Cynthia Ma, MD, PhD
Neoadjuvant treatment with abemaciclib (Verzenio) plus anastrozole induced complete cell cycle arrest as measured by Ki67 for 67.8% of patients with HR-positive/HER2-negative early-stage breast cancer, according to final results from the phase II neoMONARCH trial presented at the 2017 San Antonio Breast Cancer Symposium.
In the study, complete cell cycle arrest, defined as Ki67 index of <2.7% at 2 weeks, was the primary endpoint of the study. For those treated with abemaciclib alone, cell cycle arrest was achieved for 57.7% of patients. For anastrozole alone, 14.3% of patients experienced cell cycle arrest.
The abemaciclib combination yielded a geometric mean change in Ki67 from baseline to day 15 of -92.86%. For abemaciclib alone, there was a -90.52% reduction. With anastrozole alone, there was a mean geometric reduction of -62.78%. For the combination versus the other groups, there was a geometric mean ratio (GMR) of 0.19 (90% CI, 0.13-0.28; P
"CDK4/6 inhibitors have consistently demonstrated broad and potent anti-proliferative effect on ER-positive breast cancer in the neoadjuvant setting," Cynthia Ma, MD, PhD, from the Siteman Cancer Center, who was not involved with the trial said during a discussion of the results at the meeting. "Data justifies adjuvant evaluation of CDK4/6 inhibitors and several trials are ongoing."
The phase II neoMONARCH trial included 223 women with HR+ HER2-negative early-stage breast cancer (stage I [≥ 1 cm)], II, IIIA, or IIIB). Patients were randomized 1:1:1 to monotherapy with anastrozole (1 mg daily; n = 74) or abemaciclib (150 mg every 12 hours; n = 75), or a combined regimen of the 2 drugs at the same doses (n = 74).
After the 2-week Ki67 assessment, all patients received the abemaciclib/anastrozole combination for 14 additional weeks. Prophylactic loperamide (2 mg) was administered with each dose of abemaciclib for the first 28 days and then at the physician’s discretion thereafter.
Clinical responses were measured using caliper, radiology, and pathological findings following surgery. At 16 weeks, the ORR by caliper measurement across all patients in the study was 53.6% (95% CI, 46.8%-60.2%). This included a complete response (CR) for 7.6% of patients. By radiologic review, the ORR was 46.4% (95% CI, 39.8%-53.2%). The CR rate was 4.9%. Seven patients experienced pathologic complete response (3.7%).
From baseline to the end of the trial across all arms, there was a decrease in tumor grade for 29.4% of patients. From baseline to the 2-week measurement, 19.6% of those treated with the combination had a decrease in tumor grade compared with 28.3% and 10.2% of those in the single-agent abemaciclib and anastrozole arms, respectively. Overall, most tumors were not affected by treatment, with no change in grade indicated.
In an analysis of mutation status, PIK3CA mutation status did not impact Ki67 expression change from baseline to 2 weeks. Mean change from baseline was similar for those who tested negative and positive. There were too few patients with ESR1 alterations to conduct an analysis on this population, the researchers noted.
Safety data were reported across all 3 treatment arms at the end of 16 weeks. The most common all-grade treatment-emergent adverse events (TEAEs) included diarrhea (61.4%), constipation (43.5%), nausea (41.7%), fatigue (39.5%), abdominal pain (22.4%), decreased appetite (21.5%), neutropenia (20.6%), ALT increased (13.9%), vomiting (13.9%), and hot flush (11.7%).
The most common grade 3 TEAEs were neutropenia (9.4%), ALT increased (5.4%), diarrhea (4.9%), and abdominal pain (3.6%). The only grade 4 AEs were ALT increase (1.3%), AST increase (0.4%) and leukopenia (0.4%). There were now grade 5 events.
The phase III monarchE study is currently assessing adjuvant abemaciclib for patients with early-stage HR-positive/HER2-negative breast cancer. The primary endpoint of the study, which plans to enroll 3580 patients, is invasive disease-free survival. The primary completion date for the trial is June 2022 (NCT03155997).
Martin M, Hurvitz SA, Chan D, et al. Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD5-01.