Abemaciclib regimen shows further signs of benefit in advanced breast cancer subgroup
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The addition of abemaciclib to a nonsteroidal aromatase inhibitor prolonged median OS by more than a year among patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to data presented at ESMO Congress.
The numerical improvement, however, did not meet the prespecified threshold for formal statistical significance according to the alpha spending procedure, interim OS results of the randomized phase 3 MONARCH 3 trial showed.
Background
Abemaciclib (Verzenio, Eli Lilly), an oral, potent cyclin dependent kinase (CDK) 4/6 inhibitor, has been approved for patients with hormone receptor-positive, HER2-negative advanced breast cancer both in combination with fulvestrant following disease progression on previous endocrine therapy, based on OS results of the MONARCH 2 trial, and in combination with a nonsteroidal aromatase inhibitor as initial therapy for postmenopausal patients, based on PFS results of MONARCH 3.
The second interim analysis of OS results for MONARCH 3 has been included in the European product label at the request of European regulators, Matthew P. Goetz, MD, of the department of oncology at Mayo Clinic in Rochester, Minnesota, said during a presentation.
Methodology
MONARCH 3 included 493 postmenopausal patients with hormone receptor-positive, HER2-negative metastatic or locoregionally recurrent breast cancer. Researchers randomly assigned patients 2:1 to 150 mg abemaciclib twice daily (n = 328) or placebo (n =165) with 1 mg anastrozole (19.9%) or 2.5 mg letrozole (79.1%) daily until disease progression.
Investigator-assessed PFS served as the primary endpoint, with OS, response rates and safety as secondary endpoints.
Previously reported PFS results, with median follow-up of 26.7 months, showed a median 13.4-month improvement with abemaciclib vs. placebo (28.2 months vs. 14.8 months; HR = 0.54; 95% CI, 0.41-0.69).
Researchers conducted the second interim OS analysis in July 2021, after 252 events in the intent-to-treat population, with median follow-up of 5.8 years.
Results
Results showed median OS of 67.1 months with the abemaciclib combination vs. 54.5 months with the placebo combination (HR = 0.75; 95% CI, 0.58-0.97).
“At this interim analysis the crossing boundary was not crossed, and therefore at this point we say that statistical significance has not been reached, but again, the data are maturing favorably,” Goetz said. “The overall survival benefit is maintained in nearly all subgroups.”
In the subgroup of patients with visceral disease, the preplanned analysis showed median OS of 65.1 months with abemaciclib vs. 48.8 months with placebo (HR = 0.7; 95% CI, 0.5-0.98), which also fell short of the threshold for statistical significance.
Updated PFS data for the intent-to-treat population showed a persistent treatment effect, with a highly statistically significant improvement in the abemaciclib group (median, 29 months vs. 14.8 months; HR = 0.51; 95% CI, 0.41-0.64). In addition, adding abemaciclib to a nonsteroidal aromatase inhibitor delayed chemotherapy initiation by more than 16 months, Goetz said.
Researchers observed no new safety signals with longer exposure to abemaciclib. About two-thirds of patients (68.5%) in the abemaciclib group experienced at least one grade 3 or higher treatment-related adverse event. These included neutropenia (27.2%), diarrhea (9.8%) and anemia (8.9%).
Follow-up continues and final OS results are expected next year, Goetz said.
Perspective
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Azka Ali, MD
With an unprecedented number of new drug approvals over the last decade, the landscape of advanced hormone receptor-positive breast cancer treatment has changed greatly. Cyclin-dependent kinase (CDK) 4 and 6 inhibitors exert their therapeutic effect by causing cell cycle arrest in cyclin D-overexpressing breast cancer cells, and this class of drugs has been a game changer in hormone receptor-positive breast cancer management. Frontline therapy of advanced hormone receptor-positive, HER2-negative breast cancer includes a combination approach of utilizing CDK 4/6 inhibitors with aromatase inhibitors, which block conversion of androgens to estrogens.
We had learned about the significant improvement in PFS in the MONARCH 3 trial from a 2017 publication. Now we see the interim OS data. Results showed improved median OS in the abemaciclib group, but the predetermined statistical significance threshold had not been reached. OS data are immature, and we remain hopeful that the favorable trend toward improved OS is maintained at the final analysis in 2023.
There are three CDK inhibitors approved for ER-positive advanced breast cancer: palbociclib (Ibrance, Pfizer), ribociclib (Kisqali, Novartis) and abemaciclib. Although the three drugs are considered equivalent in clinical efficacy, the question of how to choose among these agents continues to be one that many breast oncologists — including myself — face every day in clinic.
We also have wondered if we can sequence these drugs one after the other to optimize clinical benefit. Fortunately, there are emerging data that patients may continue to derive benefit from an alternative CDK 4/6 inhibitor agent after progressing on one, and many of us are starting to employ this strategy in our clinical practice. Resistance to CDK 4/6 inhibitors, however, is a clinical obstacle, and further identification of genomic alterations predictive of response and resistance is desperately needed.
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Goetz MP, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Congress. Sept. 9-13, 2022; Paris.
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