Because phase 1 of drug development is mostly about safety assessment, these trials are typically not designed to assess drug benefit. While the reporting of this information can be beneficial when there are striking, unexpected survival benefits observed across patients in early trials, there has not historically been an emphasis on the measurement of benefit in most phase 1 studies. Now, that appears to be changing — and trialists are increasingly attempting to make sense of drug performance and clinical benefit in early-phase settings.

According to researchers who recently published their findings in the Journal of the National Comprehensive Cancer Network, however, the use of drug response as a stand-in for survival benefit may be too premature in the setting of precision oncology.

Led by oncologist Bishal Gyawali, MD, PhD, of the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and the departments of oncology and public health sciences at Queen’s University in Canada, the authors examined response rates (RRs) and durations of response (DoRs) in patients who received targeted cancer drugs in single-arm trials compared with these values in individuals enrolled in randomized controlled trials (RCTs) testing the same drugs. They found that the DoRs among patients enrolled in the single-arm studies were exaggerated.

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“When we have RCTs, we compare [progression-free survival/overall survival] outcomes between treatment arms, so DoR isn’t usually taken into account,” Dr Gyawali wrote to Cancer Therapy Advisor. And although there are several hypotheses floating around for what DoR actually does tell investigators, the common 2 reasons for assessing DoR would be to gauge whether a drug may lead to noncancer deaths (as a result of adverse events) or to allow researchers to predict whether a tumor is likely to behave more aggressively upon progression (after exposure to the drug).

Importantly, the investigators also determined in a branch analysis across the trials that RRs and DoRs from uncontrolled studies were poor surrogates for the overall survival rates that were calculated in later RCTs analyzing these same targeted therapies. In other words, the length of time a patient responded to a drug was not indicative of any subsequent improvements in survival.

In this small, meta-epidemiologic study the researchers used the US Food and Drug Administration’s Table of Pharmacogenomic Biomarkers in Drug Labeling to find targeted therapies in oncology that were approved prior to December 2017 on the basis of changes in biomarker end points. From this list, there were 21 drug-indication trial pairs (representing 19 precision oncology drugs across many tumor types) for which response rates from both non-RCTs and RCTs were available for analysis. DoRs were only recorded in 15 of these drug-indication trial pairs.