Walking the beaches around Los Angeles where she lives was one of life's pleasures for Susan Preston-Martin, a retired university professor and breast cancer patient.
That pleasure was interrupted when she began taking Afinitor (everolimus) to treat her breast cancer.
Just getting out of bed and taking a shower in the morning was difficult. Walks along the shore were impossible. She felt so bad she gave her pills, which cost $450 each, back to the pharmacy.
"I couldn't breathe," said Preston-Martin, 73, who developed a dangerous lung condition while taking the drug last year. "It was horrible. I was happy to get off it."
She knew the drug made her feel awful.
She didn't know this: The FDA approved everolimus without proof that it extended life.
Indeed, despite that lack of proof, the drug has come before the FDA five times in the last 6 years, and each time won approval for a new indication. Everolimus is now used to treat advanced breast and kidney cancer, a rare type of pancreatic cancer, and two types of nonmalignant tumors.
The drug comes -- mouth sores, infections, fatigue, diarrhea, abdominal pain, fever, cough, headache, and decreased appetite. In clinical trials, each occurred in at least 30% of patients.
, 63% of those taking everolimus had to cut the dose of the drug or temporarily stop treatment, compared with 14% who got a placebo. Some 24% had to stop using it altogether, compared with 5% who got a placebo.
And nearly one in five developed non-infectious pneumonitis -- the condition Preston-Martin developed.
Since 2009, the year the drug first got on the market, there have been nearly 9,000 reports of serious adverse reactions among everolimus users, including more than 2,700 deaths and more than 3,100 hospitalizations, according to a 番茄社区/Milwaukee Journal Sentinel .
But in the desperate world of cancer medicine, toxic and expensive drugs that aren't proven to extend life can quickly achieve blockbuster status.
For everolimus, each FDA approval for a new condition increased the pool of potential patients -- and potential sales -- for the drug, sometimes substantially.
Between 2010 and last year, prescriptions for everolimus rose from 13,000 to nearly 70,000, according to , a drug market research firm.
In the U.S., sales jumped from $110 million in 2010 to $803 million last year, making it one of the nation's top selling cancer drugs. Worldwide, the drug is on pace for its best year with more than $1.2 billion in sales through October, according to financial disclosures filed by Novartis, the manufacturer.
A 番茄社区/Journal Sentinel investigation last year found 74% of new cancer drugs approved in the past decade came to market without proof that they increased survival. Afinitor, like many of the others, was approved based on its ability to slow the progression of tumors, considered a "surrogate measure" of effectiveness.
The use of such measures allows for quicker, smaller, and cheaper clinical trials. They are favored by drug companies and are commonly accepted by the FDA, which independent experts fault for not setting the bar higher and for not requiring drug companies to develop more drugs with proven clinical benefits.
For instance, diabetes drugs may be approved based on their ability to lower blood-sugar levels, but without proof they reduce heart attacks or strokes.
Among cancer drugs, everolimus stands out for its repeated approvals despite what independent doctors say are serious concerns -- particularly for breast cancer patients.
"I don't see any real benefit to people," said , an oncologist and assistant professor of medicine at Oregon Health and Sciences University. "This is a daily medicine that can cause daily side effects."
Target: Renal Cell Carcinoma
The FDA first approved everolimus in 2009, when it was authorized to treat advanced kidney cancer in patients whose disease had progressed despite treatment with either of two other drugs.
That approval was based on progression-free survival -- the amount of time it takes for a tumor to noticeably progress, as seen on an x-ray or, in some cases, until a patient dies.
In the trial, progression-free survival was 5 months for everolimus versus 2 in those who got a placebo. But the drug failed to show its use allowed patients to live longer.
While delaying progression is desirable, the problem is cancer is complicated -- a tumor might stop growing or shrink in one spot, then reappear somewhere else, or even in multiple places.
In November, two separate studies in the New England Journal of Medicine showed that two other drugs outperformed everolimus in head-to-head clinical trials in kidney cancer patients.
, the drug Opdivo (nivolumab) produced longer overall survival and fewer severe adverse events than everolimus. , the drug Cometriq (cabozantinib) produced longer progression free survival.
Target: Pancreatic Cancer
In 2011, the FDA approved everolimus again, this time for neuroedocrine pancreatic cancer. That cancer is diagnosed in fewer than 1,000 people a year in the U.S. and those with it can live for many years.
It is perhaps best known as the cancer that killed Apple CEO Steve Jobs. A more common type of pancreatic cancer can be fatal in a matter of months.
In its pancreatic cancer trial, everolimus provided progression-free survival of 11 months, compared with 5 months in those who got a placebo. Once again, there was no statistically significant overall survival benefit.
Some doctors note they prefer other cancer drugs, because everolimus has only modest ability to shrink tumors, has serious side effects, and is expensive, with those costs often shared by patients in the form of large co-pays.
The drug can cost $11,400 a month, according to data supplied by Memorial Sloan Kettering Cancer Center in New York. The cost, based on the Medicare reimbursement price, actually has increased nearly $3,000 a month since 2014.
Before the increase, taxpayers already paid $275 million to cover everolimus for Medicare patients, according to the .
"In addition to fatigue, the drug can cause some nasty and persistent mouth sores," said , an oncologist at at the center. "So I don't love it at any price."
Target: Breast Cancer
In 2012, everolimus was granted a third cancer approval, this time for postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. Hormone positive, HER2 negative is the tumor type in about 70% of breast cancers.
That approval was based on a clinical trial using it in tandem with exemestane, another breast cancer drug, versus placebo and exemestane.
The trial, which involved women who had failed one of two other drugs, showed the everolimus combination offered progression-free survival of 8 months versus 3 months in the control arm.
But it was not shown to extend survival.
Targets: Nonmalignant tumors
Everolimus also won approval for two types of nonmalignant tumors. In 2010, the FDA approved it to treat nonmalignant tumors in the brain. Early in 2012, it was also approved approved to treat noncancerous kidney tumors that didn't require immediate surgery in some patients
The everolimus label now has five indications.
Novartis spokeswoman Julie Masow noted everolimus is considered a targeted therapy -- it's an mTOR inhibitor -- and as such is an alternative to chemotherapy. Both kinds of therapies come with toxicities, she said.
"For many patients, being able to stay on treatment is important," Masow wrote in an email. "Novartis works with healthcare providers and patients to ensure that they understand the side effects they can expect with everolimus and provides educational materials and patient support services to help them recognize and manage adverse events."
She noted everolimus was determined by the FDA to be safe and effective in several diseases and is approved for use in more than 100 countries, including the U.S., and in the European Union.
In addition to progression-free survival, another surrogate measure known as objective response rate was used in everolimus trials. That measure looks at whether a tumor has shrunk and whether it remains that way for a specified amount of time.
FDA spokeswoman Sarah Peddicord said both measures are acceptable for use in approving cancer drugs.
"Our mission at the FDA is to ensure that drugs marketed in this country are safe and effective and we strive to approve these medications as quickly as possible once we have adequately and appropriately weighed a drug's benefits and risks based on the data received in a drug application," she wrote in an email.
番茄社区/Journal Sentinel investigations have found the FDA's reliance on surrogate measures has led to a steady stream of costly drugs of dubious value over the past decade -- not just in cancer, but for conditions such as diabetes, low testosterone, and obesity.
Those stories documented more than 6,000 deaths that were attributed to side effects from the drugs that were reported to the FDA.
A separate investigation in August found reports of 8,000 deaths in patients who had used three newly approved blood thinners designed to replace warfarin in patients with a common heart condition known as atrial fibrillation.
In October, a study published in JAMA Internal Medicine, corroborated the findings of the 2014 番茄社区/Journal Sentinel investigation that found 74% of the cancer drugs approved over the past decade came without proof of a survival benefit.
The paper found that 67% of cancer drugs approved over a 5-year period came to the market based on surrogates, not because they extended or improved life.
"Our results suggest that the FDA may be approving many costly, toxic drugs that do not improve overall survival," .
Risk Versus Benefit
Everolimus's side effects can be especially hard on older women.
A had to permanently get off everolimus due to a serious adverse event. Three times as many of them -- 6% versus 2% -- died while on everolimus than their younger counterparts on the drug.
Among women ages 65 and older, an FDA review attributed nine deaths to an adverse event in the everolimus arm of the clinical trial versus one in the placebo group. All the deaths occurred within 28 days of the last dose. Some examples:
- developed lethargy and a mouth ulcer on day 7 of her treatment. On day 8, she developed kidney failure and died on day 15.
- A 76-year-old woman and decreased appetite, causing her to stop using the drug on day 28. She was hospitalized on day 31, developed a lung infection and septic shock on day 36, and had a mini stroke on day 40. She died 2 weeks later.
- in the lungs on day 148 of her treatment. She was treated with a blood thinner (heparin) and developed a hemorrhage which resolved. On day 165, she experienced respiratory failure and a bacterial infection in the blood, which caused her death on the same day.
A 2012 paper in the journal Translational Cancer Research noted the "concerning" number of deaths related to the treatment, as well as the many others who suffered serious side effects.
"In the real-world setting, patients may prefer to forego the significant risk of serious side effects in order to maintain quality of life ... ," .
That is particularly true, they added, when the treatment is unlikely to save or extend their life.
Dartmouth Medical School professors , and , co-founders of , a for-profit firm that provides information about the risks and benefits of prescription drugs, did an analysis for this story of everolimus and its side effects when used in breast cancer patients.
They examined more than two dozen side effects, including 10 that were considered serious. The side effects occurred more often with everolimus than patients receiving a placebo, often a lot more.
For instance, 67% of the women getting everolimus developed mouth ulcers, compared with 11% in the placebo group. Infections occurred in 50% of those on everolimus, compared with 25% in the placebo group. Kidney problems, including kidney failure, occurred in 24% of those on everolimus, compared with 13% in the placebo group.
"Unfortunately, everolimus has limited benefit," said Schwartz. "It delays progression by a few months, but doesn't help women live longer or feel better. And the limited benefit comes at a big cost in terms of serious and severe side effects."
Two Tales of Treatment
When Lynn Bartnicki started taking everolimus, she thought she'd found something that would work without bad side effects. The 2 years since her breast cancer diagnosis had already brought three other attempted treatments.
"Initially, I was thrilled with the drug," said Bartnicki, 67, of Manahawkin, New Jersey. Bartnicki is an active fundraiser for various causes, including metastatic breast cancer research.
But after 3 months on everolimus therapy, she went to the emergency room with shortness of breath. She was diagnosed with pneumonitis and was taken off of the drug.
"The shortness of breath was really bad," Bartnicki said. "It really came on very quickly, all of sudden."
Other patients say the risk of side effects is worth it.
Suzanne Nelson, 52, of Culver City, Calif., has been on several drugs since her diagnosis in 2006, yet the disease continued to progress.
Earlier this year, a scan showed the cancer had progressed again, this time to her adrenal gland. In February, she went on a combination of everolimus and tamoxifen.
Within 6 weeks, she developed blood clots and was hospitalized for 5 days and now has to take a blood thinner. Though she has a lot of fatigue, the two-drug combination has allowed her to continue working as a human resources manager because her cancer has not progressed.
"Maybe it is not extending life," Nelson said. "I can work because I am not dwindling. It is something else that is available. We need more for Stage 4 people."
Spending Money to Make Money
From August 2013 through 2014 alone, Novartis spent at least $2.5 million dollars on consultants and promotional activities to market the drug, according to the federal government's .
The company also funded the writing of papers that generally reached favorable conclusions about the drug. Those papers were published in peer-reviewed medical journals.
A 番茄社区/Journal Sentinel analysis found at least 10 published papers -- all funded by Novartis and written mostly by experts with financial ties to the company -- that played up the benefits of the drug for breast cancer patients such as touting progression-free survival.
Two-thirds of the 64 co-authors listed on those papers disclosed financial conflicts with Novartis. Those include employees of the company and experts who worked as consultants or paid speakers.
For instance, concluded that everolimus did not negatively affect quality of life in breast cancer patients. Twelve of the 20 authors were consultants, speakers, or employees of the company.
A year earlier, reviewers at the FDA came to a different conclusion, saying there was no proven quality of life benefit for the drug. Their review noted there was a large portion of quality of life data missing from the clinical trial.
Masow, the Novartis spokeswoman, said the company follows strict guidelines that are consistent with industry standards to ensure that published papers are free of potential bias.
"We respect and abide by the rules of each academic institution about the types of interactions its employees or affiliates may enter into with a healthcare company," she said.
Novartis is continuing its push for new label indications for the drug, with the company highlighting Afinitor's performance as a "key growth driver" in its to investors.
In July, Novartis executive David Epstein walked investors through the company's strategy of seeking new uses for its product. During , he said those new uses would mean that competitor's drugs would be "less of an issue going forward" for sales.
"We have a big opportunity to expand the use of Afinitor."
The NDAs with the FDA for three additional indications: nonfunctioning neuroendocrine tumors of gastrointestinal track and the lungs, diffuse large B-cell lymphoma, and seizures associated with tuberous sclerosis complex.
The agency is expected to rule on those in the coming months.