An Oncologist’s Concern About the Biosimilar Use in Real-World Patients With Cancer

Based on IQVIA’s data on prescription marketshare of biosimilar trastuzumab, bevacizumab, and rituximab, it seems that oncologists are showing little hesitation in adopting these biosimilar products for the active treatment of different cancers.

The oncology professional societies, such as the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology, have taken the stance that biosimilars should be considered valid options for the supportive treatment of cancer. Unfortunately, ASCO has not updated its policy statement on biosimilars since April 2018, before the three categories of oncology biosimilar therapies were approved. However, in October 2020, ASCO published an update to its guideline on treating early-stage breast cancer, in which it endorsed the use of biosimilar trastuzumab among the other trastuzumab-based options.

Unsurprisingly, oncologists may still be hesitant to prescribe a biosimilar to a patient who has already received the reference product (i.e., mid-cycle or between cycles). This parallels the reluctance of specialist prescribers to switch patients with other chronic disorders to biosimilars if their conditions are stable after months or years of reference drug use. Several payers, like Kaiser Permanente, have not been hesitant about encouraging switching patients to biosimilars.  

A Question of Drug Combinations

Earlier this month, at the Academy of Managed Care Pharmacy’s Partnership Forum on Biosimilars, a perfectly plausible objection to biosimilar use was raised by an oncologist. This concern is reasonable: Biosimilars like infliximab and filgrastim are not prescribed as part of multiple drug combinations. One the other hand, biosimilars like trastuzumab and bevacizumab are only rarely used as singular agents; more often, they are prescribed in combination with other chemotherapies. Furthermore, these oncolytics may be tried as part of off-label combinations, where little experience or evidence is available for use.

For example, consider Amgen’s Kanjinti® phase 3 clinical trial. Prior to FDA approval, it was tested only in combination with paclitaxel in patients with early-stage breast tumors expressing the HER2+-receptor mutation. Current guidelines from the National Comprehensive Cancer Network (NCCN) specify the use of trastuzumab with pertuzumab, taxanes, and/or anthracyclines, or with a slate of adjuvant chemotherapies, depending on hormone-receptor status, clinical stage, and metastases. Furthermore, patients with HER2+ status and bone disease will likely be receiving trastuzumab along with denosumab or zoledronic acid. In other words, many real-world patients with cancer being seen in oncology practices don’t reflect the populations enrolled in clinical trials. “How does the biosimilar work with pembrolizumab and other drug combinations?” asked the oncologist. “We don’t know the answer to those questions.”

This issue may be more concerning if not for the fact that Herceptin®, the reference product, has been produced for 20 years and has been subject to its share of lot-to-lot variation and manufacturing drift. This undercuts the argument: The same concern would have to be raised over Herceptin produced in 2005 versus Herceptin manufactured in 2011 or 2019.

Safety-Profile Differences With Bevacizumab Biosimilar?

She mentioned that in her institution, the use of bevacizumab biosimilars are specifically resisted, because the physicians reported the appearance of different (though not more toxic) side-effect profiles than seen in the investigational trials.

Their trepidation does involve the issue of extrapolation; yet, it goes beyond, into the question of confidence in prescribing. It is about obtaining a level of comfort in utilizing a biosimilar that has been proven to be sufficiently physiochemically alike to be approved by the FDA in other real-world patients with cancer. And this concern may extend beyond the question of and timing of a biosimilar switch: If a treatment-naïve patient requires bevacizumab for lung cancer, how does one convince the thoracic physician to use the biosimilar? In that case, it may well come down to coverage, if the payer or health system excludes reimbursement for the reference agent, there will be little choice.

One cannot effectively argue the marketshare figures from IQVIA. It is derived from actual overall prescriptions, and the types of specialists who prescribe hese agents is very limited. If the biosimilars have already captured 40% of the bevacizumab and trastuzumab markets as of the fourth quarter 2020, the oncologists have seemingly voted their acceptance with their pens.

One thought on “An Oncologist’s Concern About the Biosimilar Use in Real-World Patients With Cancer

  1. Dear Stanton – I think the scenario is not a “perfectly plausible objection to biosimilar use ”

    [1] you would have to disbelive the science of “targeted” therapy to expect co-prescription of denosimab or pertuzumab or paclitaxel would alter the receptor binding of trastuzumab to the HER-receptor molecule – what would be the mechanism of toxicity that you would have to invoke to explain why this would lead to loss or gain in effect?

    [2] The risk has to be put into perspective – fwhat is the risk of using combination drugs with the reference biologic brand over time? For the reference version of trastuzumab is itself not the same drug as was approved all those years ago – it has had both drift changes and step changes in production process. If in doubt about this read these two articles and ask yourself – which version of trastuzumab would you rather have been prescribed?

    [a] Pivot X, Bondarenko I, Petit T, Curtit E. Milestones over the development of SB3, a trastuzumab biosimilar. Future Oncol. 2018 Nov;14(27):2795-2803. doi: 10.2217/fon-2018-0270. Epub 2018 Jun 21. PMID: 29927335
    [b] Pivot X, Pegram M, Cortes J, Lüftner D, Lyman GH, Curigliano G, Bondarenko I, Yoon YC, Kim Y, Kim C. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer. Eur J Cancer. 2019 Oct;120:1-9. doi: 10.1016/j.ejca.2019.07.015. Epub 2019 Aug 21. PMID: 31445454

    For any physician who still has an opinion on this – ask them to say how many process changes have been made to the original reference trastuzumab since it was approved? To discover the answer – which is nealy always a total surprise to physicians – read this paper – Vezér B et al. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin. 2016;32(5):829-34.

    [3] now that there are 178 published trials of switching from a reference biologic to a bisomilar mid-treatment – do you think it is still reasonable to says this process, which is clearly endorsed by European Medicines regulators’, is unsafe? Novartis even ran a trial using an oncology biosimilar with 6 switches in 6 cyles of chemotherapy – the trial was called PIONEER, trial registration number NCT01519700

    Best wishes – Paul

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