Muralidhar Beeram, MD
Abemaciclib plus tamoxifen, trastuzumab (Herceptin), or one of many endocrine-based therapies demonstrated significant antitumor activity and clinical benefit in patients with advanced breast cancer, according to results presented at the 2016 ESMO Annual Congress.
Muralidhar Beeram, MD, and colleagues conducted a multicenter, open label, phase 1b study to assess the efficacy and safety of the combination of abemaciclib with other endocrine therapies in patients with different subtypes of breast cancer. Parts A through E of the study included patients with hormone receptor positive (HR+), HER2- metastatic breast cancer, while Part F included patients with HR+ and HR- metastatic breast cancer. Patients in Parts A through E were post-menopausal, but patients in Part F could be of any menopausal status. All patients receiving exemestane-based therapy must have received one or more prior nonsteroidal aromatase inhibitor treatment for metastatic disease.
“Abemaciclib is a selective inhibitor of the cyclin-dependent kinases, CDK4 and CDK6, which act with Cyclin D to drive aberrant cell proliferation in many cancers,” explained Beeram, of the START Center for Cancer Care. “Abemaciclib demonstrated clinical activity both alone and in combinations in women with hormone receptor positive (HR+) metastatic breast cancer.”
Oral abemaciclib at 200 mg every 12 hours was administered with letrozole (Femara) at 2.5 mg per day (Part A, n= 20), with anastrozole (Arimidex) at 1 mg daily (Part B, n=16), with tamoxifen at 20 mg daily (Part C, n=16), or with exemestane (Aromasin) at 25 mg daily (Part D, n=15). Oral abemaciclib was also administered at 150 or 200 mg every 12 hours with exemestane at 25 mg plus everolimus at 5 mg daily day (Part E, n=15 at 150 mg and n=4 at 200mg), or with trastuzumab at 6 to 8 mg /kg IV on day one of a 21-day cycle (Part F, n=18 at 150 mg and n=6 at 200mg).
The patients ranged in age from 29 to 77 years old, and all patients had received a median of 2 to 3.5 prior therapies, except those in part F where patients receiving the lower dose had received a median of 9 prior treatment regimens and patients receiving 200 mg of abemaciclib had undergone a median of 7 prior therapies.
Based on results from this study, the recommended dose of abemaciclib was determined at 150 mg every 12 hours when administered in combination with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus, or trastuzumab, according to Beeram.
Radiographic tumor responses were observed for patients in Part A through D, where the objective response rates (ORR), including complete and partial responses, were 10%, 18.8% 18.8%, and 40%, respectively. The clinical benefit rates, defined as complete (CR) and partial response (PR) plus stable disease, were 40%, 81.3%, 75%, and 60% at median 24 weeks.
The 6-month progression-free survival rates were 76.2%, 86.7%, 73.3%, and 88.9% in Parts A to D, respectively.
“For women with HR+ metastatic breast cancer, abemaciclib combinations show clinical activity with objective responses and durable disease control,” said Beeram.
In Part E, where patients received 150 or 200 mg of abemaciclib plus everolimus and exemestane, the ORR was 33.3% and 0%, and the CBR was 53.3% and 75%, respectively. In Part E, the 6-month PFS rates were 88.9% and 100% at the respective doses.
In Part F, which evaluated abemaciclib at 150 with trastuzumab in women with HR+ tumors, the ORR was 10%, CBR was 18.2% and 28.6% of patients achieved 6-month PFS. At the same dose in woman with HR- tumors, only a CBR of 14.3% was observed but 37.5% of patients achieved 6-month PFS. In the 200 mg abemaciclib plus trastuzumab arm, the ORR, CBR, and 6-month PFS rates were in 20%, 40%, and 50%, respectively in women with HR+ tumors. No response was observed at this dose level and combination in women with HR- tumors.
Across Parts A through F, anti-tumor activity was observed in patients with measurable disease that was most notable in Parts B (anastrozole) and E (exemestane plus everolimus) where 100% of patients showed tumor shrinkage.
“Abemaciclib showed acceptable safety when combined with endocrine based therapies or trastuzumab,” Dr. Beeram noted. Among these patients, the most common treatment related adverse events (AE) were fatigue, diarrhea, nausea, anemia, decreased appetite, abdominal pain, rash, and vomiting. No Grade 4 AEs reported.
Discussant Monica Arnedos, MD, assistant professor at the Instut Gustave Roussy, Villeneuve, France commented: “The strengths of this study are that it is relatively large for a phase 1b study with 110 patients, and interesting activity is demonstrated in some heavily pre-treated patients.” She noted that the study was limited by having too many small cohorts to extract a conclusion; furthermore, “It is not possible to compare or to group the results from different cohorts,” Arnedos commented.
Randomized phase III studies are ongoing to evaluate combination of abemaciclib with both anti-estrogens (NCT02107703) and aromatase inhibitors ((NCT02246621), the study authors noted.
Beeram M, et al. A Phase 1 Study of Abemaciclib, an inhibitor of CDK4 and CDK6 in Combination with Endocrine and HER2 Targeted Therapies for Patients with Metastatic Breast Cancer. Presented at: 2016 ESMO Congress; October 7-11 2016; Copenhagen, Denmark. Abstract LBA18