The flu can wreak havoc on anyone's health and well-being, and vaccination saves millions from the immobilizing—and sometimes deadly—symptoms each year. The CDC's National Influenza Prevention and Vaccination Campaign aims to boost vaccination rates for everyone 6 months or older, particularly at-risk populations such as health care workers, children, seniors, and those with chronic diseases.
However, some clinicians and patients still question the influenza vaccine's safety for certain patient populations, including cancer patients being treated with immunotherapy. To make matters worse, these patients could benefit from vaccination more than most, considering they are at higher risk of flu-related complications.
A 2018 review highlighted the controversy surrounding the flu vaccine for cancer patients, finding only five studies that compared vaccination with no vaccination and just one that addressed adjuvanted vaccination (Cochrane Database Syst Rev 2018; doi:10.1002/14651858.CD008983.pub3). While the data suggests the flu vaccine provides lower mortality and infection in cancer patients, the authors also noted the studies are hampered by small sample sizes and a low grade of evidence. In addition, none of the studies included patients treated with immunotherapy—a significant dearth, given the explosion of immunotherapy treatments for everything from melanoma and non-small cell lung cancer to head and neck cancers and certain lymphomas.
“The current recommendation is that all patients underdoing cancer treatment receive the inactive influenza vaccine, but the safety for patients undergoing immunotherapy has been questioned,” explained Curtis R. Chong, MD, PhD, an oncologist in the Gastrointestinal Oncology Service, Department of Medicine, at the Memorial Sloan Kettering Cancer Center (MSK).
Chong and his team at MSK recently tackled this research disparity and may finally have an answer (Clin Infect Dis 2019; doi:10.1093/cid/ciz202). Their new research findings suggest the vaccination is safe for patients being treating with immune checkpoint inhibitors (ICIs).
The researchers retrospectively reviewed 370 patients who were vaccinated for three consecutive flu seasons from 2014 to 2017. In addition, the patients were all being treated with pembrolizumab, nivolumab, or a combination of ipilimumab and nivolumab—in total, they received 5,873 doses of immunotherapy during the study time period. The cancer types were mainly lung (46%) and melanoma (19%), and 61 percent were being treated with anti-PD-1 agents alone. Another 22 percent were taking a combination treatment consisting of ipilimumab and nivolumab.
As for the vaccine administered, Chong and his team took into account whether patients received a high or standard dose, and if the vaccine was quadrivalent or trivalent. All participants received the flu vaccine within 2 months of immunotherapy.
Among the participants, 20 percent experienced an immune-related adverse event (IRAE), 60 percent of which were a grade 1 or 2, 36 percent were grade 3, and only 4 percent were grade 4. They observed no grade 5 events throughout the study period. Upon further analysis, the team discovered the rate of adverse events wasn't affected by sex, tumor type, therapy type, season, vaccine dose, or order of administration.
“Based on our retrospective study, with patients taking more than 5,800 doses of immunotherapy, we found that the incidence of immune-related adverse events was not higher than previously published registration studies of immunotherapy agents,” noted Chong.
For example, the rate of IRAEs among those taking a combination of ipilimumab plus nivolumab was 30 percent in Chong's study, while previously published data on the combination's rate of IRAEs is 50-55 percent.
Of all patients who experienced an IRAE, 28 percent had endocrine issues, 25 percent had pneumonitis, 13 percent had colitis, and another 12 percent had transaminitis. Nearly half of these patients were successfully treated with steroids or other immunosuppressive treatment, while 35 percent had to interrupt their immunotherapy and another 19 percent required supportive medications.
Another key finding, according to Chong, was the fact that they noted only two cases of laboratory confirmed influenza in the 3 years, an overall incidence of just 3.5 percent. The incidence of the flu at the entire cancer center for that same 3-year stretch was 10.7 percent.
The Question of PD-1 Inhibitors
The researchers became particularly concerned for patients being treated with ICIs, and anti-PD-1 agents in particular, after a small Swedish study found a high incidence of IRAEs among vaccinated patients also taking PD-1 inhibitors (J Immunother Cancer 2018; doi:10.1186/s40425-018-0353-7). Those researchers vaccinated 23 lung cancer patients on anti-PD-1 immunotherapy and recorded the rate of IRAEs at 52.2 percent—in one flu season. Of those, 26.1 percent presented with severe grade 3/4 adverse events, including two patients with encephalitis and another with autoimmune peripheral neuropathy. Their institution as a whole had an overall rate of IRAEs at just 25.5 percent.
Despite the study's non-randomized methodology and small cohort, “the increased rate of immunological toxicity is concerning,” the researchers concluded. “This finding should be studied in a larger patient population.”
With such surprising data, Chong and his team wasted no time taking a closer look at their own population of cancer patients, and those on immunotherapy specifically.
“Rarely with the influenza vaccine, patients can get Guillain-Barré syndrome or something like that, and it wasn't known if getting the vaccine would either, A) increase the risk of vaccine-related adverse events, or B) increase the amount of adverse events related to the specific immunotherapy drug,” Chong noted. “The Swedish study suggested it might, but we did not observe this in our retrospective study, fortunately.”
The MSK researchers conducted a subanalysis on those taking anti-PD-1 immunotherapy to ensure they weren't at increased risk compared with other immunotherapy agents. They found 18 percent of those on PD-1 inhibitors had an IRAE. Within the entire study population, patients taking anti-PD-1 therapy alone had a 6.6 percent incidence of grade 3/4 IRAEs; current published data on IRAEs in patients on anti-PD-1 therapy shows a rate of more than 20 percent. The researchers found that when patients received the vaccine—before or after beginning anti-PD-1 treatment, as well as receiving both on the same day—made no difference in the risk of experiencing an IRAE.
Non-small cell lung cancer patients within this subgroup fared even better, with a frequency of IRAEs at just 14 percent. The current literature for this patient population treated with pembrolizumab or nivolumab reports the rate of IRAEs as high as 26.6 percent.
Vaccination in the Clinic
Given the concerning findings from the Swedish research team, Chong's data comes as a relief.
“Now this is a retrospective study, so it has some limitations,” Chong clarified. “Maybe we didn't adequately identify adverse events in our chart review, for example. But I feel in this case, the benefit of the influenza vaccine outweighs any perceived risk in immunotherapy.”
While larger prospective studies are underway to corroborate these findings, Chong is confident clinicians can—and should—recommend patients on immunotherapy receive the flu vaccination each season.
“We found no increase in adverse events after the flu vaccination, so we recommend now that everyone who is getting immunotherapy get the influenza vaccine. I tell all my patients that I would much rather they have the vaccine than be at risk of getting the flu.”
Rebecca Hepp is a contributing writer.