Northwestern University economist Chuck Manski studies decision-making amid uncertainty. That prepared him better than many other cancer patients to decide whether to stay on an immunotherapy treatment that was making him very ill.
For six months in 2022, Manski received monthly infusions of nivolumab to fight advanced melanoma. The drug ruined his thyroid gland, he said, requiring him to go on a special medication for the rest of his life, and caused severe dryness in his eyes, lips and mouth.
The federal Food and Drug Administration’s protocol for the drug called for an entire year of treatment, but Manski said his oncologist couldn’t explain why. It’s FDA-approved, “so that’s what we use,” he said he was told.
By that point, Manski showed no cancer signs or symptoms. After reading a lot of medical journal articles, he concluded that the intense side effects probably meant the treatment had done about all it could do.
“She couldn’t tell me a year was the optimal dose,” Manski said of his doctor. “Nobody could. So I made my own diagnosis. I took myself off.”
Manski’s decision was in line with what doctors in Canada, Israel, Sweden and other countries already were doing: giving lower doses of nivolumab, which is sold under the brand name Opdivo, and of a similar drug, pembrolizumab — sold as Keytruda —, or giving them for shorter periods or over longer intervals than the FDA recommends. In India, oncologists found that as little as one-twelfth of the labeled dosage of nivolumab had a powerful impact on several cancers.
“There is incredible uncertainty in drug dosing,” Manski said.
His experience impelled him to join an informal yet determined community of researchers, doctors and patients pushing for extra studies to help patients and doctors find the right dosage for an array of cancer drugs. They point to evidence suggesting that taking smaller doses of some cancer drugs or remaining on them for shorter periods could save billions of dollars and prevent some of the worst side effects.
In a recent KFF survey, 43% of U.S. adults said they had skipped their medication in the past year because of cost. A 2022 Vanderbilt University study of Medicare enrollees found that 30% of cancer drug prescriptions went unfilled.
But dose-optimization studies rarely occur after the early stages of a drug’s development or once it’s on the market. By then, few parties in the U.S. healthcare system — beyond patients — have a stake in learning that a lower dosage could work as well while causing less harm.
Pharmaceutical companies have shown little interest in dialing back recommended dosages. Once they set a price for a drug, more sales mean more profit. One study that examined 29 expensive cancer drugs estimated that if minimum necessary dosages had been used in 2024, the U.S. healthcare system could have saved roughly $31 billion.
“Decisions aren’t always made with the best needs of the patients in mind,” said Dr. Matthew Goetz, a breast cancer researcher at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota. “The bottom line is another reason.”
Last year, Merck sold nearly $32 billion worth of pembrolizumab, a drug that’s FDA-approved for more than 40 cancer conditions. It accounted for almost half of Merck’s drug sales.
Bristol Myers Squibb brought in $10 billion from nivolumab, which works similarly to pembrolizumab in tweaking the immune system. Three important but often toxic breast cancer drugs — Ibrance, Verzenio and Kisqali — boosted revenue for Pfizer, Eli Lilly and Novartis by $4.1 billion, $5.7 billion and $4.8 billion, respectively.
Pembrolizumab usually is prescribed at a fixed dosage. Nivolumab is sometimes prescribed at a fixed dosage, sometimes based on the patient’s weight. If a patient is dosed less than what’s on the label, drugmakers generally get less money.
And they aren’t the only ones who lose out.
Through a federal program known as 340B, created in 1992 to subsidize the treatment of low-income patients, hospitals that treat a certain percentage of low-income patients can buy drugs at a steep discount while charging insurers or patients more. For Medicare patients, doctors are paid an additional 6% of the drug’s average price for each infusion.
From 2010 to 2024, cancer drug revenue to doctors and hospitals increased from about $9 billion to nearly $36 billion, according to research by Aaron Mitchell of the Memorial Sloan Kettering Cancer Center. About half of those profits came from immunotherapy drugs like pembrolizumab and nivolumab.
“Pembrolizumab is the lifeblood of American hospitals,” said Dr. Mark Ratain, a University of Chicago Medicine professor and cancer doctor who is also chief hospital pharmacologist. “That’s why you don’t see hospitals in this country running to do trials that test lower doses.”
Merck spokesperson Julie Cunningham said the drug’s dosage recommendations were based on extensive testing.
“In a life-threatening and challenging disease such as cancer, it is critical that the dosing for a cancer therapy is established through well-designed clinical trials,” Cunningham said. “Changes in dose or duration that have not been similarly studied may potentially compromise the therapeutic effect.”
Still, some oncologists start patients off slowly on any of a variety of cancer drugs, though there might be concerns about lawsuits by a patient or their survivors over a prescription of lower-than-labeled dosages.
Dr. Kathy Miller, a professor of oncology at the Indiana University School of Medicine, said she routinely starts metastatic breast cancer patients with 400 milligrams of Kisqali daily for three weeks, with one week off, rather than the 600 milligrams recommended on the label. Sometimes, patients ask for the standard dosage.
“I have to tell them, ‘I don’t want to kill you,’ ” she said.
Insurers routinely challenge her lower-dosage prescriptions, Miller said, presumably because price rebates from the drug company are set to the standard dosage. To avoid endless phone battles with insurers, she prescribes 600 milligrams but tells patients to take only two of the 200-mg pills and save the third for the next cycle.
Focusing on ‘the shiny new drug’
On May 31, at the annual meeting of the American Society of Clinical Oncology at McCormick Place, most of the audience of 8,000 rose in a prolonged standing ovation for the experimental drug daraxonrasib. Patients with pancreatic cancer who took the drug, according to a study presented that day, lived nearly twice as long — a median of 13 months — as those receiving chemotherapy.
The next day, in a slightly smaller hall, Dr. Amol Patel, a medical oncologist from New Delhi, discussed studies in various cancers in which 20- or 40-mg doses of nivolumab biweekly — one-sixth or one-12th the recommended dosage — gave Indian patients several months to a year longer survival than patients who underwent chemotherapy, and with fewer side effects.
Fewer than 100 people attended Patel’s talk.
The ingenious development of daraxonrasib was big news since, until now, a pancreatic cancer diagnosis has been a death sentence. But, from a global perspective, the news out of India might be just as important.
At the ASCO meeting, “The focus is always on the shiny new drug,” said Dr. Daniel Goldstein, an oncologist and drug policy researcher at the Rabin Medical Center in Israel who has fought for a decade, with some success, to lower pembrolizumab dosages in hospitals.
The data from India offered a glimpse of what could be. But the studies Patel referred to compared ultralow-dosage immunotherapy to older chemo drugs. None compared ultralow doses against standard nivolumab or pembrolizumab treatments. In India, this would be a sterile exercise because full-dose treatments are beyond the reach of any but the very wealthy, said Dr. Vanita Noronha, an oncologist at Tata Memorial Hospital in Mumbai.
Bristol Myers Squibb has a program to make its drugs available in lower-income countries. But the company hasn’t been involved in the lower-dose nivolumab trials. It says the evidence suggests that nivolumab at a lower dosage or for a shorter duration harmed patients.
The Indian data is, to most, a mere curiosity. “Can we really give 20 milligrams as opposed to 240?” asked Dr. Jessica Bauman of the Fox Chase Cancer Center in Philadelphia. “The only way we know for sure is a randomized study between the low dose and the highest.”
And such trials are unlikely to occur. That means only poorer countries are going to host “this groundbreaking research,” Ratain said. “The Indians may have better immunotherapy than we do.”
Clinicians in Europe, where maximizing healthcare dollars has long been a priority, have taken a middle course, studying lower but not ultralow doses of immunotherapy.
Dr. Michel van den Heuvel, a pulmonologist at Utrecht University in the Netherlands, is leading a study comparing the standard nivolumab dosage for lung cancer patients with one that is as much as 50% lower. He considered giving the low doses half as frequently, but that would have raised ethical concerns and led to a more cumbersome research protocol, van den Heuvel said.
In the United States, researchers led by a group at the Dana-Farber Cancer Institute in Boston are taking another tack, evaluating whether patients who’ve done well on 27 weeks of pembrolizumab can stop taking it rather than doing the additional six months per FDA protocol.
In the federal Veterans Health Administration, which has more leeway in testing money-saving medical procedures, doctors saved $1.5 million, about 10% of the previous pembrolizumab cost, over two years at three Veterans Affairs hospitals where they implemented a pilot program to dose patients less frequently, said Dr. Garth Strohbehn, a University of Michigan and VA oncologist.
It saves money and requires fewer visits for veterans who often live hours from the hospital, according to Strohbehn, who said, “It also helps other patients because it opens more slots for infusion.”
Julie Gralow, ASCO’s executive vice president and chief medical officer, has made testing dosage a priority. She’s working with scientists in India on an ambitious clinical trial to compare standard nivolumab with four lower dosage levels.
Gralow also is leading an $11 million trial, supported by the federally funded Patient-Centered Outcomes Research Institute, to see whether breast cancer patients can be effectively started on lower doses of the drugs Kisqali and Ibrance, which, along with Verzenio, are in a class of key breast cancer drugs known as CDK4/6 inhibitors.
“We want to maintain efficacy, but we also want patients to have excellent quality of life,” she said. Especially for patients with advanced cancers, where absolute cure is unlikely, “It’s our job to make sure we’re not compromising quality of life with higher doses that are unnecessary.”
In 2021, at Ratain’s urging, Dr. Richard Pazdur, who led the FDA’s cancer drug division for many years, launched Project Optimus, intended to get companies to conduct dosing studies that are more precise before launching the large clinical trials they use to obtain FDA approval for new drugs.
The agency issued nonbinding guidelines for dosing studies in 2024 and has incorporated Project Optimus principles into the approval process for new cancer drugs, according to Emily Hilliard, a spokesperson for the federal Department of Health and Human Services. For example, two dosing regimens were evaluated for each of four lung cancer drugs — fam-trastuzumab deruxtecan, tarlatamab, zongertinib and sunvozertinib — and the lower dose with fewer toxicities was approved in each case, she said.
The FDA usually can’t compel a drugmaker to conduct dose-ranging studies after a drug’s approval, Hilliard said, and, by law, the agency does not influence drug pricing.
Future drugs should have better dosage information, Bauman said, but “newer drugs will probably be just as expensive at lower doses.”
Financial toxicity
Verzenio’s side effects made Allegra Warfield feel so sick, tired and bewildered, she said, that she considered suicide. She switched to Kisqali, which was tolerable, until last September, when coverage of the drug stopped despite her monthly premium payment of $6,000. The cash price for Kisqali was at least $16,000 a month.
After fighting her insurer for three months, Warfield, 42, sold her house and belongings in Palm Desert, California, and moved with her fiancé to Durham, North Carolina, where they’d found what they considered a reasonable insurance plan.
The cancer, the side effects and the unpayable bills were bad enough. The lack of good answers for her treatment made everything worse, she said.
“I was left to research these medications on Facebook and Reddit,” Warfield said. “The only people talking about the daily reality of these drugs were other patients. But I wanted the studies. I wanted practical guidance.”
Stories like these launched a new life mission for Dr. Kelly Shanahan, who was an OB-GYN in South Lake Tahoe, California, until side effects from a breast cancer drug caused her to lose sensation in her hands. Unable to practice medicine, Shanahan became a patient advocate who works with a group called the Patient-Centered Dosing Initiative. In 2021, Shanahan developed profound fatigue (“worse than caring for a newborn baby while being on call in my solo practice”) within a few weeks of going on Ibrance. Lowering the dosage caused her worst symptoms to lift.
After gathering countless anecdotes, her group has approached drug companies seeking data — so far with little success — that might indicate what percentage of patients have needed dosage reductions and how they fare on lower doses.
“If going down two dose levels cuts effectiveness by 50%, patients need to know that while making decisions. If it doesn’t, they need to know that,” Shanahan said — even if it means “the companies won’t make as much money.”
Shanahan said the data could be found in clinical trials and post-market studies.
But if drug companies won’t provide the necessary studies, the University of Chicago’s Manski said, governments should.
“The knowledge to be gained is a common good,” he said.
KFF Health News is a national newsroom that produces in-depth journalism on health issues.