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Thursday, April 8, 2021

3 Questions on… When Enthusiasm for New Cancer Drugs Is Premature

With Bishal Gyawali, MD, PhD, of Queen's University Cancer Research Institute, Kingston, Ontario, Canada

By Sarah DiGiulio

Results from the randomized, controlled ADAURA trial, which evaluated the EGFR tyrosine kinase inhibitor osimertinib versus placebo in the adjuvant setting for patients with stage IB-IIIA EGFR mutation-positive non-small cell lung cancer were first presented at the 2020 ASCO Annual Meeting and published online ahead of print in the New England Journal of Medicine (2020; doi: 10.1056/NEJMoa2027071). The data revealed osimertinib indeed improved disease-free survival significantly, stirring much enthusiasm.

But in a new “Comments and Controversies" article in the Journal of Clinical Oncology, Bishal Gyawali, MD, PhD, cautions the excitement may be premature (2021;39:175-177). Gyawali is a medical oncologist and Assistant Professor of Public Health Sciences in the Division of Cancer Care and Epidemiology at the Queen's University Cancer Research Institute in Kingston, Ontario, Canada.

“As an adjuvant therapy for stage IB-IIIA EGFR mutation-positive non-small cell lung cancer, osimertinib currently provides only evidence of exceeding the very low bar of disease-free survival in this setting with no evidence yet of improvement in overall survival against an appropriate control arm. The decision of the independent data monitoring committee in favor of early termination focused only on a clinically dubious surrogate endpoint that is not instructive about whether it confers a survival benefit to patients," Gyawali and coauthor, Howard (Jack) West, MD, a medical oncologist and Associate Clinical Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, noted in the article.

The article also brings up the question of quality of life for patients on osimertinib. The drug is considered a well-tolerated drug, but the trial data shows it was associated with diarrhea in 46 percent of patients (2% with grade 3 or higher), paronychia in 25 percent of patients, and stomatitis in 18 percent of patients.

In an interview with Oncology Times, Gyawali shared more about the ADAURA trial and why he co-penned the JCO commentary article now.

1. What were the main red flags you wanted to raise about the ADAURA trial in your article?

“The ADAURA trial has been hailed as a game-changer in the lung cancer community. As we predicted, FDA also ended up approving osimertinib for this indication based on this [ADAURA] trial. We thought that the enthusiasm for ADAURA was emblematic of the deeper issue in oncology of too much enthusiasm for the new and jumping onto the cheerleading bandwagon without critically reviewing the data.

“We argue that, not only ADAURA, but all cancer drug trials should be evaluated on the principles of 3Es—evidence, ethics, and economics.

“In the case of ADAURA, the problems related to evidence were use of a surrogate endpoint in the adjuvant setting, early termination of trial, and lack of data on what percentage of patients received osimertinib at relapse. With regards to ethics, early termination of trial, substandard brain imaging, [and] low proportion of patients receiving standard adjuvant treatment were issues with ADAURA. Three years of adjuvant therapy with an expensive drug will have economic ramifications, which should be considered before recommending this as standard of care based on no survival data yet.

“Mature data showing overall survival benefit and transparent disclosure of brain imaging and results stratified by brain imaging and receipt of osimertinib at relapse should be provided."

2. Why is the cost question an important one when it comes to osimertinib?

“Cost is only one part of the equation, but an important one. We should also consider the quality of data and the magnitude of benefit.

“Having said that, what's the point in having a drug that does not reach patients because of unaffordability? Both high cost and low probability of clinical benefit should make us question the value of a drug, not hail it as a game-changer."

3. What's the bottom-line message that oncologists and the cancer care community should know about the ADAURA trial and how the criticisms you raise in the article apply to other drug trials, too?

“Drugs for the adjuvant setting should be held to a higher standard than metastatic setting because, in the adjuvant setting, by definition, we are overtreating many patients to help a few, response assessment during therapy is impossible, and quality of life can only have detrimental effects. Thus, without solid evidence of survival gains, the risk-benefit trade-off here tilts naturally towards greater harms and lower benefit.

“Trials should be evaluated critically for the use of surrogate endpoints (i.e., are they valid?), appropriateness of control arm, post-protocol therapy, and cost-effectiveness before declaring a new drug as a game-changer. Newer is not necessarily better."