Palbociclib Improves Cell Cycle Control in ER-Positive Breast Cancer

Cynthia X. Ma, MD

Palbociclib enhances cell cycle control when added to anastrazole in the neoadjuvant setting in women with ER-positive primary breast cancer. Phase II data demonstrated efficacy of the palbociclib combination on cell cycle control regardless of PIK3CA mutation status or luminal type A or B.

The results “support the evaluation of this combination in the adjuvant setting for ER-positive, HER2-negative breast cancer,” lead author Cynthia X. Ma, MD, Washington University, said when presenting the data the 2015 San Antonio Breast Cancer Symposium.

In the single-arm study the efficacy of palbociclib and anastrozole on complete cell cycle arrest was assessed in women with clinical stage II or III ER-positive, HER2-negative breast cancer.

Patients were initially treated with 1 mg/day of anastrozole alone for 28 days in cycle 0, followed by the addition 125 mg/day of palbociclib, in cycle 1 and continued on days 1 to 21 of each cycle. Goserelin was added to anastrozole if patients were premenopausal at study entry. Palbociclib plus anastrozole was administered for four 28-day cycles. Surgery was performed 2 to 4 weeks following the last dose of palbociclib to allow neutropenia recovery before surgery.

Palbociclib was given for an additional 10 to 12 days until the day of surgery in the last 10 patients enrolled to assess the biologic effect of palbociclib washout.

Serial tumor biopsies were obtained at baseline, cycle 1, day 1 (C1D1), and cycle 1, day 15 (C1D15). The primary endpoint was complete cell cycle arrest, defined as Ki67 2.7%, on C1D15 biopsy. This biologic endpoint was chosen because increasing levels of Ki67 on neoadjuvant therapy were previously found to be associated with an increased risk of relapse in the long term, said Ma. The hypothesis was that adding palbociclib to anastrozole would result in at least a 50% improvement in complete cell cycle arrest over anastrozole alone.

Fifty patients were registered, and 45 were evaluable for the primary endpoint. Four patients with WT PIK3CA went off study due to Ki67>10% on C1D15 biopsy. Thirty-nine patients completed study therapy and surgery.

Median age of the 50 patients registered was 57.5 years (36% were premenopausal and 64% were postmenopausal).

Seven patients required palbociclib dose reduction; 2 for elevated liver function tests, 4 because of grade 3 or 4 neutropenia, and 1 for a grade 2 rash.

Forty-one of 46 patients who were evaluable for a clinical response completed at least 3 cycles of study drug. The overall response rate was 67% (n = 31), including 11 (24%) complete responses and 20 (43%) partial responses.

“Among the 46 evaluable patients, 39, representing 87% of the patient population, achieved complete cell cycle arrest, which exceeded our expectation of 66%,” said Ma.

Complete cell cycle arrest occurred in 79% (22/28) of patients with PIK3CA wild type, 100% (15/15) with PIK3CA mutant tumors, and 100% (2/2) of patients in whom PIK3CA status could not be determined. The primary endpoint of the study was met, as anastrozole alone induced complete cell cycle arrest in 26%; adding pablociclib converted non-complete cell cycle arrest to complete cell cycle arrest in an additional 60%.

Anastrozole alone significantly reduced Ki67 levels in both PIK3CA mutant (P = .002) and wild type (P <.001) patients. Adding palbociclib resulted in a further significant decline of Ki67 levels (P <.001), regardless of PIK3CA status.

When response by molecular intrinsic subtype was examined, significant reductions in Ki67 were achieved by anastrozole alone in luminal A (P = .001) and luminal B (P = .002) subtypes, with further significant declines in Ki67 with the addition of palbociclib (P = .001) for luminal subtype A and P = .002 for luminal subtype B cancers.

“In the luminal B subgroup, 8 of the 11 patients required the addition of palbociclib to reach complete cell cycle arrest; however, 3 out of 8 patients were not able to achieve complete cell cycle arrest, indicating likely resistance,” Ma said.

Two patients with non-luminal breast cancer could achieve complete cell cycle arrest either with anastrozole alone or the combination.

Ki67 levels recovered at surgery after the 4 weeks of palbociclib washout. When pablociclib was given for 10 to 12 days immediately before surgery in 8 evaluable patients, recovery of Ki67 was diminished. These data suggest that palbociclib, like endocrine therapy, “may need to be a maintenance treatment,” Ma said.

Palbociclib inhibits the activity of CDK4/6 and has previously been shown to markedly improve time to disease progression in the metastatic setting when used in combination with an aromatase inhibitor or fulvestrant.

Palbociclib received an FDA accelerated approval in February 2015 as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. The FDA has also recently granted a priority review to a supplemental new drug application for palbociclib for use in combination with fulvestrant in pretreated patients with HR-positive, HER2-negative metastatic breast cancer. An approval decision is scheduled by April 2016.

Reference

Ma CX, Gao F, Northfelt D, Goetz M, et al. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S6-05.

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