Flu Shot May Boost Survival in Patients With Cancer on ICIs

Patients with advanced cancer treated with immune checkpoint inhibitors appear to have a survival benefit if they receive influenza vaccination, a new retrospective analysis found. The results also suggest no increase in the risk for immune-related adverse events (IRAEs) in these patients and that the improvement in survival outcomes may be stronger among those with cutaneous malignant melanoma.

“Our findings align with a growing body of evidence, mainly from retrospective studies, that suggest a potential association between influenza vaccination during immune checkpoint inhibitor treatment and improved survival among patients with cancer,” wrote senior author Antonis Valachis, MD, PhD, and colleagues in an article published in JCO Clinical Practice on February 9. “An additional clinically relevant observation is that the association between influenza vaccination and survival may vary by tumor type.”

The new research supports “current recommendations to offer influenza vaccination to all patients undergoing cancer therapy, including those receiving the drugs,” Valachis, of the Department of Oncology, Örebro University in Örebro, Sweden, and his coauthors wrote.

“What we observed is that influenza vaccination is safe for patients under immunotherapy treatment,” Valachis told Medscape Medical News. But “whether influenza vaccination can be used to boost immunotherapy effectiveness should be tested in a study with a different design,” such as a prospective interventional trial.

Discussing potential explanations for why influenza vaccination could affect immunotherapy outcomes without affecting rates of IRAEs, Valachis said that this “cannot be answered within the constraints of our study design, since all patients were treated with immunotherapy.”

It may nevertheless be hypothesized that “immune activation triggered by vaccination preferentially stimulates immune mechanisms that enhance immunotherapy efficacy, while sparing those that contribute to IRAEs.”

Steady Was 'Relatively Modestly Sized'

Question marks were raised over the study itself and, as a result, its findings.

Justin Jee, MD, PhD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that there are “a lot of challenges when looking at retrospective data.”

“The authors did a very reasonable job of trying to control for confounders and certain time dependent issues, like immortality bias,” he said. “That said, it’s a relatively modestly sized retrospective study for looking at something that has enormous potential for confounding bias that really can’t be captured with any standard statistical method.”

Jee pointed to factors such as providers potentially being more likely to refer people for vaccination if they’re healthier “vs if the patient is in hospice care,” or individuals simply not getting vaccinated because it is not uppermost in their mind.

“Those things are very, very difficult to control for.”

Jee also said he believes the benefit with influenza vaccination being stronger in cutaneous malignant melanoma could be a study artifact, while the lack of difference in rates of IRAEs could be the result of selection bias, but “it’s just impossible to say with a study like this.”

“I’ve seen several studies looking at both COVID and flu vaccines and whether or not they improve immune checkpoint blockade efficacy,” he added, explaining that “some of them say COVID vaccine good, flu vaccine not as good; others say both flu and COVID vaccines good; others say flu vaccine good, COVID vaccine not as good.”

All Patients With Cancer Should Be Vaccinated

What is clear is that “patients with cancer are [at] especially high risk of developing complications from viral illnesses, including flu, including COVID, and vaccines are a very important part of reducing morbidity, mortality, and spread,” Jee said. The “big picture” is that everyone should get the influenza vaccine, especially patients with cancer, “so in that sense I agree with that part of the conclusion of the paper” and that’s “an important message.”

Mini Kamboj, MD, chief medical epidemiologist at Memorial Sloan Kettering Cancer Center, agreed, saying that the results are “consistent with other research showing that vaccines are safe and beneficial for patients on checkpoint inhibitors.”

“While vaccinated patients with melanoma showed the greatest survival benefit, the authors note small sample size and unrecognized differences between the groups as a potential explanation for their findings. This does not change vaccine recommendations as evidence already supports flu vaccine safety and effectiveness in people with lung cancer on checkpoint inhibitors.”

Nearly 600 Patients With Advanced Cancer

The researchers performed a retrospective cohort study of patients from three regions in Sweden who had advanced solid tumors and were treated with PD-1 or PD-L1 inhibitor monotherapy, or PD-1 combination therapy with a cytotoxic T-lymphocyte-associated protein 4 inhibitor, between January 1, 2016, until December 31, 2021. Treatment was given either routinely or as part of a clinical trial.

Electronic medical records were examined to gather data on a range of variables, including age at diagnosis, sex, Charlson Comorbidity Index, type of cancer, primary treatment at diagnosis, number of previous lines of treatment, best treatment response, IRAEs, influenza vaccination status, and date and cause of death.

In all, 587 patients were treated with immune checkpoint inhibition over the study period. They had a median age of 66 years, and 58.1% were men. The most common malignancies were nonsmall cell lung cancer (NSCLC), cutaneous malignant melanoma (32.5%), and renal cell carcinoma (14.7%).

The most commonly used immune checkpoint inhibitor was nivolumab, which was administered to 47.9% of patients, followed by pembrolizumab (34.6%), atezolizumab (9.4%), and nivolumab plus ipilimumab (6.8%).

Only Patients With Malignant Melanoma Benefit

Over the study period, 17.7% of patients underwent influenza vaccination, at a median time between initiation of immune checkpoint inhibition and vaccination of 2 months. Ninety per cent of patients received the vaccine within 9 months of starting treatment.

Time-dependent Cox regression analysis revealed that real-world progression-free survival (rwPFS) was significantly longer with vaccinated patients than unvaccinated patients at a hazard ratio of 0.59 (95% CI, 0.44-0.79), as was overall survival, at a hazard ratio of 0.56 (95% CI, 0.42-0.75).

There was no significant difference in rwPFS and overall survival between vaccinated and unvaccinated patients among those with NSCLC, but significant differences were seen in those with cutaneous malignant melanoma, at hazard ratios of 0.58 (95% CI, 0.36-0.96) and 0.58 (95% CI, 0.36-0.96), respectively.

Restricting the analysis to immune checkpoint inhibitor monotherapy indicated that vaccinated patients had significantly longer rwPFS and overall survival than unvaccinated patients, at hazard ratios of 0.58 (95% CI, 0.43-0.79) and 0.50 (95% CI, 0.38-0.76), respectively.

Finally, the team found that there were no significant differences in the rates of any grade IRAEs between vaccinated and unvaccinated patients, at 48.4% vs 51.2% (P = .455), or in rates of multiple IRAEs, at 15.1% vs 19.2% (P = .297). The therapeutic management and outcomes of IRAEs were also comparable.

No funding or relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.