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Conflicting ESMO Data Raise Questions About Role of CDK4/6 Inhibitors in Adjuvant Breast Cancer

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NEW YORK – Combining Eli Lilly's CDK4/6 inhibitor abemaciclib (Verzenio) with hormonal therapy reduced the risk of recurrence by 25 percent in a subset of early-stage breast cancer patients with high-risk tumors, according to early data from a clinical trial.

The positive interim data from the Phase III MonarchE study, unveiled at the European Society for Medical Oncology's Virtual Congress on Sunday and simultaneously published in the Journal of Clinical Oncology, represent the first time the combination of a CDK4/6 inhibitor and endocrine therapy in the adjuvant setting has significantly improved invasive disease-free survival in hormone receptor (HR)-positive, HER2-negative breast cancer patients, according to lead author Stephen Johnston from the Royal Marsden Hospital, National Health Service Foundation Trust in the UK. 

In June, Lilly had already announced that MonarchE had met its primary endpoint of invasive disease-free survival and said it would submit these data with regulators in different countries to expand abemaciclib's use in this high-risk, early breast cancer subpopulation. However, since more than 70 percent of patients in the study haven't completed two years of abemaciclib as required, the full data form the trial are not mature yet and Johnston's team will follow patients to track the impact of the regimen on invasive disease-free survival, distant relapse-free survival, and overall survival, and conduct genomic analyses to home in on the subset of high-risk patients who are most likely to benefit.

Meanwhile, at the same meeting, it was announced that another Phase III study, called PALLAS, with a very similar design —exploring the benefit of adding Pfizer's CDK4/6 inhibitor palbociclib (Ibrance) to adjuvant endocrine therapy in 5,760 HR-positive, HER2-negative, early-stage breast cancer patients — was stopped based on negative results at the time of a planned interim futility analysis.

Erica Mayer of the Dana-Farber Cancer Institute, the lead investigator of PALLAS, presented data showing that at a median of 23.7 months follow up, there wasn't a significant different between the palbociclib and hormone therapy arms in terms of three-year invasive disease-free survival or distant recurrence-free survival. This raised questions among breast cancer experts at the meeting as to why MonarchE was positive and PALLAS was negative, and which breast cancer patients truly benefit from the addition of a CDK4/6 inhibitor to hormone therapy in the adjuvant setting.

HR-positive, HER2-negative breast cancer is the most common subtype of the disease, accounting for 70 percent of cases, and most patients are identified with early-stage tumors. Standard treatments typically involve surgery, radiotherapy, chemotherapy, and hormone treatment, and result in cures for the majority of patients.

However, during the first decade of treatment, approximately 20 percent of early-stage, HR-positive, HER2-negative breast cancer patients are at high risk of seeing their cancers recur in their breasts or spread to another part of their body. "That risk of recurrence is much greater for those who have certain high-risk clinical or pathological features, based on [tumor] grade, node, and size, especially in the first few years on their adjuvant, endocrine therapy," said Johnston during a media call hosted by ESMO last week. "Novel treatments are needed to overcome resistance and prevent these early recurrences and distant metastases."

A first for CDK4/6 inhibitors

In the US, Lilly's abemaciclib and Pfizer's palbociclib are approved in combination with hormone therapy for HR-positive, HER2-negative, advanced or metastatic breast cancer. Further, in the Monarch2 trial, the addition of the hormone therapy fulvestrant to abemaciclib significantly improved overall survival in advanced breast cancer patients. This and other data in the metastatic setting supported the rationale in MonarchE and PALLAS to test whether giving a CDK4/6 inhibitor with hormone treatment to patients earlier in their disease trajectory — in the adjuvant setting — could stave off recurrence.

MonarchE enrolled more than 5,600 patients with early-stage, high-risk, HR-positive, HER2-negative breast cancer from July 2017 to August 2019. Researchers identified high-risk patients based on clinical and pathological factors, including the number of positive lymph nodes, tumor size, histologic grade, and Ki-67 testing.

Patients who had completed their primary treatment were randomized to receive either abemaciclib for two years with endocrine therapy or just endocrine therapy. The majority of patients, around 95 percent, had received prior chemotherapy. The primary endpoint in the study is invasive disease-free survival, which is defined as the length of time before any cancer comes back or death.

At the end of the two-year study, the invasive disease-free survival rate was 92.2 percent on the abemaciclib-endocrine therapy arm and 88.7 percent in the endocrine therapy only arm, resulting in a 3.5 percent absolute difference. In the abemaciclib-endocrine therapy arm, 136 patients had experienced relapse or died versus 187 in the comparator arm, translating to a 25 percent reduction in the risk of developing invasive disease.

Johnston pointed out that the invasive disease-free survival benefit between the arms was apparent early in MonarchE, after patients were on the study for nine months to a year. As such, by intervening early and adding abemaciclib, recurrences may be avoided in high-risk breast cancer patients within the first two years of treatment, he said.

The fact that most patients in the study received prior neoadjuvant or adjuvant chemotherapy further underscores the benefit seen with adding abemaciclib to hormone therapy. "Despite patients having received chemotherapy … there was still a level of risk in the control arm such that by two years, nearly 12 percent were already relapsing," Johnston said. "A 25 percent reduction in that risk of disease is clinically meaningful."

When Johnston and his colleagues focused on patients who saw their disease come back not in their breast, but in other regions of their body, the results were similar: 106 patients experienced a relapse or death in the abemaciclib arm versus 152 in the hormone therapy only arm. This translated to a 28 percent reduction in the risk of developing metastatic disease at two years.

"If you look at the sites of metastases that we were preventing, you can see it was predominantly bone and liver metastases," Johnston said. "These are high-risk patients who are at risk of early recurrence on their endocrine therapy, despite the standard of care therapy we're giving, [and they] are now actually having those sites of metastases prevented through treatment in the early phase of the study due to the addition of a CDK4/6 inhibitor."

Practice changing or proof of concept?

The MonarchE findings are potentially practice changing, said Giuseppe Curigliano, a breast cancer specialist from the University of Milan and chair of ESMO's guidelines committee, in reviewing the data. In the early-stage breast cancer setting, oncologists are primarily trying to figure out whether to escalate or de-escalate treatment for a particular patient. High-risk breast cancer patients usually receive chemotherapy, and then endocrine therapy for five to 10 years. The fact that the addition of abemaciclib not only reduced local recurrence but also metastases to distant sites "is very important information," he said.

George Sledge, a breast cancer specialist from Stanford University, approached the MonarchE data more cautiously, particularly in light of the negative results from the similarly designed PALLAS trial. He conceded that the trial results were positive but pointed out that only 12.5 percent of patients enrolled in MonarchE so far have received the abemaciclib-hormone therapy regimen for two years, and that most study participants are still completing the requisite treatment period. "This is a very early presentation, and indeed, some might argue premature," he said.

Specifically, the median follow up in the interim analysis of 15.5 months was "quite short," Sledge said, and made him wonder what the invasive disease-free survival and distant relapse-free survival data will look like with longer follow up. Importantly, "will the improvements seen in disease-free survival lead to what we really care about: improved overall survival?" he posited.  

He further pondered why MonarchE was positive but PALLAS, involving palbociclib, failed. Given the positive outcomes seen in MonarchE, it's unlikely that the hypothesis underlying PALLAS — that adjuvant treatment with a CDK4/6 inhibitor and hormone therapy will reduce breast cancer recurrence — is necessarily wrong. Differences in drug potency and administration in the trials (continuous versus intermittent dosing) may also play a role, though Sledge noted that the drugs appear to be similarly efficacious in the metastatic setting.

Ultimately, the different results in these two trials may be due to divergences in study design. "MonarchE was clearly weighted toward a higher-risk population," Sledge said, noting that more patients in the trial had breast cancer that had spread to four or more lymph nodes and had other high-risk features. "This has the effect of generating more events, and more early events, and might allow a trial a better chance of showing a difference."

By comparison, only around 60 percent of HR-positive, HER2-negative breast cancer patients in PALLAS had high-risk clinical features. And although the researchers considered outcomes based on clinical risk in the study, the outcomes were no different for the high-risk subpopulation.

Within both MonarchE and PALLAS, researchers are trying to improve understanding of the role of CKD4/6 inhibitors in the adjuvant treatment of HR-positive, HER2-negative breast cancer. In PALLAS, patients will continue to be followed in the trial for the next decade. Additionally, in the TRANS-PALLAS translational and clinical science program, researchers have collected almost 6,000 tumor blocks and tens of thousands of blood samples to improve understanding of patients with this type of breast cancer, according to Mayer.

MonarchE investigators have similarly collected tissue and plasma samples and are exploring whether certain genomic signatures can predict more precisely which patients will benefit with the abemaciclib-endocrine therapy regimen. A spokesperson for Lilly said that MonarchE will continue to report data, including for translational research, as the data mature, but declined to provide any specifics on the genomic platforms or signatures researchers may use in this analysis.

Although MonarchE showed a benefit of the combination treatment over a two-year period, the risk/benefit profile of the regimen beyond that time frame is not known, Johnston acknowledged. Curigliano added that further follow up will be necessary to learn if the abemaciclib-hormone therapy regimen improves overall survival. MonarchE investigators will continue to follow patients in the study until June 2027 to gauge the impact of the treatment on overall survival and other endpoints.

Moreover, the safety profile of abemaciclib in this setting will also be an important factor in whether patients decide to continue taking the drug for two years or longer. The rate of discontinuation in the abemaciclib arm in MonarchE was 17 percent; 463 patients stopped treatment because of adverse events from the drug. Comparatively, very few patients stopped treatment in the endocrine therapy alone arm.

The most common adverse event with abemaciclib treatment was diarrhea, which Johnston said was manageable with anti-diarrheal medications and dose adjustments. Less than 5 percent of patients stopped abemaciclib because of diarrhea. Venous thrombotic events, lung disease, and febrile neutropenia were more frequent in the abemaciclib arm than with just endocrine therapy. "Although there were no new side effects reported in MonarchE, abemaciclib clearly adds toxicity to adjuvant endocrine therapy," Sledge observed.

Chemotherapy also imparts toxicities to patients, and in MonarchE, 95 percent of patients received prior chemotherapy and 5 percent were chemo naïve. Curigliano observed that a randomized study is needed to understand if "a special population" of early-stage, high-risk HR-positive, HER2-negative breast cancer patients can receive abemaciclib and hormone therapy but avoid chemotherapy altogether. The Lilly spokesperson agreed that a randomized trial will be needed to explore whether a less toxic alternative to chemotherapy can be given in a subset of high-risk breast cancer patients in the adjuvant setting, but the company hasn't yet looked at the small cohort of patients in MonarchE who didn't received prior chemo to explore this issue in detail.

For Sledge, given the toxicities and yet unanswered questions in MonarchE, the interim analysis wasn't mature enough to be practice changing but rather provided a "proof of concept" that a CDK4/6 inhibitor may be efficacious in an adjuvant high-risk breast cancer setting. The list price of abemaciclib is   approximately $12,377 per month, and most breast cancer patients around the world will not be able to afford two years of adjuvant treatment with the drug.

"A patient cannot benefit from a drug she cannot take," Sledge said. "The decision to use adjuvant CDK4/6 inhibitor therapy is more complex than a simple perusal of disease-free survival or distant relapse-free survival data. It will need to be weighed against evolving measures of benefit."