Biosimilar Era Gets Rolling in Oncology

Francisco J. Esteva, MD, PhD

After years of discussion and debate, the oncology drug development pipeline is pulsing with biosimilar candidates for at least four of the most widely used monoclonal antibodies in cancer treatment, raising the possibility of price competition at a time of increased anxiety about rising costs.

The 2016 ASCO Annual Meeting featured phase III clinical trial results demonstrating that MYL- 1401O, a biosimilar version of trastuzumab (Herceptin), is equivalent in efficacy and safety to the branded product among patients with HER2-positive metastatic breast cancer (Rugo et al. Abstract LBA503). The Heritage study evaluating MYL- 1401O represents one of the first trials in which an oncology biosimilar has shown similar efficacy, safety, and immunogenicity against the reference product, researchers said.

The findings will help support biosimilar applications for MYL-1401O in the United States and Europe that are expected to be filed within the next several months, according to Mylan NV, a generic and specialty pharmaceutical company developing the drug along with Biocon Ltd.

Table. Therapeutic Oncology Biosimilars in Development, Selected Studies^a

^aMost trials listed on www.ClinicalTrials.gov.

^bListed on Amgen website at http://goo.gl/g1NgCb. CRC indicates colorectal cancer; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin lymphoma; NSCLC, non—small cell lung cancer; ORR, objective or overall response rate; pCR, pathological complete response.

If approved, MYL-1401O would be the first oncology therapeutic biosimilar available in the United States but industry activity suggests a wave of new agents will be coming to the market in the next several years (Table).There are multiple companies working on biosimilar versions of the monoclonal antibodies trastuzumab, rituximab (Rituxan), bevacizumab (Avastin), and cetuximab (Erbitux). The field has attracted large pharmaceutical companies that develop innovative drug portfolios, such as Amgen and Pfizer, along with generic drug makers. Many of the clinical trials are being conducted outside of the United States.

Despite the intensifying activity, however, pharmaceutical industry analysts expect the market for biosimilars to unfold in the United States at a slower pace than the number of projects underway suggests. The price discount for new biosimilars will not be as deep as a comparable new generic would be—and probably not as dramatic as initial projections— and there are important clinical and regulatory issues that remain unresolved, experts say.

Additionally, US oncology specialists and their patients may be reluctant to embrace the new drugs. “We will need a lot of education both for the patients and the physicians to make sure they’re comfortable with this approach and that we communicate this effectively to both patients and physicians,” said Francisco J. Esteva, MD, PhD, director of Breast Medical Oncology at the Perlmutter Cancer Center at NYU Langone Medical Center, during an education session presentation at ASCO.

Notably, ASCO is using its clout with oncology specialists to promote acceptance of biosimilars on a conceptual level. In February, ASCO Connection featured an article exploring what it called misconceptions about biosimilars within the oncology community including concerns about whether the reduced cost would imply a compromise on safety and whether adverse events experienced by patients would be adequately tracked (https://goo.gl/J2sMIP). “Perhaps the largest hurdle to the integration of biosimilars will be acceptance of these agents by physicians and patient consumers,” wrote Robert M. Rifkin MD, of Rocky Mountain Cancer Centers.

Current Biosimilar Landscape

“Toward this end, careful regulatory review during the approval process and rigorous postapproval monitoring of safety and efficacy will be essential in building confidence in the use of these agents.”The move to developed biosimilars in oncology therapeutics is part of a broader push across the healthcare spectrum.

The FDA approved the first biosimilar for the US market in March 2015. Zarxio (filgrastim-sndz) was approved as a biosimilar to Neupogen (filgrastim), a supportive care drug with several cancer indications including for patients undergoing myelosuppressive chemotherapy or bone marrow transplantation. In April, the agency approved Inflectra (infliximabdyyb) as a biosimilar for Remicade (infliximab), whose indications including rheumatoid arthritis. As of May, 60 biosimilar programs involving 19 reference products were participating in the FDA’s biosimilar development pathway, Steven Lemery, MD, MHS, associate director of the FDA’s Division of Oncology Products, said in an ASCO presentation.

However, only five sponsors had announced the submission of eight biosimilar applications as of December 2015. These include two applications for biosimilar versions of pegfilgrastim (Neulasta) and one for filgrastim.

In oncology, development efforts are being fueled by patent expirations on the branded products; in the United States, key patents are expiring from 2016 through 2019 on rituximab, trastuzumab, and bevacizumab (Cancer Treat Rev. 2016;46:73- 79). These agents have topped the list of the world’s best-selling cancer drugs for years.

To some industry observers, the pace of biosimilar development in the United States has been glacial thus far, particularly considering that the European Medicines Agency has been approving biosimilars since 2006. There are now 20 authorized and available biosimilars in the EMA’s 28 member states. These include five biosimiliars for epoetin and eight for filgrastim but no therapeutic cancer drugs.

The EMA has 14 biosimilar marketing applications including one for a rituximab biosimilar under review, according to Martina Weise, MD, an EMA official who offered a European perspective at ASCO.

Meanwhile, other countries have approved therapeutic oncology biosimilars. These include biosimilars for trastuzumab in Korea and bevacizumab in Russia, according to reports.

In the United States, biosimilars for the top three oncology drugs are expected to be introduced within the next 5 years, said Ryan Million, PhD, a partner at Trinity Partners, a strategic life sciences consulting company, in an interview with OncologyLive. Although biosimilars would generate savings for the healthcare system, the price discount would not be an immediate bonanza. Biosimilars are likely to launch onto the US market at a 10% to 15% discount from the branded drug as opposed to a generic drug with a deeper discount, said Million.

The biosimilar discounts could be as steep as 40% to 50% of the reference drug price within 5 years, Million noted.

“There’s reason to believe that biosimilar adoption in the long run will happen but will play out over time,” said Million. “…Unlike a small-molecule generic partnership, this is going to be a little bit more slow motion.”

There are key outstanding questions about biosimilars in the United States that will affect their development, Million indicated. These include whether a biosimilar drug approval in one indication could be extrapolated to other indications for which the reference product already is approved and whether the biosimilar drug is deemed to be interchangeable with the original product, thus enabling it to be automatically substituted.

“All of those dynamics about substitution have yet to be worked out,” Million said. “I think it will happen over time. That’s one of the reasons it’s going to take several years for biosimilars to be adopted in the US market.”

Million also noted that Europe has single-payer healthcare systems that are driving the uptake of biosimilars by prescribing physicians. By contrast, the United States has more of a free market system and oncologists in particular have the ability to make their own therapeutic choices.

How the FDA Decides

US oncologists are going to want to believe that a biosimilar product can perform in the same way as the branded drug and may be reluctant to extrapolate a biosimilar to an indication for which it has not been specifically tested even in the same tumor type, Million said.The FDA defines a biosimilar as a biological product, derived from a living organism, that is approved based on whether it is shown to be highly similar to an already approved biological product with no clinically meaningful differences in terms of safety, purity, and potency from the reference product. The biosimilar drug must use the same mechanism of action, route of administration, dosage, and strength as the reference product.

The agency determines whether a drug is a biosimilar based on the “totality of the evidence.” This includes analytical studies of the drug’s properties, animal studies where toxicity would be assessed, and a clinical study to establish how the drug performs in a human population.

“The goal of biosimilar development is not to independently reestablish the safety and effectiveness of the US-licensed reference product,” Lemery said in his ASCO presentation. “Rather, the goal is to demonstrate biosimilarity.”

Although biosimilars are more complex to produce than a generic version of a small molecule because of their dynamic nature, Lemery noted that the reference biological products are not static agents either. “Approved or innovator products are also not identical to themselves from batch to batch and lot to lot,” he said.

When it comes to determining whether a biosimilar agent should be approved for all indications in which the reference drug is indicated, another layer of scientific justification is required. The key question is the extrapolation from the clinical setting where a study was conducted into other areas without an additional trial.

Lemery said the FDA’s process was designed with extrapolation in mind. “If the program is implemented to its fullest extent, the biosimilar pathway has the potential to facilitate increased access and decrease the cost,” Lemery said.

Study Supports Biosimilar Trastuzumab

The EMA’s Weise put the need for extrapolation more starkly. “The reduced clinical program with the possibility to extrapolate is the single greatest benefit of biosimilar development,” she said. “Without that possibility, that pathway of biosimilars would be dead. However, it is also the most contentious issue.”In order to develop MYL-1401O, investigators chose a treatment setting in which the agent already has demonstrated a clear signal of activity, lead investigator Hope S. Rugo, MD, a professor of Medicine and director of the Breast Oncology Clinical Trials Program at the UCSF Hellen Diller Family Comprehensive Cancer Center, indicated during an ASCO presscast.

In the Heritage trial, 500 patients with measurable HER2-positive metastatic breast cancer who had not received prior chemotherapy or trastuzumab for metastatic disease were randomized to receive either MYL-1401O or Herceptin with docetaxel or paclitaxel. Response data were reported for 458 patients, including 230 in the MYL- 1401O arm and 228 in the Herceptin arm.

The trial was conducted at more than 90 locations outside the United States including in Brazil, Europe, India, and South Africa, according to the ClinicalTrials.gov website (NCT02472964).

Participants were treated for a minimum of 8 cycles, with trastuzumab continuing until progression.

Both forms of trastuzumab were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression- free survival, overall survival, time to progression, safety, and tolerability.

After 24 weeks, MYL-1401O demonstrated an ORR of 69.6% among women who received the biosimilar in combination with a taxane compared with a 64% ORR for patients who took Herceptin plus a taxane. The ratio of ORR for MYL-1401O to Herceptin was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237) were within the predefined equivalence margin.

Safety data also were comparable. Serious adverse events (SAEs) occurred in 38% of the patients in the MYL-1401O arm compared with 36.2% in the Herceptin arm, with neutropenia as the most frequently reported SAE in both arms (27.5% vs 25.2%, respectively). There were four fatalities in each arm of the trial and, notably, no significant change in cardiac function from baseline to week 24 in either group, according to the conference abstract.

A version of MYL-1401O already has been used in India, generating additional safety and pharmacovigilance data, said Rugo. “There is actually quite a substantial body of safety data for this agent,” she said.

“The drug is very safe,” Rugo said in an interview. “The only toxicities we saw were related to the chemotherapy—really none that we could directly attribute to the antibody.”

Looking for Savings

For its part, Genentech, which developed Herceptin, stressed the years of data that have accumulated about the branded product. Initially approved in 1998 by the FDA, Herceptin is indicated in HER2-overexpressing breast cancer in adjuvant and metastatic settings as well as in HER2-positive gastric cancer. “Until there is more direct clinical experience with biosimilars, it will be important to closely monitor safety and effectiveness to ensure there are no meaningful differences that would impact patients," Genentech said in a statement. “It’s also important to consider that biosimilars are approved under an abbreviated FDA pathway. At the time of approval, biosimilars will have a more limited set of clinical data than the original medicines.”Healthcare systems throughout the world are looking toward biosimilars as a means of saving money on the cost of cancer care. Rugo referenced this goal in discussing MYL-1401O.

“It is expected that having biosimilars will reduce the costs by some amount worldwide for these agents,” said Rugo. “In the United States, most patients have insurance coverage that covers branded trastuzumab and we haven’t had any other option. I have not ever seen a situation where it wasn’t covered for a standard indication. In the US, it’s less of a financial issue in terms of access to drugs but having alternative agents will be important worldwide.”

For US patients, concern has been growing about the “financial toxicity” of cancer treatment, as even patients with insurance are paying a rising share of costs. In the United States, Herceptin costs approximately $5500 per month, although the cost for a course of treatment varies by indication, according to Genentech. Treatment in the metastatic breast cancer setting is approximately $41,100 based on a drug course of approximately 7.2 months; a patient with early-stage breast cancer typically takes Herceptin for 52 weeks and a 12-month course of treatment costs approximately $70,200.

The company said it employs more than 350 people to help patients gain access to their drugs through services such as providing free medicine for the uninsured and assistance with co-pays.

Regardless of the specifics of current trastuzumab pricing, the broad goal of the biosimilar pathway “is to have more drugs available,” Rugo said. “The impact is that for patients who can’t afford the drug, this drug may be less expensive,” she said of MYL-1401O in an interview. “If nothing else, it will cause competition between branded Herceptin and the biosimilar, so maybe we’ll get a good price deal for people who are working as a group so that they can better afford the drug.”