For the first time, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) has reduced the risk of invasive disease recurrence in patients with early breast cancer when combined with standard endocrine therapy, investigators reported at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1
A total of 2 years of abemaciclib given with endocrine therapy significantly reduced the risk of an invasive disease recurrence by 25% vs endocrine therapy alone in the global phase III monarchE trial reported by Stephen R.D. Johnston, MD, Professor of Breast Cancer Medicine at the Royal Marsden Hospital NHS Foundation Trust in London. Distant recurrences were reduced by 28%.
The positive results of monarchE were presented at the Presidential Symposium and also at an earlier press briefing where Dr. Johnston said, “The results attest to the efficacy of abemaciclib in having an impact in the early disease setting.”
Stephen R.D. Johnston, MD
Giuseppe Curigliano, MD
“This is really an important trial,” commented Giuseppe Curigliano, MD, Associate
Professor of Medical Oncology at the University of Milan, Italy, and Chair of the ESMO Guidelines Committee. “It will potentially change clinical practice.”
Perhaps surprisingly, another CDK4/6 inhibitor, palbociclib, failed to show an adjuvant benefit in the phase III PALLAS trial, also reported at ESMO 2020.2 The divergence of results between the pivotal trials became a topic of discussion.
The open-label phase III monarchE trial enrolled 5,637 patients (43% of whom were premenopausal) with hormone receptor–positive, HER2-negative early breast cancer with clinical and/or pathologic risk factors that rendered them at high risk for relapse. High risk was defined as the presence of at least four lymph nodes or one to three nodes and at least one of the following: tumor ≥ 5 cm, histologic grade ≥ 3, or high proliferation rate (ie, Ki67 ≥ 20%).
After completing their primary treatment (surgery, endocrine therapy, and, for some, chemotherapy) patients were randomly assigned to abemaciclib (150 mg twice daily for up to 2 years) plus physician’s choice of endocrine therapy (5–10 years as clinically indicated) or endocrine therapy alone. Approximately one-third of patients received tamoxifen, and two-thirds received an aromatase inhibitor; 15% also underwent ovarian suppression; 43% of patients were premenopausal at diagnosis, and 95% had received prior chemotherapy with 37% in neoadjuvant setting.
The primary objective was invasive disease–free survival. The interim analysis was performed after a median follow-up of 15.5 months.
monarchE: Reduction in Recurrence and Metastases
The addition of abemaciclib to endocrine therapy resulted in an invasive disease–free survival rate of 92.2% at 2 years vs 88.7% with endocrine therapy alone (hazard ratio [HR] = 0.747; P = .0096). The absolute difference was 3.5%, which began to emerge between 9 and 12 months, Dr. Johnston said.
“Beyond 2 years, the data are immature. Obviously, further follow-up will be important to see the ongoing magnitude of this early separation of the curves,” he commented.
Distant recurrence–free survival followed the same pattern, with 2-year rates of 93.6% and 90.3%, respectively (HR = 0.717; P = .0085), a 3.3% absolute difference. Treatment was most likely to prevent metastases to the bone and the liver.
“My belief is we are impacting primary innate endocrine resistance in high-risk patients who may well have micrometastatic disease and relapse early,” Dr. Johnston said. “Nearly 12% had already relapsed on endocrine therapy alone, and that’s improved by 3.5% with the addition of abemaciclib.” Whether these patients are biologically different from patients with dormant cells in the bone marrow—who will relapse 10 years or so later—is as yet unknown and requires further follow-up, he added.
The most frequent adverse events with abemaciclib were diarrhea, neutropenia, and fatigue; interestingly, more arthralgia, hot flashes, and fatigue were seen in the control arm. Diarrhea was managed well with antidiarrheal medications, and dose adjustments were resolved in the majority of patients after 3 months.
Although rare, venous thromboembolism occurred in 63 patients (2.3%) in the abemaciclib arm, compared with 15 patients (0.5%) who received endocrine therapy alone; 75 (2.7%) vs 33 (1.2%) developed interstitial lung disease.
PALLAS Trial: No Benefit for Palbociclib
In the same type of patient population, 2 years of adjuvant palbociclib provided no additional benefit over endocrine therapy alone in the international phase III PALLAS trial reported at the ESMO Virtual Congress 2020 by Erica Mayer, MD, MPH, of the Dana-Farber Cancer Institute, Boston.2
Erica Mayer, MD, MPH
“The benefits observed in the metastatic setting with palbociclib did not translate into the earlier adjuvant setting,” Dr. Mayer said.
PALLAS randomly assigned 5,760 patients with stage II or III hormone receptor–positive, HER2-negative early breast cancer to palbociclib for 2 years plus adjuvant endocrine therapy or endocrine therapy alone. Most patients had received prior chemotherapy; initial adjuvant endocrine therapy was an aromatase inhibitor or tamoxifen. The primary endpoint was invasive disease–free survival.
A futility boundary was crossed at the second interim analysis, and the independent monitoring committee recommended discontinuation of palbociclib. After a median follow-up of 23.7 months, invasive disease–free survival rates were 88.2% in the palbociclib/endocrine therapy arm compared with 88.5% in the control arm (HR = 0.93; P =.51). Distant recurrence–free survival rates were 89.3% and 90.7% (HR = 1.00; P = .9997). In the high-risk subgroup, a similar pattern was seen. Adverse events were more common with the palbociclib arm, and 42% of patients discontinued palbociclib early (64% of those due to unacceptable toxicity).
DISCLOSURE: The monarchE study was sponsored by Eli Lilly. PALLAS is co-sponsored by the Alliance Foundation and the Austrian Breast Cancer Study Group, in collaboration with the Eastern Cooperative Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, the German Breast Group, the Breast International Group, with funding from Pfizer. Dr. Johnston has received honoraria from AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer, and Roche; has served as a consultant or advisor to Eli Lilly, Novartis, Pfizer, and Puma Biotechnology; and has received institutional research funding from Pfizer and Puma Biotechnology. Dr. Curigliano has received honoraria from Ellipses Pharma; has served as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Foundation Medicine, GSK, Eli Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; has participated in a speakers bureau for Daiichi Sankyo, Foundation Medicine, Eli Lilly, Novartis, Pfizer, Roche/Genentech, and Samsung; has received institutional research funding from Merck; and has been reimbursed for travel, accommodations, or other expenses by Pfizer and Roche/Genentech. Dr. Mayer has served as a consultant or advisor to Eisai, Eli Lilly, Novartis, and Sanofi and has received institutional research funding from Pfizer.
1. Johnston SR, Harbeck N, Hegg R, et al: Abemaciclib in high risk early breast cancer. ESMO Virtual Congress 2020. Abstract LBA5_PR. Presented September 20, 2020.
2. Mayer EL, Gnant MI, DeMichele A, et al: PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy vs endocrine therapy alone for HR+/HER2- early breast cancer. ESMO Virtual Congress 2020. Abstract LBA12. Presented September 20, 2020.
The results of monarchE were discussed by George W. Sledge, Jr, MD, Professor of Medicine and Chief of Oncology at Stanford University Medical Center, who offered some possibilities as to why its results were positive and those for palbociclib, in the phase III PALLAS trial, were “resoundingly...