Biosimilars to Avastin and Herceptin Head for US Market

Pam Harrison

July 14, 2017

Two important cancer biosimilar products, equivalent to bevacizumab (Avastin, Genentech/Roche) and trastuzumab (Herceptin, Genentech) have been judged by the Oncologic Drugs Advisory Committee (ODAC) of the Food and Drug Administration (FDA) to be pure, potent, and safe enough to be recommended for approval.

The bevacizumab biosimilar, ABP 215, developed by Amgen, Inc, received a vote of 17 in favor, with no votes against or and no abstentions. ODAC members concluded that it is a highly similar, high-quality product and that there are no clinically meaningful differences between it and the reference product, Avastin. As such, the voting committee approved the use of ABP 215 for the same indications for which the reference drug is currently approved.

Similarly, the trastuzumab biosimilar, MYL-1401O, developed by Mylan GmbH, received a vote of 16 in favor, with no one voting against and no abstentions. ODAC members concluded that there were no clinically meaningful differences between this product and the reference product, Herceptin.

The biosimilar trastuzumab could be used for the treatment of adjuvant and metastatic HER2+ breast cancer, given either as monotherapy or in combination with approved chemotherapy regimens, depending on the stage of the disease being treated, the panel members said.

However, MYL-14010 was not approved for use in HER+ metastatic gastric cancer, because Herceptin has a protective approval for this disease that will be in effect for several more years.

"Worldwide, there is limited access to treatment for patients with HER2+ breast and gastric cancer, particularly for expensive drugs like Herceptin," Hope Rugo, MD, professor of medicine, University of California, San Francisco, told the meeting. She was presenting data to show that MYL-1401O was highly similar in efficacy and safety to trastuzumab.

"Biosimilars for both of these drugs have the potential to expand patients' access to important treatment options," she added.

ABP 215 vs Bevacizumab

Members of the Amgen Inc research team first presented fastidious data proving that their biosimilar was analytically similar to trastuzumab with respect to structural, functional, and purity attributes.

Analytically similar results are critical, pointed out by Richard Markus, MD, PhD, Amgen Global Development, because similarities justify the extrapolation of findings from clinical studies undertaken for one indication for ABP 215 to all indications for which the reference drug is approved.

"Given that vascular endothelial growth factor binding and neutralization is the mechanism of action across the different types of tumors, the analytical similarity between ABP 215 and bevacizumab provides compelling evidence in support of extrapolation," the Amgen team said.

A pharmacokinetic study carried out in 202 healthy male volunteers also demonstrated that the pharmacokinetic dynamics of Amgen's product was largely comparable to that of Avastin licensed in the United States, Dr Markus also demonstrated.

Most importantly, a comparative study involving 642 patients with advanced non–small cell lung cancer (NSCLC) showed that ABP 215 performed virtually identically to bevacizumab when delivered together with carboplatin and paclitaxel.

For the study, 328 patients were randomly assigned to receive six cycles of ABP 215 at a dose of 15 mg/kg; 314 other patients received six cycles of bevacizumab, given at the same dose. Both drugs were administered intravenously together with four to six cycles of either weekly paclitaxel or, more commonly, docetaxel, given every 3 weeks.

"After the sixth dose, subjects were followed for adverse events (AEs) for 21 days, and that was the end of the treatment phase," Dr Markus noted.

However, patients remained in the study to enable detection of any differences in progression-free survival (PFS) until study endpoint or until patients received any other anticancer treatment, at which point patients' participation in the study was terminated.

The overall response rate — either complete response (CR) or partial response (PR) — as documented by CT scans admnistered through an independent central radiation review was 39% in the APB 215 arm vs 41.5% for the bevacizumab arm.

There were two CRs in each treatment arm and 126 vs 129 PRs in the ABP 215 vs bevacizumab arm, respectively.

The magnitude of tumor response in terms of a reduction in tumor size was also very similar between the two arms, Dr Markus added.

PFS was also virtually identical for the two arms, at 39.9% for ABP 215 and 39.8% for bevacizumab.

For those who achieved a tumor response to initial therapy, the median duration of response was again similar, at 5.8 months for APB 215 and 5.6 months for bevacizumab, he noted.

Side effects were also similar, including AEs of particular interest, such as neutropenia, hypertension, venous and arterial thromboembolism, gastrointestinal perforation, and infusion reactions.

Table. Adverse Events Associated With Each Study Protocol

  APB 215 Bevacizumab
AEs of grade 3 or greater 42.9% 44.3%
Serious AEs 26.2% 23%
Fatal AEs 4.0% 3.6%

 

Very few patients developed drug antibodies in either group, Dr Markus noted, and none of the patients in either group developed neutralizing antibodies, demonstrating that both agents have comparable immunogenicity profiles.

"This study demonstrated similar efficacy, safety, and immunogenicity [between APB 215 and bevacizumab]," Dr Markus said.

"And we conclude that ABP 215 is highly similar to bevacizumab with no clinically meaningful differences in any clinical parameter," he concluded.

Members of the FDA in turn analyzed all aspects of bioequivalence data presented by Amgen for their biosimilar and pronounced the data valid and robust.

Voting Members Approve

With their unanimous endorsement of APB 215, members of the ODAC voting panel agreed with the company's and with the FDA's conclusions that the biosimilar is equivalent to bevacizumab.

"I thought the analytical package was very strong, well laid out, and in my view, very convincing," Antonio Moreira, PhD, professor of chemical, biochemical, and environmental engineering, University of Maryland, Baltimore, said, adding that the clinical information presented by Amgen was also "very persuasive."

"I think both the sponsor and the FDA presented convincing analytical, preclinical, PK, and clinical data demonstrating that ABP 215 is sufficiently similar to Avastin," said Thomas Uldrick, MD, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

"I also appreciated the sponsor's scientific justification for extrapolation [of the data] to other indications for bevacizumab, as I believe the mechanism of action is substantially similar across tumors for all indications," he added.

Gregory Riely, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City, also endorsed the validity of data demonstrating that this new molecule is highly similar to licensed Avastin in the United States.

"I'm particularly impressed by the uniformity of the results in the clinical trials they observed," Dr Riely noted.

"When we do clinical trials, there are all sorts of opportunities for variability, and we didn't see significant variability between the two arms in their trial," he added.

Deborah Armstrong, MD, MPH, Dana Farber Cancer Institute, Boston, Massachusetts, was also impressed by the "really remarkable data" presented in support of APB 215, as well as the clinical findings with regard to the comparable efficacy and toxicity of the two products.

"In an ideal world, it would be nice for each of the indications to have a trial like the one the company had for NSCLC, but that's a hurdle we shouldn't be putting in the way of getting at those other indications," Dr Armstrong said.

"Since we make extrapolations in the clinic all the time, I think it's reasonable that [we consider APB 215] for all of the current indications for bevacizumab," she added.

Indications for which ABP 215 may now be considered include first-line or second-line treatment of metastatic cancer of the colon or rectum given with a variety of approved combinations.

The biosimilar may also now be used as first-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC, again in combination with approved lines of chemotherapy as well as for the treatment of patients with progressive glioblastoma and women with persistent, recurrent, or metastatic carcinoma of the cervix.

MYL-1401O vs Trastuzumab

Following the same format, Mylan GmbH researchers presented analytical and nonclinical data supporting the similarity between their candidate molecule and the reference product, Herceptin (trastuzumab), which is licensed in the United States.

The MYL-1401O scientists demonstrated that their product was structurally and functionally similar to Herceptin, notwithstanding minor differences in clinically inactive components.

"Pharmacokinetic data again showed that MYL-1401O is bioequivalent to Herceptin," added Abhijit Barve, MD, PhD, head of global clinical research of Mylan.

Mylan's clinical studies program for MYL-1401O is more extensive than that for ABP 215. The most important study was the phase 3 HERITAGE study, in which the safety and efficacy of MYL01401O 2343 were compared to that of Herceptin in patients with HER2+ metastatic breast cancer (MBC). Results from this study were presented at an annual meeting of the American Society of Clinical Oncology (ASCO), as reported at the time by Medscape Medical News.

A total of 500 patients were randomly assigned to receive either MYL-1401O or Herceptin given together with docetaxel or paclitaxel for a total of eight cycles. Both biologics were continued as monotherapy until disease progression in patients who had at least stable disease following 24 weeks of concomitant chemotherapy.

As Dr Barve explained, data up to week 48 are currently available, but the study will continue for 36 months.

At week 24, the overall response rate was 70% for the MYL-1401O arm vs 64% for the Herceptin arm, confirming comparable efficacy between the two arms.

PFS rates at week 48 again support absolute equivalency between the two biologics, with an equal number of events occurring in both arms at 44.3% in the MYL-1401O arm and 44.7% in the Herceptin arm.

Estimated PFS rates at week 48 were 11.1 in both arms. Medium overall survival has not yet been reached.

"Overall, rates of grade 3 or higher AEs and serious AEs at week 48 were comparable across both arms, and most of the events appeared to be related to concomitant taxane use during the first 24 weeks of therapy," Dr Barve noted.

There were no meaningful differences in rates of AEs of particular interest, such as cardiac toxicities, and immunogenicity profiles were almost identical.

The FDA reviewed all analytical, preclinical, pharmacokinetic, and clinical efficacy and safety data and pronounced them to be scientifically convincing.

Clinical Practice

Commenting on the findings, Dr Rugo noted that the potential use of MYL-1410O in clinical practice is quite significant.

"Any patient who would receive Herceptin will be a candidate for this agent," she noted, "and newly diagnosed HER2+-disease patients will have an option to start treatment with a lower-cost biosimilar," she added.

Dr Hendrix also felt that evidence was "very strong" in showing that the two products were highly similar and that there were "no clinically meaningful differences between the two agents."

He also felt the science supported extrapolation for proposed indications.

"I think the scientific justification for extrapolation of the data to HER2+ gastric cancer is also reasonable," Dr Uldrick agreed.

Donald Mager, PharmD, PhD, professor of pharmaceutical sciences University of Buffalo State University of New York, also agreed that the extrapolation of data allowing MYL-1401O to be used in other settings of HER2+ disease is "scientifically sound."

"The clinical studies showed no signal at all of any clinically important differences between the two products," noted Bernard Cole, PHD, professor of mathematics and statistics, University of Vermont in Burlington.

Courtney Preusse, Fred Hutchinson Cancer Research Center, in Seattle, Washington, commented that she felt the equivalence results for MYL-1401O appeared to be "very solid."

Dr Armstrong noted that if applied to the metastatic setting, MYL-1401O will almost immediately be used with pertuzumab.

"It would be very nice for us to have some data on the use of this biosimilar with pertuzumab," Dr Armstrong commented.

"But I do think MYL-1401O is biosimilar to trastuzumab, so I voted to recommend approval," she added.

Dr Rugo's institute has received research funds from Genentech/Roche, and she received travel support from Mylan.

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