Existing biosimilars are safe, effective alternatives to their reference biologics, and are increasingly being incorporated into oncology treatment guidelines.

Technological advances that have emerged in the years since biologic agents entered the market allow for the careful assessment of “critical clinical attributes” of biosimilar agents. This helps ensure the safety and efficacy of biosimilars, as well as their structural, functional, and behavioral similarities to the original reference biologics, according to Gary Lyman MD, MPH, professor and senior lead, health care quality and policy at the Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, Seattle.

Biosimilars are increasingly being included as acceptable alternatives in treatment guidelines, and in this episode Dr. Lyman discussed the reasons why they are considered safe and effective, how they can add value for oncology patients, and the need for ongoing diligence in monitoring their effects.

Biosimilars in oncology – key points:

• The developers of biosimilar agents must prove biosimilarity to the reference agent, and generally go through “many of the same, if not all, preclinical steps.” Regulatory requirements are sufficient to ensure there are no clinically meaningful differences in the safety, purity, strength, and efficacy of biosimilars.
• Unlike the originator biologics, biosimilars aren’t typically required to complete multiple costly phase 3 clinical studies that drive up drug costs. This has the potential to rein in drug prices for biologics, which have revolutionized oncology and many other fields – but at a significant price.
• There has been some progress with respect to biologic cost reductions in the wake of biosimilar approvals, but the cost effects of biosimilars for newer reference agents will take time to emerge. Further prolonging the cost-reducing effects of biosimilar availability is the fact that early biosimilars were mainly used for supportive care whereas newer biosimilars are more often used for curative intent, which may lead to slower uptake due to hesitancy among clinicians and patients.
• The European Medicines Agency (EMA) is about a decade ahead of the United States when it comes to approvals and acceptance of biosimilars. Of note, no approved biosimilar has been removed from the market due to concerns about safety and efficacy. This is “a huge testament to the durability of biosimilars and the strength of the regulatory process,” Dr. Lyman said, noting that the EMA and FDA have similar processes when it comes to such approvals.
• “Drift,” the inevitable changes over time in an agent’s characteristics, can lead to changes in safety and efficacy. This means that diligence in monitoring effects and outcomes with both biologics and biosimilars is essential. Any concerns should be reported immediately and investigated.

Show notes written by Sharon Worcester, MA, a reporter for MDedge and Medscape.

Disclosures

Dr. Henry has no relevant disclosures. Dr. Lyman disclosed relationships with Amgen, Jazz Pharmaceuticals, Partners Therapeutics, Sandoz, Seattle Genetics, Bristol Myers Squibb, BeyondSpring, Samsung, G1 Therapeutics, and Merck.

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Systemic treatment for advanced urothelial cancer is quickly evolving. On this week’s podcast, Arjun Balar, MD, director of the genitourinary medical oncology program at New York University discusses his approach amid changing times with guest host Alan Lyss, MD, a community-based medical oncologist and clinical researcher in the St. Louis area before his recent retirement. 

Chemotherapy or immunotherapy first line?

• With the negative phase 3 results for chemotherapy in combination with either pembrolizumab or atezolizumab, “if I use immunotherapy, I use it alone,” Dr. Balar said.
• Patients who need “a response right away” for aggressive disease get chemotherapy. In general, first-line chemotherapy “probably is the better route for a lot of people,” he said.
• There is a role for immunotherapy in the first line when chemotherapy can’t be tolerated because of age or other reasons, and in the second line, immunotherapy is standard of care.
• PD-1/PD-LI expression is too inconsistent to help guide the decision. It’s based instead on clinical judgement, given patient and disease characteristics.

Antibody-drug conjugates

• The class includes enfortumab vedotin and sacituzumab govitecan, both approved for third-line treatment after chemo and immunotherapy.
• Essentially, they are homing molecules targeting cancer-specific antigens coupled with a potent cytotoxic payload.
• They have strong potential in combination with immunotherapy. “I think, in the next 3-5 years, we're going to find ADCs plus immunotherapy become the new standard of care,” Dr. Balar said.
• New enfortumab vedotin data show activity in the second line among medically frail patients ineligible for chemotherapy who were treated instead with immunotherapy for metastatic disease. “This drug can potentially rescue those patients as an option after immunotherapy,” said Dr. Balar, an enfortumab vedotin investigator.

Next-generation sequencing

• There’s no role yet for sequencing in the first line, but it’s necessary in later lines to check eligibility for drugs aimed at specific mutations, such as the tyrosine kinase inhibitor erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations.
• Assays are available commercially from Foundation and other companies.
• Results can take up to 6 weeks, so “I do it early on. I know that information is potentially going to be useful in making treatment decisions,” Dr. Balar said.

Enfortumabe vedotin adverse events

• Side effects can include hyperglycemia within the first one or two cycles. Sometimes it’s asymptomatic, sometimes it’s accompanied by acid-base disturbances, and in very rare cases, it’s fatal. The problem is possibly linked to higher baseline body mass index.
• At least half of patients develop a sunburn-like rash, also within the first one or two cycles, that spares the face and can be pruritic. It’s manageable by topical steroids, oral antihistamines, dose reductions, or dose interruptions.
• “If anything severe is going to happen, it's going to happen within the first one or two cycles. I see [patients at] every visit” in the first two cycles “primarily to catch anything untoward,” Dr. Balar said.
• Neuropathy is the “most significant dose-limiting toxicity, and tends to develop about 4 months into treatment,” he said.

Show notes written by M. Alexander Otto.

Dr. Balar disclosed research, advisory, and/or speaker relationships with Genentech, Incyte, Bristol-Myers Squibb, Janssen, Merck, Pfizer, AstraZeneca, and other companies. Dr. Lyss writes a column for MDedge Hematology/Oncology called “Clinical Insights” and had no other conflicts of interest.

A “very basic” type of gene therapy could potentially cure hemophilia, but a major hurdle has been the lack of an effective mode of delivery. Recent strides in using adeno-associated virus (AAV) vectors are changing that, and Glenn Pierce, MD, World Federation of Hemophilia Vice President, Medical, predicts approvals in the next 12-18 months.

Dr. Pierce shared his personal experience with hemophilia and discussed his and others’ ongoing research on the use of AAV-mediated gene therapy with host David Henry, MD, in this episode.

Hemophilia and AAV gene therapy key points:

• Hemophilia is caused by a monogenic defect and could, theoretically, be cured by gene replacement or augmentation, says Dr. Pierce, who notes that “it sounds disarmingly simple, but behind that simplicity is a very complex procedure.”
• The approach uses “gene addition,” which is a basic gene therapy involving the addition of a normal gene to the variant in an individual. This ultimately corrects the clotting factor deficiency.
• The complexity is in getting the normal gene into the body where it can have the intended therapeutic effect.
• After more than 20 years of working to overcome that barrier, Dr. Pierce and others are finding success with using AAVs.
• The approach has some similarities to that used in developing the mRNA COVID-19 vaccines but requires the use of DNA established within the virus (rather than mRNA) to provide a more stable effect. Questions about how long it will last are currently being investigated.
• Multiple phase 3 trials are underway or completed. Data from two of those have been released in recent months, and the results are very encouraging: “It’s a remarkable achievement – many patients are doing well and, for all intents and purposes, could be considered free of [hemophilia],” Dr. Pierce says, adding that he would “potentially … use the ‘C word’ – cured – for at least a period of time.”
• The therapy is generally well tolerated. Efforts are ongoing to identify the best ways to proactively and reactively use prednisone to manage side effects such as mild increases in transaminase levels.
• To date, the risk-benefit profile appears reasonable for patients with clotting factor IX deficiency, and it is likely that the therapy in that setting “will march toward the regulatory process to determine if it’s safe and effective for approval,” he said.
• Responses in those with clotting factor VIII deficiency have been more variable, with some patients requiring long-term prednisone use, which is problematic. More information is needed about this, but investigation is ongoing, he said.
• Registries are available and many companies are involved in clinical trials. Clinicians and patients can look for information at clinicaltrials.gov, wfh.org (which publishes trial results and conducts workshops and meetings), and at the US National Hemophilia Foundation (Hemophilia.org) and the Society of Thrombosis and Hemostasis (ISTH.org).

Show notes written by Sharon Worcester, MA, a reporter for MDedge and Medscape.

Disclosures

Dr. Henry has no relevant disclosures. Dr. Pierce disclosed relationships with Ambys Medicines, BioMarin, BridgeBio, CRISPR Therapeutics, Decibel Therapeutics, Frontera, Geneception, Generation Bio, Novo Nordisk, Pfizer, Regeneron, Third Rock Ventures, Voyager Therapeutics, Global Blood Therapeutics, VarmX SAB, the National Hemophilia Foundation Medical and Scientific Advisory Council, and the World Federation of Hemophilia.

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For more MDedge Podcasts, go to mdedge.com/podcasts

Email the show: podcasts@mdedge.com

Interact with us on Twitter: @MDedgehemonc

David Henry on Twitter: @davidhenrymd