cancer capitalism
This is the third story in a series about how the hunt for profit can harm cancer patients.
A cancer-drug revolution over the last 15 years has helped many thousands of people live longer, with immunotherapies like Opdivo and Keytruda among those proven to work the best. The drugs bind onto white blood cells to trigger an immune response from the body itself against tumors. Once seen as a backwater for drug companies, cancer is now a prime money maker for many of them, generating more than $200 billion in worldwide sales last year alone.
The financial windfall is in part due to the drugmakers’ ability to find ever more ways to administer their drugs early in treatment, for long periods of time, and in relatively high amounts – sometimes even in the face of their own evidence.
In early trials of Keytruda, Merck’s own pharmacologists found no clinical advantage to doses even five-fold higher than the original amount, based on weight. Later, as it began testing the generally higher fixed dosage, it said the change would be more convenient for doctors and nurses. It eventually removed all mention of the original dose from the adult dosing instructions.
Companies have significant influence over dosing decisions in part because they run their own trials. In charge of determining the questions to be answered, they have little incentive to study, in effect, how to make less money.
The FDA last year issued new guidance recommending more randomized testing of various doses in cancer drug studies. Still, the agency relies on the manufacturers to submit their own supporting data and only has the authority to force labeling changes for marketed drugs based on new safety information. “FDA will continue to use golden standard science in its evaluation of drugs and appropriate dosing,” a spokesperson says.
The more-is-better approach is in part a legacy of oncology’s reliance on toxic chemotherapy, given in maximum tolerated doses. But modern targeted drugs work more subtly, and the response can vary considerably among individuals. Some patients in the US have discovered serendipitously that they can get by with less, after experiencing side effects that forced a change. That’s led to benefits that aren’t captured in most trials – like fewer trips to the hospital and more time with loved ones.
James Davie, 69, runs a biotech company near Seattle and thought he was going to die when he was diagnosed with melanoma that had spread to his brain and both lungs in June 2020. After starting Opdivo that fall, his tumor quickly shrank 80%. But the side effects, including severe colon inflammation, were so intolerable that he stopped taking it after four doses.
His oncologist at Fred Hutchinson Cancer Center, Shailender Bhatia, had him resume treatment at one-tenth of the normal dose, and later cut the frequency to every three months instead of once a month. The tumors have continued to shrink, and he’s no longer in agony. The improvised regimen, Davie says, “made all the difference in the world.” He got his last dose in August and is now off treatment.
Bhatia says doctors are “hungry” for more studies proving that doses can be spread out safely – but the companies are “never gonna sponsor” them.
Merck and Bristol were two of the first drugmakers to spot the potential of new immunotherapies early last decade, prompted by the realization that the targeted treatments might work on a variety of different cancers. Tumors grow, in part, by turning the immune system off. They contain proteins that latch onto what are known as PD-1 receptors, which act as crucial checkpoints in the system. The drugs blanket the receptors to spur the immune system against tumor cells.
Bristol reported promising early results from testing of its first PD-1 drug in 2010. Less than a year later, Merck began its own tests of a PD-1 treatment called pembrolizumab. “Really just incredibly exciting results, which we have never seen before in oncology, where patients are living and basically getting complete responses to these drugs,” Ken Frazier, then Merck’s chief executive, said at a conference in 2013.
As it sought the initial approval for melanoma, Merck combined the typical three phases of testing into one large trial. That allowed it to beat Bristol to the market in September 2014 with a drug it dubbed Keytruda. Opdivo followed a few months later, first for melanoma and then for lung cancer patients. Keytruda also gained approval for lung cancer in 2015.
Dinesh de Alwis, a pharmacologist for Merck at the time, says researchers found no difference in efficacy when they compared two doses, one five times larger than the other, in early trials. As a result, the company selected the lower dose it had tested for its initial approval: 2 milligrams per kilogram of body weight, given every three weeks. The average patient in one study weighed a bit above 75 kg. That meant the treatment might come to 150 mg for many patients. Merck originally sold the drug in 50 mg vials, so a typical person might require three vials.
Bristol’s initial studies of Opdivo showed that even tiny doses were enough to blanket the receptors responsible for immune response. Doses as little as 3% of the amount eventually approved dramatically shrank melanoma tumors. Low doses were also effective in kidney cancers. But in patients with lung cancer, tumor shrinkage was pronounced at higher dosage levels. The company chose to move forward with a dose of 3 mg per kilogram every two weeks across treatments, in part due to the better response in lung cancer.
Both drugmakers soon began considering moving to fixed dosages for all patients. Roger Perlmutter, who ran Merck’s research lab, told investors on a quarterly earnings call in April 2015 that there was nothing wrong with the dosage approved months earlier. “Our data are persuasive,” he said, “that 2 milligrams per kilogram given every three weeks is as efficacious as higher doses across all tumor types studied.” But Perlmutter said using a fixed amount would “simplify dosing for the vast majority of patients.”
In 2016, Bristol did so by multiplying the weight-based-dose – 3 mg per kilogram – by the average weight in its trials to come up with a 240 mg flat dose that it now sells, in vials as small as 40 mg.
Merck, though, did something different. That same year, it sought approval for Keytruda for a new broader use in lung cancer at a flat dose of 200 mg, based on a new trial it had done. The dose was higher than the 150 mg that a typical 75-kilogram patient would have been given previously. Subsequent approvals in other cancers, and most follow-up trials, were based on the new flat dose. This same guidance was eventually added to the label across treatments, except for children and those weighing less than 40 kilograms.
De Alwis, the former Merck pharmacologist, says the fixed dose is simpler for nurses to administer and reduces the risk of a dosing error. He rejects the idea that financial considerations played into the decision. He says the company chose the dose of 200 mg “to make sure all patients at the very highest weight ranges were covered.” De Alwis left Merck in 2022 and now works at a biotech startup company.
An FDA spokesperson says the agency’s approval of flat dosing for each drug was informed by clinical data provided by the applicants showing the change was unlikely to compromise safety or efficacy.
Even before the new flat dosing was approved, researchers at Memorial Sloan Kettering Cancer Center reported in 2016 that Merck had already stopped selling the 50 mg vials in the US and introduced a new 100 mg vial. That made it difficult for any doctor who wanted to use the often lower weight-based dosing without throwing away large amounts of the drug. The financial difference was considerable. It meant that the typical person would now have to use two 100 mg vials. The Memorial researchers estimated this would boost Keytruda’s US sales by 12% through additional waste.
The change caught the attention of Goldstein, the doctor in Israel. “In effect, it was a price hike,” he says. Goldstein, 45, had grown up in the UK, where the country’s pride in a nationalized health system – and struggle to maintain it – convinced him that healthcare spending isn’t an infinite resource. After attending the University of Leeds, Goldstein did a medical residency in New York and moved on to an oncology fellowship at Emory University in Atlanta from 2012 to 2015. He watched in frustration as multiple colon cancer drugs came to market with high prices despite marginal improvements in patient survival.
“Bored of shouting into the wind,” as he puts it, he latched onto Keytruda. A 2017 study he and several colleagues published in the Journal of the National Cancer Institute proposed restoring the drug’s original dosing for lung cancer. He calculated it would save $825 million per year in the US alone.
By then working at the Rabin Medical Center near Tel Aviv, Goldstein heard from someone at Merck who invited him to present his findings at the company’s local offices in Israel. He gave a 45-minute lecture to about 20 people. The smaller vial size was then still available in Israel, and he remembers asking the Merck officials not to discontinue it, as the company had in the US. They listened and asked a few questions, as he recalls it. The next day he got a polite WhatsApp message thanking him for his time.
At the medical center, Goldstein talked to fellow doctors about switching back to weight-based dosing for the drug. Many of them privately agreed there was no difference, he says, but were nervous about implementing the change on their own, since the previous dose was no longer on the official label. Colleagues told him it would be better if there was an official guideline.
Goldstein brought up the idea with officials at Clalit Health Services, a health insurer that covers 5 million in Israel. He says Merck got wind of their discussions ahead of a big annual conference in Chicago of the American Society of Clinical Oncology in 2019 and arranged for him to talk to representatives of the company in a private meeting room.
There by himself, Goldstein walked into a roomful of Merck executives and researchers. He says they told him weight-based dosing could be dangerous and might be less effective – at odds with its earlier statement on the matter. “It felt like an ambush,” Goldstein says. An email invitation he received shows that eight people from Merck were invited, including two vice presidents involved in cancer research and the senior vice president in charge of cancer research. (He doesn’t remember which of them actually attended.)
Goldstein continued talking to Clalit about making the change. He took an official role at the insurer as medical manager of drug and technology policies in 2021, while also remaining at the medical center. That year, the insurer invited public comment on its proposal for weight-based dosing.
The response was furious. The Knesset, Israel’s parliament, held a hearing after newspaper stories accused the insurer of risking patients’ lives. The Israeli Lung Cancer Foundation was among those opposed to the change. “This is a matter of life and death. You can’t play around,” testified Shani Shilo, co-founder of the nonprofit patient advocacy group. It lists Merck and Bristol among several drug company sponsors. In an interview, Shilo says the companies had nothing to do with the group’s opposition. “The doctors on our board said we have to fight this, this is not okay,” she says. One of those board members, an oncologist named Nir Peled, testified that the change would leave doctors in an untenable position merely to save a few bucks. “This puts doctors in a legal, regulatory and ethical predicament,” he said. Peled had earlier collaborated with Merck researchers on a study that suggested the fixed and weight-based doses produced similar effects in the body. In an email, Peled says “the wish for cost reduction is important” but it “should not interfere with any clinical decisions.”
Ultimately, Israel’s health ministry decided in favor of the change for lung cancer patients in March 2022. Goldstein remembers thinking it was only the first domino. But when Clalit sought to make similar dosing changes for other types of cancer the next year, he says, it faced more resistance. Exhausted by the fight, Goldstein left his role there earlier this year to return to academia.
A Clalit spokesperson declined to comment, other than to forward a statement from a health ministry committee that said the insurer had “full medical justification” for making the dosing change across all approved indications. The ministry, though, never made a final decision allowing the insurer to do so. In an emailed statement to Bloomberg, the health ministry said that after extensive discussions, it decided at this stage not to expand use of the lower dosage to other types of cancer.
Goldstein suspects the dispute has limited his career prospects. “I’m considered a troublemaker,” he says. “Some people view me as a pariah.”
Tata Memorial Hospital in central Mumbai is one of the busiest cancer centers in India, registering 50,000 new cancer patients each year. Late into one evening in May, patients crowd the waiting room, some camped out on the stairwell and others on mats on the floor. Guards sometimes sweep by to usher people out of crowded hallways.
Cancer rates in India are less than one-third those in the US, but they’ve been rising as the population ages and middle-class lifestyles bring more desk work and processed foods. In absolute terms, the country has far more cancer deaths: some 900,000 people a year, up from 700,000 a decade previously – more than the 600,000 in the US.
Top doctors at Tata fly to international conferences to stay abreast of the latest treatments. They routinely test all lung cancer patients using the latest DNA scanning technology. But few people in India have access to comprehensive health insurance, and the hospital estimates only a small fraction of its patients can afford the $200,000-a-year personalized drugs that those tests suggest might work for them.
So about seven years ago, oncologist Kumar Prabhash and his colleagues at Tata did something radical: They began a trial testing Bristol’s Opdivo at 6% of the dose normally used in the US.
Prabhash says they informally asked Bristol to help fund the study – the primary cost of a trial is the medicine itself – but were politely turned down. Instead, the hospital got most of the 17 million rupees ($192,000) for the study from an Indian charity called Motivation for Excellence. The researchers’ original hope was to compare the effects of the much lower dose to the full dose. They didn’t have the money, so the trial compares the low dose with patients getting chemotherapy.
The results were astonishing. After a year of treatment, more than twice as many people with advanced head and neck cancer who got low-dose Opdivo plus chemo were still alive compared with chemotherapy alone. It was one of the first controlled trials to show that even tiny doses of immunotherapy drugs could produce life-prolonging results. It doesn’t prove they’re as effective, but the results have motivated doctors across India to pursue similar strategies.
Vijay Patil, a doctor who first experimented with low-dose immunotherapies at Tata, later moved to a private institute and began using them in patients with earlier-stage operable cases. In his exam room in Mumbai, Patil traces his fingers along a 10-centimeter tumor bulging from the neck of Hemant Champanekar, 46, a chauffeur who makes about $200 a month driving for a wealthy client. Champanekar says he tried to ignore it at first, worried about affording treatment. “We have to think about the family’s future, children’s education, we need to look after the house, we need to pay rent,” he says.
Patil enrolled Champanekar into a new study, where patients could get the medication for free. After the first low dose, his pain started to subside and he could move his neck better. By June, and two more small doses, the tumor had shrunk about 80%. Champanekar went in a month later for surgery to try to remove all of it. He’ll still need chemo and radiation to minimize chances of a relapse, but Patil is optimistic about his odds. So is Champanekar’s 19-year-old son, Pawan, who shared a photo of his father beaming with family.
At Christian Medical College Vellore, the hospital system three hours from Chennai with a line of people outside, a spotless but undecorated basement treatment room contains refrigerators full of medicines, including 40 mg vials of Opdivo. They give patients a single vial, one-sixth of the US dose, or even split it in half and give them 20 mg, saving the rest in the refrigerator. Recently, the hospital has also started using a newer PD1 drug called toripalimab, sold in India by Dr. Reddy’s Laboratories Ltd. under license from a Chinese company.
“With immunotherapy, I am living, I am alive still,” 66-year-old lung cancer patient Chinnappan S says, shortly after finishing an infusion. A recently retired accountant for a small parochial school, he says he couldn’t possibly have afforded full-dose immunotherapy on his salary of $300 a month.
Ashish Singh, head of the rapidly expanding medical oncology department, started Chinnappan on low-dose Keytruda in 2023 after his tumor came back in both lungs following chemotherapy. Singh was able to obtain charitable funding for just four 50 mg doses – the amount in a single US dose. Even that small amount, he says, caused a dramatic shrinkage in his tumors. When they came back this year, Singh put Chinnappan on low doses of toripalimab, leading to a partial remission.
Singh, 44, says he hasn’t noticed any obvious difference in the tumor shrinkage or rates of remission between patients getting the high dose and those getting a tiny fraction of the listed dose. He would like to do formal trials to prove that low doses work just as well. He even approached local Bristol and Merck representatives to propose various studies of reduced doses – and was turned down. “They say if you do a trial you have to use the approved dose,” he says.
A Merck spokesperson says the company has already done extensive clinical testing, and “we would be concerned that empiric reductions in dose or duration might compromise efficacy.” A Bristol spokesperson says it encourages healthcare providers to “refer to the most current prescribing information” and adds that it has sponsored more than 300 studies of the drug, including some involving lessening the dose. India, the spokesperson says, is part of a Bristol program called Aspire that seeks to broaden access to new medicines in low- and middle-income countries
Another Vellore patient, 17-year-old PG Shrinidhi, is in remission after receiving just one-twelfth the cumulative Opdivo dose she might have been given in the US. A high school senior, she wants to become an astrophysicist. At age 14 she developed swelling in her neck, then a severe cough. Doctors at first blamed a thyroid problem and finally diagnosed her with advanced Hodgkin’s lymphoma. “I am just grateful,” Shrinidhi says. “There are so many people like me who have been diagnosed but don’t have any facility to get such treatments.”
The teenager received the drug after her doctor, Anu Korula, got a grant from the government of India for a trial that examines using ultra-low doses of Opdivo to treat lymphoma in combination with chemotherapy. “It is a struggle to get the money to do the studies,” says Korula, visibly frustrated, in her windowless office. “It is a struggle to get them published.”
Tata, the hospital in Mumbai that pioneered low-dose treatments, does have funding for another trial, says its director, CS Pramesh. This one will test how well patients with operable esophageal cancer do with a short course of low-dose Opdivo before surgery compared with not using it at all. In informal conversation, according to Pramesh, Bristol hasn’t expressed interest in funding it so far. “They said this wasn’t a research priority for them,” he says, before offering his own explanation. “It would cut into their market,” he says with a laugh.
For now, that market remains buoyant. Opdivo generated about $2.6 billion in second-quarter sales for Bristol, the top-selling drug in what the company calls its “growth portfolio.” A decade after it won approval, Keytruda is Merck’s biggest single product, with second-quarter sales of $8 billion, thanks in part to its dominant position in lung cancer, the biggest cancer killer.
But India isn’t the only place experimenting with using less.
Researchers in France, the UK and the Netherlands are all pursuing various studies that examine whether doses can be spread out or given in smaller amounts. The Netherlands Cancer Institute, for instance, plans to lead a trial in 1,000 patients to see if some early-stage breast cancer can be treated with Keytruda before surgery instead of the usual regimen both before and after surgery, potentially sparing them months of infusion visits. More than 20 Dutch hospitals are already using weight-based dosing of Keytruda for lung cancer, and one study estimated they used 22% less with no difference in outcomes for patients.
Gabe Sonke, the institute’s head of medical oncology, faults the manufacturers for skipping or ignoring research that might have benefited patients earlier. “We’re doing studies that we shouldn’t have needed to be doing,” he says. “It should have been done right in the first place.”
In Seattle, where the biotech executive James Davie was treated after his melanoma diagnosis, his doctor Bhatia co-authored a University of Washington study of 23 advanced skin cancer patients. The study found that after starting with standard dosing, most did well with less frequent doses of Keytruda and Opdivo and it saved about $70,000 per patient. Skeptical of getting funds for similar work in the US, Bhatia says the team next plans to study the approach for patients in Uganda with a variety of cancers.
Almost two-thirds of cancers are in developing countries. Making smaller doses available more widely could save billions of dollars and benefit hundreds of thousands of people who otherwise wouldn’t have access to them, says Prabhash, the Tata doctor who conducted the early trials in India, where households often rely on a single income. “These cancer patients, if they become sick, it doesn’t only affect the patient, it affects the whole family,” he says.
Updating its list of essential medicines this month, the World Health Organization added several new uses of Keytruda and endorsed the use of weight-based dosing to improve access. It said ultra-low doses like those in India “could be a viable strategy” pending further research. A group of cancer experts advising the health group had said in January that “clinical evidence supporting dose reduction” for immunotherapies “is rapidly growing.” They said the idea has “the merit of being immediately implementable” and called it “noteworthy” that the initial trials in melanoma and lung cancer used weight-based dosing.
In those initial trials a decade ago, Merck had cited “persuasive” evidence that weight-based doses were effective across cancer types. In its own letter to the health organization earlier this year, though, the company said reduced intensity treatments were “not appropriate.” The data on ultra-low doses like those used in India, it added, were “not conclusive” and based on small studies with potential for bias.
The company said it’s working on other ways to get drugs to developing countries.