stelara) biosimilar for the treatment of Crohn disease, ulcerative colitis, plaque psoriasis, and psoriatic arthritis. Clinical studies for the ustekinumab candidate, AVT04, were initiated in July 2021. The company also intends to bring other biosimilars to market, but these have not reached the clinical stage.  

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Treatment of Human epidermal growth factor receptor 2 (HER)–positive early stage breast cancer with a candidate biosimilar (EG12014) yielded equivalent efficacy and safety in comparison with the reference product, Herceptin, in patients who received concurrent taxane chemotherapy.

 presented at the 2021 San Antonio Breast Cancer Symposium, investigators said neoadjuvant treatment in combination with anthracycline/paclitaxel–based systemic therapy demonstrated positive outcomes for the EirGenix candidate biosimilar in a multinational phase 3 study.

The study (NCT03433313) was conducted during the COVID-19 pandemic and yet the objectives and functioning of the trial were uncompromised, the investigators said. The last patient to enroll joined the trial in March 2020.

HER2 cancer is fast growing and spreads to the lymph nodes faster than HER2-negative breast cancer. Therefore, amplification, or overexpression, of HER2 in breast cancer is associated with poorer outcomes.

Trastuzumab is a standard therapy for HER2-positive breast cancer, and the investigators said the addition of trastuzumab to neoadjuvant treatment involving anthracyclines and taxane-based therapy has improved pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS).

In this trial, they sought to verify that efficacy and safety between the reference product and EG12014 were equivalent.

In the neoadjuvant phase, investigators enrolled 807 patients and randomized them to 2 cohorts. One arm received epirubicin (90 mg/m

) every 3 weeks for 4 cycles, followed by EG12014. The second arm received the same chemotherapy regimen but with reference trastuzumab instead of the biosimilar candidate. 

Trastuzumab in both arms was administered at a loading dose of 8 mg/kg and maintenance dose of 6 mg/kg. Both arms received paclitaxel (175 mg/m

Patients subsequently underwent surgery and the trial’s primary end point of pCR was assessed.

In the adjuvant phase of the trial, following surgery, patients received the biosimilar candidate or reference product (loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) to complete a total of 12 months of trastuzumab treatment.

The investigators assessed differences in study treatments and procedures resulting from the pandemic, but said no sensitivity analysis was conducted regarding COVID-19 because virus infections were not expected to affect the primary end point analysis.

They said the primary end point, pCR of eradication of tumor from both breast and lymph nodes, was reached with a relative risk ratio (RR) of 0.992 (90% CI, 0.880-1.118) between the 2 treatment cohorts. Secondary end points of tumor eradication from breast and lymph notes also were reached.

The investigators said objective clinical response was similar between the 2 treatment arms and that EFS, OS, safety end points, and toxicity assessments also were similar between arms, supporting equivalence.

They also said incidence of COVID-19 infections was spread evenly between the 2 trial arms and did not cause any discontinuations or deaths. “The influence of the pandemic on this clinical study has been relatively low considering timing and the participating countries,” the  investigators concluded.

A trastuzumab biosimilar candidate demonstrated equivalence to Herceptin in patients with early-stage human epidermal growth factor receptor 2 (HER2)–breast cancer.