Reducing how often patients receive immune checkpoint inhibitors can dramatically reduce medical costs while allowing patients to remain on lifesaving drugs, according to a recent study from Fred Hutchinson Cancer Center.
“One of the questions in the field is, how long do we keep patients on immunotherapy if they’re doing well?” said Fred Hutch medical oncologist Lisa Tachiki, MD, who led the new analysis, recently published in the journal Cancer Immunology, Immunotherapy.
Even when cancer appears to be gone, it looms. Patients whose tumors have responded well to treatment worry that going off that treatment will give their cancer an opportunity to recur. For many treatments, patients and providers can turn to evidence-backed guidelines. But immune checkpoint inhibitors, or ICIs, are too new.
In the last few years, ICIs have transformed care for patients with aggressive skin cancers like melanoma and Merkel cell carcinoma. But patients whose tumors respond to an ICI eventually face a tough choice: continue an eye-wateringly expensive therapy, or stop treatment and hope their cancer stays at bay.
“A lot of people in the community, oncologists, especially patients, have the same question,” said Fred Hutch medical oncologist and study co-author Shailender Bhatia, MD. “‘OK, I started immunotherapy. It's working well for me. How long should I continue it for?’”
After two years, clinicians must judge whether to continue or halt a patient’s ICI treatment — there are no guidelines, he said. So Bhatia offered his patients a third option: continue the same dose of ICI, but receive it every three months instead of every two weeks.
“We can provide immunotherapy for up to six years for the same amount of time in the chair and financial cost [to the patient] as one year of standard dosing,” Bhatia said.
He helped guide Tacoma, Washington-based melanoma patient John Allen through this choice. John had dismissed an early and transient lump in his armpit as a symptom of stress. But a few years later in 2010 when he was 59, it returned as a bump on his neck. When the growing bulge made John self-conscious at the beach — despite his lifelong love affair with surfing — he knew he needed a diagnosis.
It was late-stage melanoma.
John underwent several brutal surgeries and had an astounding but short-lived response to an experimental drug that inhibits the melanoma-driving molecule BRAF. To tackle John's latest recurrence, Bhatia recommended treatment with pembrolizumab, a type of ICI, after it had been approved by the FDA in 2014.
After two years of successful treatment at the standard dosing frequency of every three weeks, Bhatia helped John weigh his options: he could either stop treatment altogether, or ramp down his dosing frequency. Together they decided to transition to an every-two-months ICI regimen, then later further reduced John's doses to once every three months.
“John got almost two more years of therapy [at this reduced frequency],” Bhatia said.
At this point, John and Bhatia decided to halt John’s ICI treatment. Fourteen months later, his tumor progressed. This time, Bhatia recommended treatment with nivolumab, an ICI similar to pembrolizumab, at the standard frequency of every four weeks. Sixteen months of standard-frequency dosing helped John’s tumor shrink, and he again transitioned to less-frequent dosing of every three months. Three years later, John’s melanoma remains controlled on this regimen.
“The big takeaway [of the study] is that providing nivolumab and pembrolizumab at reduced frequency dosing does not harm the patients and is potentially equally efficacious as standard dosing,” Tachiki said.
She and Bhatia showed that reducing the frequency at which patients with advanced melanoma and Merkel cell carcinoma receive ICIs could help keep them on lifesaving treatments for longer, while saving them (and the health care system) both time and money. They hope that their analysis will help other clinicians looking to map out long-term treatment plans for patients who have responded well to checkpoint inhibitors.
Fred Hutch file photos
Melanoma and Merkel cell carcinoma are two aggressive skin cancers with often dim prognoses.
Before the introduction of ICIs, “initially, the average stage 4 melanoma patient would live for less than a year. Now that average lifespan is more than five years,” Tachiki said. “But with that new advancement come a lot of additional questions.”
There’s no long-term treatment roadmap, said Bhatia, who sees patients with skin and kidney cancers. He co-wrote the guidelines to help clinicians using ICIs to treat Merkel cell carcinoma, but there was no data he could use to draft recommendations for the drugs’ extended use.
“Some oncologists arbitrarily stop treatment at two years because that was the precedent set by early clinical trials,” Tachiki said. “That can be a pretty challenging conversation to have with patients who are doing well on immunotherapy: to tell them that they no longer can receive this drug that is working so well for them.”
Plus, follow-up analyses of patients who receive ICIs have shown that patients who go off these drugs are more likely to see their tumors recur, just as John Allen did, she said.
Unfortunately, immune checkpoint inhibitors are expensive. A single dose costs the health care system several thousands of dollars, and patients undergoing standard treatment receive a dose every two to three weeks.
“And you’re asking patients to come into the clinic every two to four weeks — indefinitely,” Tachiki said.
Each visit, a patient spends time and money to get themselves (and possibly a caregiver) to the clinic. A patient who misses work for treatment may lose income. John is retired, but treks from Tacoma to Seattle for his clinic visits. The bus trips to and from home, plus the ICI infusion, can take up most of his day.
Work by Fred Hutch’s Hutchinson Institute for Cancer Outcomes Research has revealed how financially toxic cancer can be: cancer patients are about 2.5 times more likely to declare bankruptcy than the average person. Bhatia wanted to develop a strategy that helps prevent recurrence while reducing the financial burden on patients and the health care system.
“So what we propose in this paper is taking a middle path,” Tachiki said. “Instead of completely stopping or continuing [the standard regimen] indefinitely, we give patients doses of immunotherapy at extended-frequency intervals.”
Bhatia proposed his reduced-frequency approach to patients with advanced melanoma or Merkel cell carcinoma who had tolerated ICIs well and whose tumors had shrunk significantly in response. He discussed dosing options with each patient and together they chose whether to ramp down treatment or switch to an every-two-months schedule immediately.
Most patients chose to decrease their ICI dosing in a somewhat step-down fashion: a patient might go from getting a dose every two weeks to initially every two months. Many patients felt comfortable switching to an every-three-months schedule if their disease remained controlled on the every-two-months schedule.
Patients received a range of ICIs, including pembrolizumab (Keytruda), nivolumab (Opdivo) and avelumab (Bavencio) as either single drugs or in combination with ipilimumab (Yervoy).
“The rationale for picking that [two-to-three-month] dosing schedule was that in an early phase 1 study of nivolumab, they showed that it’s still present on the immune cells for up to 100 days after a single dose,” Tachiki said.
She analyzed the results from 23 patients, 18 with melanoma and five with Merkel cell carcinoma, all treated at Fred Hutch. To estimate drug costs, she used $28.90/mg for nivolumab and $51.35/mg for pembrolizumab, the average sales price from the Center for Medicare and Medicaid Services for Part B drugs from the first quarter of 2021.
She estimated patient travel expenses by recording distances traveled between a patient’s home address and the cancer clinic, then multiplying this by $0.56/mile, the U.S. Internal Revenue Service travel reimbursement rate for 2021. Tachiki and Bhatia used published estimates for average time patients spent traveling, getting blood drawn, interacting with (and waiting for) their providers, as well as waiting for and receiving their ICIs.
Tumor control rates at the reduced frequency dosing compared favorably to historical control rates at the standard dosing frequency, and rates of side effects were not significantly different. The researchers calculated that, in the subset of 15 patients who received at least two years of therapy, reducing dosing frequency saved $1.1 million in drug costs and 384 hours, compared to two years of a standard regimen.
“We showed that for the same drug cost as one year of standard dosing, a patient can stay on the immune checkpoint inhibitor for six years,” Tachiki said.
A cancer patient must weigh the risks and benefits with every decision they make, planning for an unknown future.
John found the decision to reduce the frequency of his ICI dosing easy: “I trust Dr. Bhatia completely,” he said. He and other patients who receive less-frequent doses still undergo surveillance to monitor tumor growth — a fact that helped him feel comfortable stepping down his dosing frequency, John said.
Other patients may wrestle with the benefits and risks of the decision. Tachiki and Bhatia hope that their results can give patients and providers more solid information that they can use to guide their choices.
To further bolster the case for reducing immune checkpoint inhibitor dosing, Tachiki is digging into the molecular interactions between ICIs and the immune system.
“We want to come up with a dosing regimen that is supported by that pharmacodynamic data to demonstrate what that reduced frequency dosing should look like,” she said.
Her results, though preliminary, also hint that smaller doses might be as effective as current doses. Reducing dose size and frequency (perhaps even at the start of therapy) could potentially slash costs even further, said Bhatia. It could also be possible that a similar approach could be successfully applied to other tumor types treated with ICIs.
Ultimately, Tachiki wants to make immunotherapy available to all the patients who need it, wherever they are.
“Globally, most cancer patients in low- to middle-income countries don’t have access to immunotherapy,” she said.
This includes places like Uganda, where ICIs are not available to the cancer patients at all due to their prohibitive costs. And in the U.S., ICIs are not easily accessible to patients who live far from urban centers. Tachiki and Bhatia are hoping to work with scientists at the Uganda Cancer Institute, a collaborating partner of the Fred Hutch, to test whether a less-frequent dosing schedule could make ICIs a viable therapy option there.
“Hopefully we can generate additional research and investigation into optimizing the doses at which we administer immune checkpoint inhibitors, given the high cost and extensive resource burden of these drugs,” Tachiki said.
This work was supported by the Kuni Foundation, the National Cancer Institute and a Kelsey Dickson Team Science Courage Research Award.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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