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Increased Immune-Related Adverse Event Rates for Checkpoint Inhibitors

Samson, Kurt

doi: 10.1097/01.COT.0000552847.45400.cb
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checkpoint inhibitors; cancer

checkpoint inhibitors; cancer

SAN DIEGO—Immunotherapy treatment with checkpoint inhibitors may carry greater risk of adverse events than was found during clinical trials that served as the basis of their approval, according to findings described at the 2018 Palliative and Supportive Care in Oncology Symposium, sponsored by ASCO (Abstract 184).

Elizabeth J. Cathcart-Rake, MD, Professor in the Oncology Department at Mayo Clinic in Rochester, Minn., presented the retrospective analysis of adverse events in a large U.S. commercial insurance database. Records were reviewed for 2,800 patients treated with one of the immunotherapy agents nivolumab, pembrolizumab, or atezolizumab. The PD-L and PD-L1 checkpoint inhibitors have been approved for various cancers, but for this study Cathcart-Rake and her colleagues focused on patients treated for non-small cell lung cancer (NSCLC).

The most commonly reported immune-related adverse event (irAE) was hypothyroidism, which occurred in 9.2 percent of patients. This was not unexpected, she said, because the thyroid is sensitive to immune stimuli. Other adverse events are noted later in the article.

“Immunotherapy continues to be well-tolerated, and severe side effects are less frequent than those seen with conventional chemotherapy,” Cathcart-Rake noted. “Still, immunotherapy can, in rare occasions, cause other serious medical problems.”

For comparison purposes, she pointed to the initial clinical trial results of aromatase inhibitors for breast cancer, where about 8 percent of patients experienced joint pain. According to the most recent patient-reported outcomes and more comprehensive analyses over the last 2 decades, about 50 percent have now reported joint pain.

“It's important to understand the full extent of cancer treatments' side effects, and patients and providers should be aware that it can take a while to fully assess them for newer therapies,” she told the conference.

Nivolumab was approved for the indication last August, while pembrolizumab was approved in May 2017 and atezolizumab in October 2016.

“We believe that our study is the first to look at adverse events based on claims data, which gives a much broader, population-based perspective on outcomes than a single trial,” Cathcart-Rake explained. “While there have been studies comparing data from multiple trials, our approach includes a comprehensive look at outcomes for most insured patients.”

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Methodology, Other Findings

The investigators identified NSCLC patients treated with PD-1 or PD-L1 inhibitors between Jan. 1, 2015 and Dec. 31, 2017. The reported frequencies of irAEs were identified by reviewing new medical claims with a corresponding ICD-9 or ICD-10 code.

Most of the 2,798 patients had received standard chemotherapy prior to their immunotherapy treatment and more than half of the subjects received a PD-(L)1 inhibitor as second-line therapy. In addition, a majority of patients (744) received alkylating agents and antimetabolites prior to receiving PD-(L)1 therapy. Their median age was 69 years, and 71.4 percent received nivolumab, 699 were treated with pembrolizumab, and 101 were given atezolizumab.

In general, only about 14 percent of clinical trials report adverse events at the time they are published, according to Cathcart-Rake. She noted that in one trial (KEYNOTE-24) investigators compared pembrolizumab to chemotherapy, which allowed comparison of the initial results with population-based data. The trial found 0.6 percent of patients experienced acute or chronic inflammation of the pituitary gland, but the KEYNOTE-24 researchers reported the rate to be 2.4 percent. The following is a list of other adverse events found: acute kidney injury 78 (2.8%), hepatitis 49 (1.8%), neuritis 40 (1.4%), colitis 38 (1.4%), pancreatitis 12 (0.4%), mucositis <11 (<0.4%), conjunctivitis 13 (0.5%), dysrhythmia 12 (0.4%), myocarditis <11 (<0.4%), and pericarditis <11 (<0.4%).

The researchers are continuing to analyze the data to obtain a better understanding of the absolute differences between trial-reported toxicities and those reported in the population at large, said Cathcart-Rake. They also might review the timing of autoimmune side effects.

She told Oncology Times that she suspects that the scope and frequency of irAEs will increase as clinicians glean an improved understanding of the scope and frequency of irAEs. “But I am hopeful that with better understanding of the potential for irAEs, we will also get better at treating them over time, decreasing patient morbidity. We may even learn who is at higher or lower risk for irAEs, or potential ways to prevent these events.”

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Commentary

“Immunotherapy checkpoint inhibitors are extending the lives of many cancer patients, but as with any new therapy, their use is not without risk of side effects. We've only been using these therapies for a few years, so this new analysis gives us more information on the prevalence of these side effects in patients as the therapies gain wider use,” said Joseph Rotella, MD, Chief Medical Officer at the American Academy of Hospice and Palliative Medicine and a palliative care specialist in Louisville, Ky.

Joshua Adam Jones, MD, Assistant Professor of Clinical Radiation Oncology at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, said immune checkpoint inhibitors have dramatically changed the landscape of oncologic treatment for patients with many types of cancer, and many patients are deriving tremendous benefit both in terms of quality and quantity of life.

“This study does not change those facts, however, it does raise questions about counseling for patients/families about the risks of adverse events,” he told Oncology Times.

“How do we balance the potential for significant benefit with the risks of potentially serious side effects? The overall risk of serious side effects is quite low, but it will be important to continue to discuss with patients how to balance benefits versus risks as we learn more about the impact, both positive and negative, of the various therapies,” he said.

A primary aim of personalized medicine is to better understand who is likely to benefit from which medicines, he noted. Toward this end, Jones said that ongoing studies are needed about the molecular characteristics of both the cancer and each patient.

Kurt Samson is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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