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BARCELONA -- Abemaciclib (Verzenio) showed benefits in a broader group of breast cancer patients beyond its in HR-positive/HER2-negative advanced disease, a researcher reported here.

In the randomized, phase II monarcHER trial, progression-free survival (PFS) was superior among postmenopausal women with HR-positive/HER2-positive locally advanced or metastatic breast cancer treated with abemaciclib plus trastuzumab (Herceptin) plus fulvestrant (Faslodex) versus trastuzumab plus standard-of-care chemotherapy of the investigators' choice, reported Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in Boston, at the European Society for Medical Oncology (ESMO) annual meeting.

Median PFS was 33% longer at 8.3 months in the abemaciclib-trastuzumab-fulvestrant arm compared with 5.7 months in the trastuzumab-chemotherapy arm (hazard ratio 0.67, 95% CI 0.45-1.00, P=0.05).

Previous has indicated that abemaciclib, a selective inhibitor of the cyclin dependent kinase 4 (CDK4) and 6 (CDK6) pathways, improved the overall response rate (ORR) and PFS in these patients who have progressed while receiving endocrine therapy. A showed that the same CDK4/CDK6 inhibitor given together with a non-steroidal aromatase inhibitor similarly improved ORR and PFS when given as initial treatment in this patient population. Tolaney and colleagues reported positive results from the APT trial in August 2019.

In , 237 patients with HR-positive/HER2-positive advanced breast cancer who had received at least two prior HER2-directed therapies for advanced disease were randomized to:

• Arm A: twice daily abemaciclib (150 mg) on days 1-21 of a 21-day cycle, plus trastuzumab on day 1 of a 21-day cycle, plus fulvestrant (500 mg) intramuscularly on day 1 of cycle 1 plus on day 15 of cycle 2, then every fourth week
• Arm B: same dose and schedule of abemaciclib and trastuzumab
• Arm C: same dose and schedule of trastuzumab plus the investigators choice of chemotherapy

The median age at baseline ranged from 54 to 57, and the majority of participants had visceral disease; >85% of patients in all three arms had bone-only metastatic spread. Almost all patients had received prior trastuzumab or trastuzumab emtansine (Kadcyla).

The ORR rate in arm A was 32.9% compared with 13.9% in arms B and C, respectively.

However, duration of response appeared to be shorter at 10.4 months (95% CI, 24.5-46.9 months) in arm A vs 9.5 months in arm B (95% CI, 7.4-24.9 months), despite a higher ORR. The duration of response had not been reached in arm C (95% CI, 7.3-24.6 months), Tolaney reported.

On exploratory analysis, there were no significant differences in overall survival between the three treatment arms:

• Arm A: median 24.3 months
• Arm B: median 24.0 months
• Arm C: median 21.5 months

Rates of grade ≥3 treatment-emergent adverse events (TEAE) were higher in arm A (56.4%) versus arm B (37.7%) and arm C (33.3%), most of which were hematologic in nature. However, fewer patients in arm A discontinued treatment due to an AE (7.7%) compared with arm B (14.2%) and arm C (8.3%).

The investigators concluded that the combination of abemaciclib plus trastuzumab plus fulvestrant has a generally tolerable safety profile. As noted in earlier , resistance to endocrine therapy remains a challenge in advanced breast cancer as patients eventually develop progressive disease.

Inhibition of CDK4 and CDK6 has been shown to attenuate resistance to endocrine therapy. Tolaney explained that, in preclinical models, inhibition of the same two pathways with abemaciclib was shown to enhance the activity of HER2-directed agents such as trastuzumab, re-sensitizing resistant tumors to HER2 blockade.

ESMO discussant Mafalda Oliveira, MD, PhD, Vall d'Hebron University Hospital in Barcelona, pointed out that patients enrolled in the monarcHER study were very heavily pretreated, with approximately half of those in each of the three treatment arms having received over three lines of prior therapy.

While Oliveira acknowledged that it was a "statistically positive trial," she said there were a number of unanswered questions, including the rates and duration of grade 2 diarrhea, and whether that side effect affected patients' quality of life.

Oliveira said she also wanted to know how often the investigators were obliged to dose reduce in response to TEAEs, and what caused the treatment-related deaths, which occurred in all three arms (two in arm A; one each in arm B and arm C).

However, Oliveira concluded that "monarcHER was a well designed, hypothesis-generating trial that address clinically relevant questions," including whether CKD4/CKD6 inhibition now has broader application in patients with advanced breast cancer.

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