OK for Flu Shot With Nivolumab, Other Checkpoint Inhibitors?

Nick Mulcahy

October 08, 2015

PHILADELPHIA — The cancer treatment strategy of immune checkpoint blockade has produced unprecedented results in melanoma and lung cancer, as well as in experimental settings with other tumor types, including renal cell carcinoma and mesothelioma.

Clinicians are not alone in taking notice, according to Niesha Griffith, MS, RPh, a pharmacist at the James Cancer Hospital of The Ohio State University in Columbus.

Multiple patients at her center have requested these drugs for off-label use, and offered to pay upfront and out-of-pocket for the expensive therapies, she said. Such offers were rare before the advent of cancer immunotherapy, but now occur regularly.

"We've never seen anything like this," Griffith told an audience here at the Institute for Clinical Immuno-Oncology (ICLIO) 1st Annual National Conference. The ICLIO is an affiliate of the Association of Community Cancer Centers, and has recently been launched to help community-based clinicians use this new type of treatment.

Despite the enthusiasm, there are uncertainties about the use of checkpoint inhibitors, which have been the most prominent form of immunotherapy to date, but clinical data and information on history of use are still limited.

One such grey area surfaced at the ICLIO meeting: Can patients receive a flu shot, which activates the immune system, while being treated with a checkpoint inhibitor?

Gary Cohen, MD, medical director of the Cancer Institute at the Greater Baltimore Medical Center, and a panelist at the meeting, said that he is uncertain about the "risk and efficacy" of giving flu shots to patients on checkpoint inhibitors, which activate the immune system to attack cancer.

Dr Cohen received an answer from Sigrun Hallmeyer, MD, a medical oncologist at Oncology Specialists SC, Advocate Lutheran General Hospital, in Park Ridge, Illinois, who was also a meeting panelist.

She said that her practice team has decided that patients on nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck), which are both approved immune checkpoint blockade drugs that act as programmed death (PD-1) inhibitors, can receive flu shots. However, patients on ipilimumab (Yervoy, Bristol-Myers Squibb), which employs checkpoint blockade but works as a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, should wait 6 to 8 weeks after the last dose, she said. Ipilimumab generally has worse adverse events than nivolumab, and she and her colleagues decided to err on the side of caution.

This decision was made after Dr Hallmeyer and another doctor at her nine-oncologist practice reviewed the package inserts for nivolumab and pembrolizumab, which state that there are no contraindications and that pivotal studies allowed killed or attenuated vaccinations during the trial therapy.

Dr Hallmeyer also referenced Cancer Research UK, a London-based non-profit, and its website, which has detailed practical advice for patients on nivolumab. "It is safe to have the flu vaccine," according to the site, which also advises against any live vaccines during treatment and for at least 6 months afterward. Flu shots are not live vaccines.

However, Dr Cohen is cautious about the advice. He said he has yet to see a study on the matter, including on the Cancer Research UK website.

I don't think the science...has been adequately elucidated.

"I don't really know the effect of introducing a new antigen as a vaccine in [patients] on checkpoint inhibitors," he said. "This is my personal knowledge gap. Someone must surely understand this, but I don't think the science on that has been adequately elucidated to practicing physicians."

The flu vaccine is "very important" to the cancer patient population, said Dr Cohen, who pointed out that "the flu season is upon us."

To vaccinate or not for the flu "is a critical question, and I hope you can get to the bottom of it, and publicize that," he told Medscape Medical News in an email.

What BMS and a Nivolumab Researcher Say

Bristol-Myers Squibb (BMS), the maker of ipilimumab and nivolumab, suggested to Medscape Medical News that there is not a definitive answer about the safety and efficacy of the flu vaccine in patients on their drugs.

About ipilimumab, company spokesperson Carrie Fernandez said in an email: "Controlled clinical trials have not been conducted to investigate the combination of influenza vaccines with ipilimumab."

However, there are some data on the activity of the flu vaccine in ipilimumab-treated patients.

According to a BMS summary, some patients in a phase 2 study received an influenza vaccine after the first ipilimumab dose for the treatment of advanced melanoma (J Immunother. 2012;35:89-97). Most vaccinated patients had an increase in antibody levels (humoral response) to influenza B, A/H1N1, A/H3N2 antigens, whereas most nonvaccinated patients showed no response. In other words, there is some evidence that the flu shot produces an immune response in some ipilimumab-treated patients.

With regard to nivolumab, influenza vaccine (killed or attenuated) was permitted at any time in a phase 1 trial (CA209-003), but the outcomes were not published when the study results appeared in print (N Engl J Med. 2012;366:2443-2454).

Medscape Medical News spoke to one of the authors of that phase 1 study, Charles Drake, MD, PhD, who said that "there is no prohibition" to giving a flu shot to cancer patients being treated with nivolumab or other PD-1 inhibitors.

This is my opinion, based on personal experience.

Dr Drake, who is an immunologist and oncologist at the Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, emphasized that "this is my opinion, based on personal experience." There have been "no obvious adverse clinical outcomes" in his flu-shot treated patients.

"I just recommended one last week for a guy on pembrolizumab," he said, talking about a recent male patient from Pennsylvania who traveled to Johns Hopkins to be treated for bladder cancer. The man's primary care physician was uncertain about giving him a flu shot and phoned Dr Drake for counsel.

Dr Drake explained why flu shots do not pose a threat to patients on nivolumab or pembrolizumab.

Nobody has done that part of the experiment.

Both drugs are anti-PD-1 agents that work by activating CD8 killer T-cells, he explained. The flu shot, in contrast, involves a "very different arm of the immune system response." CD4 T-cells are involved in the response to the flu shot, and are different types of cells, known as helper T-cells.

However, although Dr Drake is confident about recommending and giving flu shots to his patients treated with nivolumab and other checkpoint inhibitors, with regard to safety, he stated that the "formal proof of efficacy has not been done."

"If you give a vaccine, you can measure antibodies in patients to see if it works," he said. "Nobody has done that part of the experiment."


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