Immunotherapy with drugs that act as checkpoint inhibitor drugs has had a dramatic impact on the treatment of many different cancer types.
But the rapid expansion of this class of drugs has “largely been uncoordinated,” resulting in a growing number of problematic issues, say top officials at the Food and Drug Administration (FDA).
“The unbridled and rapid growth of checkpoint inhibitors has led to a ‘Wild West’ of drug development, featuring a stampede of commercial sponsors, clinical trials, and redundant development plans,” write Julia A. Beaver, MD, and Richard Pazdur, MD, both from the FDA.
They co-authored a perspectives article published November 15 in the New England Journal of Medicine.
The FDA has approved seven checkpoint inhibitors in the last seven years, for more than 85 oncology indications.
These drugs are antibodies directed against the programmed death 1 (PD-1) or programmed death ligand (PD-L1) pathway, and the seven approved drugs are: atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab (Libtayo), dostarlimab (Jemperli), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda).
Lots more are on their way to market — there are currently more than 2000 clinical trials investigating at least 33 new anti–PD-1 or anti–PD-L1 antibody products, the FDA authors note.
They all have similar, if not identical, mechanisms of action, safety profiles, and clinical activity — but these drugs have not been formally compared in studies, they point out. This proliferation of “me-too” drugs is expensive, and these “duplicative development programs may erode the resources available for innovation,” they write.
Manufacturers making claims about “developing ‘a better’ checkpoint inhibitor should directly compare their agent with those that are already approved,” the authors comment. “Unfortunately, there is no evidence that such randomized trials are underway.”
“This rapid expansion of the checkpoint inhibitor class has largely been uncoordinated,” they continue. “These efforts have thus led to large financial expenditures on separate development programs for each antibody, including investments in manufacturing processes, nonclinical studies, in vitro diagnostic tests, and the clinical trials required for approval.”
Beaver and Pazdur point to the use of multiple in vitro diagnostic tests that are currently being used to select patients who may be the best candidates for immunotherapy. Thus far, there are three different approved companion diagnostics that detect PD-L1 expression, as well as tests being developed that have various cutoff points. There is a lack of consensus as to whether these different tests identify the same patient groups, and most indications for checkpoint inhibitors have been approved among patients who were unselected for biomarker status.
Another issue is the increasing belief in industry that the future of drug development in oncology lies in using combination treatments involving immunotherapy.
“Many have leapt to develop or license unapproved antibodies for use in combination regimens,” they write. “These development programs, which frequently do not isolate the effects of the combination’s components, are problematic because the safety and efficacy of the new antibody has not been established and extrapolation from an approved checkpoint inhibitor is not legally possible.”
‘Dangling’ Accelerated Approvals
Then there is the issue of “dangling” accelerated approvals for drugs that show benefit on a surrogate endpoint (such as response rate) but then fail to show clinical benefits (eg, on survival) in later clinical trials.
The FDA has identified 10 such dangling approvals. Of these, four were voluntarily withdrawn due to low response rates. The remaining six were discussed at an April 2021 meeting of the Oncologic Drugs Advisory Committee; three were slated to be withdrawn and one was converted to regular approval for a more limited indication. Two others are in the middle of confirmatory trials and regulatory review.
Finally, the FDA authors say that collaboration is needed for more efficient drug development and optimized use of resources. The agency has tried to foster collaboration, but it is limited in its ability to compel drug manufacturers to work together, Beaver and Pazdur write.
“Competitive commercial interests may frequently trump cooperation,” they add.
Beaver is chief of medical oncology in the FDA Oncology Center of Excellence (OCE) and acting deputy director in the Office of Oncologic Diseases in the Center for Drug Evaluation and Research at FDA. Pazdur is the director of the FDA OCE.
N Eng J Med. Published online December 15, 2021. Full text
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