Chemo can be brutal. This FDA effort aims to make it less so.

04/05/2024

When doctors began using the drug sotorasib in 2021 with high expectations for its innovative approach to attacking lung cancer, retired medical technician Don Crosslin was an early beneficiary. Crosslin started the drug that July. His tumors shrank, then stabilized.

But while the drug has helped keep him alive, its side effects have narrowed the confines of his life. “My appetite has been minimal. I’m very weak. I walk my dogs and get around a bit, but I haven’t been able to golf since last July,” said Crosslin, 76, who has Stage 4 lung cancer and lives in Ocala, Fla.

He wonders whether he’d do better on a lower dose, “but I do what my oncologist tells me to do,” he said. Every day, he takes eight 120-milligram pills, sold under Amgen’s brand name Lumakras.

Crosslin’s concern lies at the heart of a Food and Drug Administration effort to make cancer drugs less toxic and more effective. Cancer drug trials are structured to promote high doses, which then become routine patient care. With evidence that thousands of patients become so ill that they skip doses or stop taking the drugs — risking resurgence of their cancers — the FDA has begun requiring companies to pinpoint the right dosage before drugs reach patients.

The initiative, Project Optimus, launched in 2021 just as Amgen was seeking to market sotorasib. At the time, the FDA’s leading cancer drug regulator, Richard Pazdur, co-wrote an editorial in the New England Journal of Medicine that said Amgen’s trials of the $20,000-a-month drug were “hampered by a lack of robust dose exploration.”

The FDA conditionally approved sotorasib but required Amgen to conduct a study comparing the labeled dosage of 960 mg with one of 240 mg. The trial, published in November, showed that the 960 mg dose may have given patients another month of life, on average, but it also caused severer side effects.

Amgen is keeping the 960 mg dosage as it conducts further tests to get final approval for the drug, said spokesperson Elissa Snook, adding that the higher dose was superior in one study. The $20,000 monthly cost of the 960 mg dose would buy four months of the 240 mg dose. The lower dosage would dramatically cut Amgen’s revenue for sotorasib, which brought in nearly $200 million in the United States last year.

And the FDA lacks the legal power to change the dose.

“There’s a gap in FDA’s authority that results in patients getting excess doses of a drug at excess cost,” said Mark Ratain, a University of Chicago oncologist who has pushed for more-accurate dosing. “We should do something about this.”

Project Optimus

It’s too late for the FDA to change the current sotorasib dosage, although in principle it could demand a new regimen before granting final approval, perhaps in 2028. Under Project Optimus, however, the agency is doing something about dosage guidelines for future drugs. It is stressing dose optimization in its meetings with companies, particularly as they prepare to test drugs on patients, FDA spokesperson Lauren-Jei McCarthy said.

“When you go in front of FDA with a plan to approve your drug now, they are going to address dosing studies,” said Julie Gralow, chief medical officer of the American Society of Clinical Oncology. “A lot of companies are struggling with this.”

That’s largely because the new requirements add six months to a year to the process and millions in drug development costs, said Julie Bullock, a former FDA drug reviewer who advocated for more-extensive dosing studies and is now senior vice president at Certara, a drug development consultancy.

In part, Project Optimus represents an effort to manage the faults of the FDA’s accelerated approval process, begun in 1992. While the process gets innovative drugs to patients more quickly, some medicines have proved lackluster or had unacceptable side effects.

That’s especially true of pills developed in the past decade or so to treat cancer, said Donald Harvey, an Emory University pharmacology professor who has led or contributed to more than 100 early-phase cancer trials.

Toxic doses of chemotherapy

Of 46 cancer types treated with drugs that won accelerated approval from 2013 to 2017, 19 failed to result in longer survival or better quality of life after more than 5 years, according to a study published in April in JAMA.

Many of these drugs flop because they have to be given at toxic dosages to have any effect, Harvey said. Sotorasib, in contrast, might perform better overall if the company had found an appropriate dosage earlier on, he said.

“Instead, they followed the old model and said, ‘We’re going to push the dose up until we see a major side effect,’” Harvey said. “They didn’t need to do that. They just needed more experience with a lower dose.”

The FDA noted in its review of sotorasib that in Phase 1 studies, tumors shrank when exposed to as little as a fifth of the 960 mg daily dose Amgen selected. At all doses tested in that early trial, the drug reached roughly the same concentration in the blood, suggesting that at higher doses, the drug was mostly just intensifying side effects such as diarrhea, vomiting and mouth sores.

For most classes of drugs, companies spend considerable time in Phases 1 and 2 of development, homing in on the right dosage. “No one would think of dosing a statin or antibiotic at the highest tolerable dose,” Ratain said.

Cancer drugs are different

Things are different in cancer drug creation, whose approach originated with chemotherapy, which damages as many cancer cells as possible, wrecking plenty of healthy tissue as part of the bargain. Typically, a company’s first series of cancer drug trials involve escalating doses in small groups of patients until something like a quarter of them get seriously ill. That “maximum tolerated dose” is then employed in more-advanced clinical trials, and goes on the drug’s label.

Patients can find the experience rougher than advertised. During clinical trials, the side effects of the cancer drug osimertinib (Tagrisso) were listed as tolerable and manageable, said Jill Feldman, a lung cancer patient and advocate. “That killed me. After two months on that drug, I had lost 15 pounds, had sores in my mouth and down my throat, stomach stuff. It was horrible.”

Some practitioners have responded to the FDA’s cues on sotorasib. In the Kaiser Permanente health system, lung cancer specialists start with a lower dose of the drug, spokesperson Stephen Shivinsky said. [Kaiser Permanente is not related to KFF Health News.]

Switching to a 240 mg dosage could mean a huge hit to Amgen’s revenue. For every patient who could get by with a quarter of the 960 mg dose marketed by Amgen, the company’s revenue would fall by roughly $180,000 a year.

Amgen declined to comment on the dosage and pricing issues.

Crosslin, who depends on Social Security for his income, couldn’t afford the $3,000 a month that Medicare required him to pay for sotorasib, but he has received assistance from Amgen and a charity that covers costs for patients below a certain income.

In the company’s Phase 3 clinical trial for advanced lung cancer patients, sotorasib kept patients alive for about a month longer than docetaxel, the current, highly toxic standard of care. Docetaxel is a generic drug for which Medicare pays about a dollar per injection. The sotorasib and docetaxel arms of the trial had so many differences that the FDA said the study was uninterpretable, and sent Amgen back to do another.

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