monarchE: Abemaciclib Reigns on in High-Risk Breast Cancer

Much Longer Follow-up Still Needed

Liam Davenport

December 10, 2020

The addition of CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy continues to offer improved event-free survival in women with high-risk hormone receptor positive (HR+), HER2-negative breast cancer, indicate updated results, which now extend to about a year and a half, from the landmark monarchE trial.

However, experts warned that longer follow-up — at least to 5 years — will be required to understand the impact of the combination treatment on survival, particularly as HR+ breast cancer is associated with a high rate of late recurrences.

The research was presented December 9 at the 2020 San Antonio Breast Cancer Symposium, being held online this year because of the pandemic.

An earlier preplanned interim analysis the phase 3 trial of over 5600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As previously reported by Medscape Medical News, this showed that, after a median follow-up of 15.5 months, abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of invasive disease-free survival (IDFS) vs endocrine therapy alone.

At the time, the findings were hailed as practice changing and, once approved for high-risk HR+ HER2-negative early breast cancer, as the "new standard of care" by one expert.

Now, with median follow-up extended to 19.1 months, Priya Rastogi, MD, associate professor at the University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, presented new study data, including additional results on patients with a Ki67 index ≥20%, which is indicative of fast tumor growth.

Abemaciclib plus endocrine therapy was associated with a significant 28.7% reduction in the relative risk of developing an IDFS event vs endocrine therapy alone across the whole patient population, and with a 30.9% risk reduction in those with a Ki-67 index ≥20%.

Moreover, patients taking the drug combination had a significant 31.3% reduction in the relative risk of a distant relapse-free survival (DRFS) event.

Crucially, these improvements, which were deemed clinically meaningful, were not gained at the expense of additional safety concerns, although high rates of any grade diarrhea, fatigue, and neutropenia were noted.

Rastogi said the findings underline that abemaciclib combined with standard endocrine therapy "is the first CDK4/6 inhibitor to demonstrate efficacy and tolerability for patients with HR+ HER2-negative, node-positive, high-risk early breast cancer."

Longer Follow-up Is "Reassuring" but Still "Quite Short"

George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, California, was the study discussant for the earlier interim analysis presented at ESMO 2020.

At the time, he said that the study had "very, very short follow-up" and it was consequently unclear whether the improvements will "lead to what we really care about: improved overall survival."

Approached to comment on the current analysis, Sledge told Medscape Medical News they "appear quite consistent" with those presented earlier this year, "which is certainly reassuring."

Referring to the analysis in patients with a Ki-67 index ≥20%, he added the results "show a higher absolute benefit in patients with more rapidly proliferating tumors, as might be expected for a drug affecting cell cycle division."

The majority of recurrences and deaths occur after 5 years in many studies. Dr George Sledge

However, Sledge underlined that the median follow-up time "is still quite short for a study of ER-positive adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies".

Consequently, "we still have a long way to go to understand the ultimate effects of CDK 4/6 inhibition on early stage ER-positive breast cancer, particularly on late recurrences."

Agreed, said C. Kent Osborne, MD, codirector of SABCS and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Texas.

Commenting in a press conference, he said the results are "very encouraging, especially in the subgroup of tumors with high proliferation."

However, Osborne also urged "caution" in the interpretation of the results "given the still rather short follow-up, given that that ER+ disease is known for its persistent recurrence rate, even past 10 years."

He also noted "this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells." Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once the drug is stopped.

Osborne nevertheless said that, "with these caveats in mind, this is still an extremely important trial that could be practice changing in this very high-risk patient population…if the results continue to be positive and show improved overall survival with longer follow-up."

During the press conference, Rastogi confirmed that the study will indeed continue out to 10 years until the final assessment of overall survival.

More Study Details

The 5637 women who were enrolled in monarchE were divided into two cohorts:

  • Cohort 1, which included patients with four or more positive nodes, or those with up to three positive nodes and a tumor size ≥5 cm or grade 3 disease

  • Cohort 2, which included women with up to three positive nodes, and a Ki-67 index ≥20% based on a standard assay

"Cohort 2 opened one year after Cohort 1 and enrolled 517 patients," Rastogi said.

Regardless of cohort, the patients were randomly assigned in a 1:1 fashion to abemaciclib for 2 years plus endocrine therapy for 5 to 10 years, as clinically indicated, or endocrine therapy alone.

At the primary efficacy outcome analysis, 395 IDFS events had occurred in the intention-to-treat analysis. The median follow-up was 19.1 months, and 25.5% of patients had completed the 2-year treatment period. A further 58.2% were still on treatment.

The results showed 163 IDFS events had occurred with abemaciclib plus endocrine therapy vs 232 with endocrine therapy alone, to give a 2-year IDFS rate of 92.3% vs 89.3%, at a hazard ratio of 0.713 (P = .0009).

Moving on to the subgroup analysis, Rastogi added that there is "no statistically significant interactions observed, indicating a consistent treatment benefit across all groups."

The researchers also looked at IDFS rates in patients from both cohorts with Ki-67 index ≥20%, again finding that abemaciclib plus endocrine therapy was again associated with significantly fewer events than endocrine therapy alone.

There were 82 events with the combination treatment vs 115 with endocrine therapy, at a 2-year IDFS rate of 91.6% vs 87.1% and a hazard ratio of 0.691 (P = .0111).

Distant relapse-free survival (DRFS) also significantly improved with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a 2-year DRFS rate of 93.8% vs 90% or a hazard ratio of 0.687 (P = .0009).

"Safety remained consistent with the known profile of abemaciclib," Rastogi said, "and what was observed at the second interim analysis, [with] minimal increases in any grade and grade ≥3 treatment-related adverse events."

The most common adverse events were diarrhea, fatigue, and neutropenia, which were largely grades 1 and 2.

Notably, 2.4% of combination therapy patients experienced a venous thromboembolic event of any grade vs 0.6% of endocrine therapy patients, while 2.9% and 1.2%, respectively, had any grade interstitial lung disease.

At least one dose hold because of an adverse event was reported by 59.5% of abemaciclib plus endocrine therapy patients, while 42.5% had at least one dose reduction because of an adverse event. In both cases, the primary reason was diarrhea.

Finally, Rastogi said that "over half of the discontinuations due to abemaciclib due to adverse events occurred during the first 5 months of treatment, with the highest number…in the first month."

Ki-67 Issues

During the press conference, Virginia Kaklamani, MD, codirector of SABCS  and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, asked about the practicalities of the Ki-67 index.

She said that testing is "great when it's centrally done but what do we expect physicians to do when some institutions do it, some don't, and obviously it's not really validated in most institutions around the world."

Rastogi replied that is a "great question," adding "this is something that is going to have to be sorted as we continue to have discussions and get more granularity of what to do when abemaciclib is administered in that patient population."

Carlos L. Arteaga, MD, codirector of SABCS and director of the Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, added that "most of us think of 10% as a cutoff between high and low" for the Ki-67 index, rather than ≥20%.

He said that he knows it is "arbitrary" but he thinks of 20% as "extremely high" and asked whether the researchers would be able to conduct a retrospective analysis to look at Ki-67 as a gradient to determine "at what point it stops predicting."

Rastogi replied that at the time monarchE was developed some of the international guidelines used a Ki-67 index ≥20% as the cutoff.

She also noted that, although Ki-67 index ≥20% was an entry criteria for cohort 2, cohort 1 patients also provided tissue after randomization, "and so we'll be able to look at these types of questions with our translational research committee."

This study was sponsored by Eli Lilly. Rastogi has has financial ties to AstraZeneca, Genentech/Roche, and the study sponsor, Eli Lilly. Regan has ties to Lilly and multiple other pharmaceutical companies. Sledge has ties to Lilly and other companies. Osborne has ties to Lilly and other companies.  

2020 San Antonio Breast Cancer Symposium: Abstract GS1-01. Presented December 9, 2020.

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