With many new lung cancer treatments approved through accelerated tracks based on early-phase (I/II) trial data, we have become increasingly aware of the lack of standards for disclosing toxicities when new therapies debut at professional conferences, which may be months to a few years before they are licensed.
We collected toxicity data from all lung cancer–associated phase I and II trial presentations and posters at the American Society for Clinical Oncology Annual Meetings from 2017 through 2019.1 Conferences are a critical avenue for sharing information on new therapies; phase I and II trials provide the initial human safety and tolerability data for new drugs. We captured toxicity features including the minimum incidence selected for reporting; whether adverse events (AEs) shown were treatment emergent or treatment related and grouped by organ system or separated by individual descriptors; whether AEs were combined or separated across dose levels when a dose escalation component was included; and whether dose-limiting toxicities, serious AEs, dose reduction rules, and denominators for laboratory tests were described.
Ultimately, 209 trials were analyzed. There was wide variability in toxicity-reporting practices. Six different incidence thresholds for selecting which AE to present were used. Some trials reported all AEs of any grade that occurred in as few as one or two patients, whereas others only reported AEs of any grade that occurred in a minimum of 40% of patients, leaving observers uninformed of symptoms that occurred at any lower frequency. The variability in the minimum incidence threshold for reporting an AE was not explained by trial size.
Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. An AE is considered “treatment-related” if the investigator, trial clinician, or another involved in processing trial data deems a symptom to be related to the study drug based upon its mechanism of action, observations from animal models, or toxicities seen with other drugs in the same class. This layer of adjudication can be helpful in distinguishing true toxicities from symptoms due to the cancer itself or another component of a treatment combination. Providing only “treatment-related” AEs, however, has the potential to miss AEs that were not expected to occur. Overall toxicity could be under-reported as a result of this approach.
For trials with multiple dose levels (i.e., those with dose-escalation to identify the recommended dose), toxicities were equally likely to be reported across dose level as by dose level. Although in theory this could either over-estimate or under-estimate toxicities at the recommended dose, in general, it is probably more likely to under-represent AEs, as more patients are likely to have been treated at dose levels at which minimal toxicity occurred rather than to have been treated at highly toxic doses.
Finally, critical definitions and denominators were often missing. For example, the AEs that qualify as a dose-limiting toxicity (DLT) or a serious AE (SAE) vary by trial protocol, but DLT and SAE were rarely defined in presentations. Dose-reduction rules and denominators for laboratory tests were never defined. Relevant denominators (e.g., all patients or only those tested) are essential to interpret lab data. For example, non-industry studies on crizotinib found a drug-associated drop in testosterone of 84%-100% of men in whom these levels were checked.2-3 In contrast, in both the PROFILE 1014 and 1007 studies, which were sponsored by the manufacturer of crizotinib, Pfizer, this rate is reported as occurring in less than 1% of patients (with the numerator representing those with proven low levels, noting that testing was not part of the protocol, and the denominator representing all patients, across both sexes combined, regardless of whether tested or not).4
Given the increased speed of drug licensing, early-phase trial data is essential in helping us form accurate impressions of a new drug. Unfortunately, a lack of standardization in how toxicity data are presented leaves the field open to intentional or unintentional abuse. We propose the introduction of minimum elements for adequate reporting of toxicities for phase I and II clinical trials in our paper. There is a tremendous opportunity for conferences and academic journals to standardize their requirements for the reporting of side effects to help accurately communicate risk.
Read the full Journal of Thoracic Oncology article by Drs. Simons, Camidge, and their colleagues.
- Simons EA, Smith DE, Gao D, Camidge DR. Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences. J Thorac Oncol. 2020;S1556-0864(20)30335-X.
- Weickhardt AJ, Rothman MS, Salian-Mehta S, et al. Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer 2012;118(21):5302-5309.
- Weickhardt AJ, Doebele RC, Purcell WT, et al. Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients. Cancer. 2013;119(13):2383-2390.
- 2019 Product Monograph: Xalkori Crizotinib Capsules. Pfizer. Revised March 27, 2019. Accessed August 1, 2020. https://www.pfizer.ca/sites/default/files/201904/XALKORI_PM_215123_27Ma…;