Checkpoint-Inhibitor Adverse Events Difficult to Categorize

By David Douglas

September 28, 2019

NEW YORK (Reuters Health) - Compared with the toxicities of standard chemotherapy, reactions to checkpoint inhibitors are markedly more heterogeneous and unpredictable, according to a small study.

"This study demonstrates that diagnosis and characterization of immune-related adverse events may be quite challenging," Dr. David E. Gerber of the University of Texas Southwestern Medical Center, in Dallas, told Reuters Health by email.

While the adverse reactions to conventional chemotherapy "are usually readily recognized and quantified through routine laboratory tests," he added, "immune-related adverse events are far more diverse and far less predictable."

In a paper online September 18 in JAMA Network Open, Dr. Gerber and colleagues note that, "Now that single-agent and combination immune checkpoint inhibitor regimens are in broad clinical use for multiple cancers, the timely and reliable diagnosis of immune-related adverse events (irAE) is critical for safe and effective disease management."

To investigate how consistent such assessment might be, the researchers examined the concordance of algorithm-driven medical record review by two medical oncologists. The data set included eight irAE in 52 patients treated with immune-checkpoint inhibitors, with a median of 82 documents reviewed per case.

Most patients (80.8%) had non-small-cell lung cancer and all received anti-programmed cell death 1 or anti-programmed cell death ligand 1 antibodies. Three patients received combinations with anti-cytotoxic T-lymphocyte antigen 4 antibodies. The median duration of therapy was 50 days.

The frequency of irAE ranged from 4% to 35% for one observer and from 6% to 27% for the other. For both observers, pneumonitis was the most common and hypophysitis was the least common of such events.

However, with the exception of hypothyroidism, there was limited or poor agreement between raters on irAE occurrence (Cohen kappa, 0.37-0.64). This was also the case for irAE grading.

The observers had a high degree of agreement for the exact start date (98%) and end date (96%) of immunotherapy, but differences in assessed irAE onset time ranged from five to 188 days.

In multivariable analysis, therapy duration (adjusted odds ratio, 4.80) and Charlson Comorbidity Index (aOR, 4.09) were significantly associated with discordant irAE assessment.

"Given the importance of accurate and timely assessment of toxic effects for clinical trials and real-world disease management," the authors conclude, "efforts to improve irAE diagnosis and characterization are needed."

Dr. Gerber added, "Clinicians prescribing immune checkpoint inhibitors must remain vigilant for these toxicities throughout and even after treatment. They should also have access to consultants with expertise in endocrinology, gastroenterology, radiology, pulmonary medicine, and other fields to assist in toxicity diagnosis and management."

Dr. Hossein Borghaei of Fox Chase Cancer Center in Philadelphia, told Reuters Health by email, "I am not surprised that there is disagreement between doctors in this study. Diagnosis of immune-related adverse events requires experience and a high index of suspicion."

Dr. Borghaei, who is chief of the division of thoracic medical oncology, pointed out, "Severe reactions are easier to recognize and identify due to the fact that the patient experiences difficulties and in this analysis there does appear to be more agreement between the observers in assessing Grade 3 and 4 side effects. In the absence of a marker that clearly shows an adverse event, like (thyroid-stimulating hormone) for thyroid dysfunction, one relies on patient-reported symptoms and subjective assessments by the healthcare providers."

"I agree with the authors," he concluded, "that more education about detection of lower-grade immune-related side effects is important. Identifying these could avoid progression to more severe cases in some patients treated with the currently available checkpoint inhibitors."


JAMA Netw Open 2019.