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.<\/p>\n

But while the drug has helped keep him alive, its side effects have gradually narrowed the confines of his life, said Crosslin, 76, who lives in Ocala, Florida: \u201cMy appetite has been minimal. I\u2019m very weak. I walk my dogs and get around a bit, but I haven\u2019t been able to golf since last July.\u201d<\/p>\n

He wonders whether he\u2019d do better on a lower dose, \u201cbut I do what my oncologist tells me to do,\u201d Crosslin said. Every day, he takes eight of the 120-milligram pills, sold under Amgen\u2019s brand name Lumakras.<\/p>\n

Crosslin\u2019s concern lies at the heart of an FDA 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. In the face of evidence that thousands of patients become so ill that they skip doses or stop taking the drugs \u2014 thereby risking resurgence of their cancers \u2014 the FDA has begun requiring companies to pinpoint the right dosage before they reach patients.<\/p>\n

The initiative, Project Optimus, launched in 2021 just as Amgen was seeking to market sotorasib. At the time, the FDA\u2019s leading cancer drug regulator, Richard Pazdur, co-authored an editorial in the New England Journal of Medicine that said Amgen\u2019s trials of the $20,000-a-month drug were \u201champered by a lack of robust dose exploration.\u201d<\/p>\n

The FDA conditionally approved sotorasib but required Amgen to conduct a study comparing the labeled dosage of 960 mg with a dosage of 240 mg. The trial, published in November, showed that the 960-mg dose may have given patients a month more of life, on average, but caused more severe side effects than the lower dose.<\/p>\n

Amgen is keeping the 960-mg dosage as it conducts further tests to get final approval for the drug, spokesperson Elissa Snook said, adding that the dose showed superiority in one study<\/a>. Whether medically justified or not, the heavier dosage allows the company to protect 75% of its revenue from the drug, which brought in nearly $200 million in the United States last year.<\/p>\n

And there appears to be nothing the FDA can do about it.<\/p>\n

\u201cThere\u2019s a gap in FDA\u2019s authority that results in patients getting excess doses of a drug at excess costs,\u201d said Mark Ratain, a University of Chicago oncologist who has pushed for more accurate cancer drug dosing. \u201cWe should do something about this.\u201d<\/p>\n

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Deciding on Dosage<\/strong><\/p>\n
It may be too late for the FDA to change the 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 for the first time, spokesperson Lauren-Jei McCarthy said.<\/p>\n
\u201cWhen you go in front of FDA with a plan to approve your drug now, they are going to address dosing studies,\u201d said Julie Gralow, chief medical officer of the American Society of Clinical Oncology. \u201cA lot of companies are struggling with this.\u201d<\/p>\n
That\u2019s largely because the new requirements add six months to a year 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.<\/p>\n
In part, Project Optimus represents an effort to manage the faults of the FDA\u2019s 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.<\/p>\n
That\u2019s especially true of the newer pills to treat cancer, said Donald Harvey, an Emory University pharmacology professor, who has led or contributed to more than 100 early-phase cancer trials.<\/p>\n
A study released last month<\/a> in the Journal of the American Medical Association showed that 41% of the cancer drugs granted accelerated approval from 2013 to 2017 did not improve overall survival or quality of life after five years.<\/p>\n
Many of these drugs flop because they must be given at toxic dosages to have any effect, Harvey said, adding that sotorasib might work better if the company had found an appropriate dosage earlier on.<\/p>\n
\u201cSotorasib is a poster child for incredibly bad development,\u201d Harvey said. The drug was the first to target the KRAS G12C mutation, which drives about 15% of lung cancers and was considered \u201cundruggable\u201d until University of California-San Francisco chemist Kevan Shokat figured out how to attack it<\/a> in 2012.<\/p>\n
Given the specificity of sotorasib\u2019s target, Harvey said, Amgen could have found a lower dosage. \u201cInstead, they followed the old model and said, \u2018We\u2019re going to push the dose up until we see a major side effect.\u2019 They didn\u2019t need to do that. They just needed more experience with a lower dose.\u201d<\/p>\n
The 960-mg dose \u201cis really tough on patients,\u201d said Yale University oncologist and assistant professor Michael Grant. \u201cThey get a lot of nausea and other GI side effects that are not pleasant. It hurts their quality of life.\u201d<\/p>\n
The FDA noted in its review<\/a> 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 concentrations in the blood, which suggested that at higher doses the drug was mostly just intensifying side effects like diarrhea, vomiting, and mouth sores.<\/p>\n
For most classes of drugs, companies spend considerable time in phases 1 and 2 of development, homing in on the right dosage. \u201cNo one would think of dosing a statin or antibiotic at the highest tolerable dose,\u201d Ratain said.<\/p>\n
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 in the bargain. Typically, a company\u2019s 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 \u201cmaximum tolerated dose\u201d is then employed in more advanced clinical trials, and goes on the drug\u2019s label. Once a drug is approved, a doctor can \u201cgo off-label\u201d and alter the dosage, but most are leery of doing so.<\/p>\n
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. \u201cThat 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.\u201d<\/p>\n
Some practitioners, at least, have responded to the FDA\u2019s cues on sotorasib. In the Kaiser Permanente health system, lung cancer specialists start with a lower dose of the drug, spokesperson Stephen Shivinsky said.<\/p>\n
Smaller Doses \u2014 And Revenue<\/strong><\/p>\n
Amgen was clearly aware of the advantages of the 240-mg dosage before it sought FDA approval: It filed a provisional patent application<\/a> on that dosage before the agency gave breakthrough approval for the drug at 960 mg. The company doesn\u2019t appear to have disclosed<\/a> the patent filing to investors or the FDA. McCarthy said the FDA was prohibited by law from discussing the particulars of its sotorasib regulation plans.<\/p>\n
Don Crosslin visits Flagler Beach, Florida, in 2018. The retired medical technician has been taking the drug sotorasib (Lumakras) to treat his advanced lung cancer disease since 2021. Crosslin says he\u2019s grateful for the drug\u2019s role in keeping him alive but wonders whether he could be on a lower dose.(Don Crosslin)<\/span><\/figcaption><\/figure>\n
Switching to a 240-mg dosage could register a huge hit to Amgen\u2019s revenue. The company markets the drug at more than $20,000 for a month of 960-mg daily doses. Each patient who could get by with a quarter of that would trim the company\u2019s revenue by roughly $180,000 a year.<\/p>\n
Amgen declined to comment on the patent issue or to make an official available to discuss the dosage and pricing issues.<\/p>\n
Crosslin, who depends on Social Security for his income, couldn\u2019t 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.<\/p>\n
While the drug has worked well for Crosslin and other patients, its overall modest impact on lung cancer suggests that $5,000, rather than $20,000, might be a more appropriate price, Ratain said.<\/p>\n
In the company\u2019s 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 $1 per injection. The trial was so unconvincing that the FDA sent Amgen back to do another.<\/p>\n
Ratain, a staunch critic<\/a> of Amgen\u2019s handling of sotorasib<\/a>, told Centers for Medicare & Medicaid Services officials at a recent meeting that they should pay for sotorasib on a basis of 240 mg per day. But CMS would do that only \u201cif there is a change in the drug\u2019s FDA-approved dosage,\u201d spokesperson Aaron Smith said.<\/p>\n
Drug companies generally don\u2019t want to spend money on trials like the one the FDA ordered on sotorasib. In 2018, Ratain and other researchers used their institutions\u2019 funding to conduct a dosing trial on the prostate cancer drug abiraterone, marketed under the brand name Zytiga by Johnson & Johnson. They found that taking one 250-mg pill with food was just as effective as taking four on an empty stomach, as the label called for.<\/p>\n
Although J&J hasn\u2019t changed the Zytiga label<\/a>, the evidence generated in that trial was strong enough for the standards-setting National Comprehensive Cancer Network to change its recommendations.<\/p>\n
Post-marketing studies like that one are hard to conduct, Emory\u2019s Harvey said. Patients are reluctant to join a trial in which they may have to take a lower dosage, since most people tend to believe \u201cthe more the better,\u201d he said.<\/p>\n
\u201cIt\u2019s better for everyone to find the right dose before a drug is out on the market,\u201d Harvey said. \u201cBetter for the patient, and better for the company, which can sell more of a good drug if the patients aren\u2019t getting sick and no longer taking it.\u201d<\/p>\n
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