A relatively new type of cancer drug may help stop tumors from recurring in some patients with the most common form of breast cancer, detailed results from a study run by Eli Lilly show.
The data, from a 5,637-patient Phase 3 trial testing a medicine called Verzenio, are being presented Sunday at the European Society of Medical Oncology's virtual meeting. They've been highly anticipated since the Indianapolis drugmaker in June announced the study had succeeded because they could help change how patients with a form of early-stage breast cancer are treated.
Researchers involved in the MONARCHe trial found that patients on Verzenio and standard hormone therapy were 25% less likely than those on hormone therapy alone to see their cancers return after a median of 15.5 months of follow-up.
The absolute risk reduction between the two groups is more modest: 11.3% of patients in the control group relapsed, compared to 7.8% of those who got Verzenio, a 3.5% difference. Nonetheless, the results are a "big step forward," said Debu Tripathy, the chair of MD Anderson Cancer Center's breast medical oncology department, in an interview.
"Even though it's only a few percentage points, it means the difference between living and dying," said Tripathy, who isn't involved in the trial. "Everything we can do to prevent recurrence is critical."
Still, the study, published today in the Journal of Clinical Oncology, leaves questions. A rival medicine from Pfizer failed a similar trial that is also being detailed as ESMO. That trial raised doubts about the potential of these drugs, which are known as CDK 4/6 inhibitors. More time is needed, too, to determine whether Verzenio, alongside hormone therapy, actually helps patients live longer than they would have otherwise.
Verzenio causes gastrointestinal side effects, mostly diarrhea, that caused some patients to stop treatment.
"Even hormone therapy, just by itself, is accompanied by a lot of side effects, and it's hard for women to stay on it," said Niki Patel, a medical oncologist at City of Hope, and an investigator in the Verzenio trial. "I think this is going to be practice changing, but it's going to be challenging."
What's more, the drug has a list price of $12,000 per month, and would significantly add to the cost of care for these patients, who typically receive hormone therapy that is generic and comparatively cheap.
Breast cancer is both the most commonly diagnosed cancer and the second-leading cause of cancer death among women. The American Cancer Society estimates 42,170 women will die from the disease in the U.S. this year, although the death rate has declined 40% between 1989 and 2017. That improvement is largely due to better early cancer detection and new treatments, from hormone therapies to targeted drugs.
Patients who have had the disease are at risk for their cancers recurring, when tumors can spread and become more deadly. In breast cancer, the risk of that happening depends on the type and size of a patient's tumor, the stage at which it was found and how it was treated. Those factors also change the treatment options for the three main disease types, which are each associated with proteins or hormones.
As drugs have improved, doctors have sought to use them earlier, City of Hope's Patel said. That's led to considerable progress in "adjuvant" treatment — after surgery but before a tumor returns and spreads — in two of the three main breast cancer types, triple-negative and HER2 positive.
That hasn't been the case, however, in hormone-positive, or HR-positive patients, which account for more than 70% of women with the disease. Their tumors grow slowly and usually don't respond well to chemotherapy, Patel said. The majority of women diagnosed, therefore, get surgery, radiation and years of hormone therapy afterwards to keep their tumors at bay.
Some 30% of women with HR-positive breast cancer will see their cancers return at some point, according to Lilly oncology president Anne White. That's why CDK 4/6 inhibitors, which block enzymes tumors use to grow and multiply, have been closely watched.
Since 2015, the Food and Drug Administration has approved three such drugs from Lilly, Pfizer and Novartis, for advanced breast cancer patients whose tumors have already spread. Pfizer's drug, Ibrance, has become the top-seller of the group, with $5 billion in sales in 2019.
Lilly and Novartis' drugs haven't sold as well, but their makers aim to expand their market share. Studies have already shown the drugs can help advanced breast cancer patients live longer.
All three companies have since started large clinical trials in earlier lines of treatment, too.
The first of those studies, a Pfizer study of Ibrance called PALLAS, was unexpectedly stopped early in May because investigators judged it likely to fail. That result drove down expectations for the other ongoing studies, among them Lilly's MONARCHe trial. But Lilly surprised in June when it declared success a year earlier than the trial was expected to read out results
Though there are technical differences between the drugs and how they block their molecular targets, the reason for the divergent outcomes may come down to trial design.
PALLAS enrolled a broad group of women and men with either Stage 2 or Stage 3 cancers and different risk levels for recurrence. MONARCHe recruited patients with Stage 1 to Stage 3 cancer who were deemed at "high-risk" of recurrence based on disease markers such as tumor size and how many lymph nodes were affected.
That's an important difference, because under typical circumstances, HR-positive breast cancer can resurface "years later," said MONARCHe study author Erika Hamilton, an oncologist and program director at the Sarah Cannon Research Institute. Lilly's study "was designed for that ultra-risk population," she said.
MONARCHe researchers tracked what's called invasive disease-free survival, a measure of how long until patients relapse and an established trial goal for an adjuvant cancer treatment.
According to the results unveiled at ESMO, 136 people on Lilly's drug and hormone therapy relapsed, compared to 187 on hormone treatment alone after a median of 15.5 months. Some 70% of patients are still on the trial's planned two-year treatment course for Verzenio, so the difference could widen over time, Hamilton said.
PALLAS results disclosed at ESMO, by comparison, found that patients who got Ibrance and hormone therapy were statistically more likely to see their cancers return than those who didn't get the Pfizer drug. After a median of 23.7 months, 11.8% of patients on Ibrance and hormone therapy relapsed, versus 11.5% for those only on hormone therapy.
MD Anderson's Tripathy noted another edge for Verzenio in MONARCHe. Verzenio-treated patients had a 28% lower risk of more lethal "distant" tumors that appear elsewhere, like the liver or lung. "Those are the ones that are not curable," he said.
But 463 Verzenio patients stopped treatment because of side effects, compared to 306 on hormone therapy. Verzenio is"not an easy pill to take," City of Hope's Patel said, referring to the drug's gastrointestinal side effects. She said she has "tens of patients'' on Pfizer's Ibrance and Novartis's Kisqali, compared to just two who have been able to tolerate Verzenio.
Hamilton, at Sarah Cannon, noted the majority of diarrhea cases in MONARCHe were mild to moderate, while side effects typically associated with hormone therapy, like bone aches and hot flashes, were unexpectedly lower among the Verzenio-treated group.
The push of newer drugs — from targeted treatments to immunotherapy — into earlier lines of care is driving the costs of cancer treatment higher. Even if Verzenio is only approved for the type of high-risk patients enrolled in MONARCHe, for instance, its use would substantially increase the cost of standard adjuvant treatment for that particular group. Hormone therapy like tamoxifen can cost $50 a month, Patel said.
"We'll have to see how that plays out, but it's definitely going to be more expensive than what we are typically used to," agreed Tripathy.
According to White, the company hasn't had problems getting insurance coverage for Verzenio in the metastatic setting: some 97% of insured patients have gotten access, she said. White confirmed the company doesn't plan to change Verzenio's price tag if it's approved for adjuvant use.
White estimates there are about 20,000 U.S. patients per year who would fit the criteria of those tested in MONARCHe. Roughly 50,000 in the U.S. are eligible for treatment currently.
Competition could come fast for Verzenio, given the momentum underway in breast cancer research. Pfizer's other adjuvant trial for Ibrance, PENELOPE-B, which is in higher-risk patients, should produce results later this year. A Kisqali adjuvant trial, NATALEE, wraps up in 2022 and could deliver data earlier.
Correction: A previous version of this article misstated which patients were enrolled in MONARCHe.