SAN DIEGO — Adverse events may be more common with checkpoint inhibitors than was reported in the initial clinical trials that led to their entry into the marketplace, according to a new study.

The study used "real world data" from a large cohort of patients with non–small cell lung cancer (NSCLC) who were treated with nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck Sharp & Dohme ), or atezolizumab (Tecentriq, Genentech) and found that many patients experienced unexpected medical problems related to their treatment.

The findings were presented here at the 2018 Palliative and Supportive Care in Oncology Symposium as part of a session on immunotherapies.

"Immunotherapy continues to be well tolerated, and severe side effects are less frequent than those seen with conventional chemotherapy," commented lead author Elizabeth Jane Cathcart-Rake, MD, a fellow at the Mayo Clinic, Rochester, Minnesota.

She noted that when the initial trials of immunotherapy, such as the Checkmate 057 study, reported adverse events, such events were compared with those encountered with standard chemotherapy.

These initial trials "looked at events such as infection or alopecia, and those risks are significantly lower with immunotherapy," said Cathcart-Rake. "However, they had little mention of immune effects, and you have to search through the text and the supplemental material to find that."

As data continued to be published from these trials, there was a trend for increasing rates of immune effects. In Checkpoint 057, published in 2015, pneumonitis was reported to occur at a rate of 3%. But the following year, the Keynote 024 trial reported the rate of pneumonitis at 5.8%, and that climbed higher in 2018 — the Keynote 042 trial reported a rate of 8.3%. "This mimics what we are seeing clinically, as we are seeing these immune-related events much more frequently," she noted.

Most Toxicities Higher Than in Trials

For their study, Cathcart-Rake and colleagues used claims data from a large insurance database that included more than 150 million people in the United States. From these data, the investigators retrospectively identified 2798 patients with NSCLC who received programmed cell death–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) inhibitors between January 1, 2015, and December 31, 2017. Of this group, 1998 (71.4%) received nivolumab, 699 (25.0%) received pembrolizumab, and 101 (3.6%) received atezolizumab. More than half (n = 1463, 52.3%) received a PD-L1 inhibitor as second-line therapy; the majority (n = 744) received alkylating agents and antimetabolites prior to receiving PD-L1 therapy.

Most of the toxicities revealed in the current study occurred at higher rates than had been reported previously. Hypophysitis occurred at a rate four times higher than was previously reported, Cathcart-Rake noted. The KEYNOTE-24 investigators reported that 0.6% of patients developed hypophysitis, whereas the current analysis showed a rate of 2.4%. Additionally, the incidence of pneumonitis was as high as 10.9%. "Our data are different from prospective data, but they still offer an idea of what is occurring on a population level," she said.

Hypothyroidism occurred in 9.2% of patients, anemia was reported in 5.7%, and acute kidney injury occurred in 2.8% of patients. Gastrointestinal and cardiac events were relatively rare. "Interestingly, hypothyroidism was lower than what was seen in trials, and that speaks to the limitations in claims data," Cathcart-Rake pointed out. "I think we may not be coding for primary hypothyroidism because it is so quickly and easily treated that it may be missed."

Preliminary associations also showed that among Hispanics, immune-related adverse events occurred more frequently (odds ratio [OR], 1.44) and that PD-L1 agents given as second line or later were associated with less frequent events (OR, 0.71). "We have a lot of work to do, though and we plan to complete time-to-event analyses," said Cathcart-Rake.

She emphasized that all clinicians who care for these patients, including oncologists, primary care physicians, and palliative care providers, need to be aware of these side effects. "These are not uncommon phenomena," she said. As an example, she pointed out that it took years after the US Food and Drug Administration initially approved aromatase inhibitors for the treatment of breast cancer before it came to be known that arthralgia with associated with their use. Studies reported joint pain in about 8% of patients, but findings during the past 2 decades indicate that about half of all patients who use these drugs report joint pain. "I think that we are going to be seeing the same thing with these agents," she said. "So what we found was that real world data may differ from the initial trials, and claims data can complement trial data to allow for a broader view of true adverse event frequencies."

Recognition and Integration

In a related discussion, Allison S. Betof Warner, MD, PhD, a medical oncology fellow at Memorial Sloan Kettering Cancer Center, New York City, noted that although the study discussed the more common immune-related events, "there are many others that may go unrecognized. These include uveitis, aseptic meningitis, or encephalitis. One of the things that often gets underrecognized is rash and vitiligo in these patients, which is actually very common but underreported both in our own notes and in the literature," said Warner.

She noted that it is important to have a "a high index of suspicion that any new symptoms are treatment related, such as hypophysitis," which was mentioned in the study. "But what about myocarditis or meningitis?" Warner noted. "We can save someone's life if we catch it early enough."

We can save someone's life if we catch it early enough. Dr Allison Betof Warner

Another problem is that the treatment for immune-related events, which involves immunosuppression, can in turn lead to opportunistic infections. "It is important to know that we can harm patients with our treatments for toxicity," she emphasized. "It is important to consider prophylaxis for opportunistic infections for patients who are going to be getting the equivalent of 20 mg of prednisone or more for at least 4 weeks."

The take-home message is that "recognition is key," and although immune-related adverse events are common, they are also treatable. "Guidelines are available for treatment," she added.

Betty Ferrell, RN, PhD, director of the Division of Nursing Research and Education and a professor at City of Hope National Medical Center in Duarte, California, explained that the paradigm of cancer care is changing and that an increasing number of treatment options have become available for those with advanced disease. The era of immunotherapy thus presents new challenges for the palliative care team.

She emphasized the importance of integrating palliative care into the regimen of patients receive immunotherapy. "The palliative care team need to be familiar with the symptoms that occur with new therapies," she noted.

Dr Cathcart-Rake, Dr Warner, and Dr Ferrell have disclosed no relevant financial relationships. Study coauthor Aaron Scott Mansfield, MD, has a consulting or advisory role with Trovagene, Genentech, Bristol-Myers Squibb, and AbbVie and has received institutional research funding from Novartis.

2018 Palliative and Supportive Care in Oncology Symposium. Abstract 184, presented November 17, 2018.