Duration of Docetaxel Treatment Affects Clinical Outcomes: Post-Hoc Analysis of the CLEOPATRA Trial

Results from the phase 3 CLEOPATRA trial showed that first-line treatment with docetaxel, trastuzumab, and pertuzumab led to significantly improved median progression-free survival (PFS) and overall survival (OS) compared with docetaxel and trastuzumab alone in patients with HER2-positive, metastatic breast cancer.^1-3 This triple regimen is also used as neoadjuvant therapy for patients with HER2-positive, high-risk breast cancer.

The American Society of Clinical Oncology guidelines on systemic therapy for advanced HER2-positive breast cancer recommend that, in patients being treated with a combination of chemotherapy and targeted therapy, the chemotherapy should be administered for approximately 4 to 6 months (or longer) as long as the cancer is responding to the treatment.⁴ However, the use of chemotherapeutic agents, such as docetaxel, can negatively affect quality of life.⁵ To assess the clinical effects of docetaxel treatment duration within the triplet regimen in the CLEOPATRA trial, Miles and colleagues performed a post-hoc analysis, which was recently published in Annals of Oncology.6Their analysis also evaluated the effect of adding pertuzumab to a regimen of trastuzumab plus docetaxel.

In the pivotal phase 3 CLEOPATRA trial, 808 patients with unresectable, locally recurrent, or metastatic HER2-positive breast cancer were randomized to first-line treatment with docetaxel, trastuzumab, and pertuzumab (the pertuzumab arm) or docetaxel, trastuzumab, and placebo (control arm). Docetaxel was administered at a starting dose of 75 mg/m² every 3 weeks but could be increased to 100 mg/m² if the safety profile during cycle 1 was acceptable. The docetaxel dose could also be reduced by 25% (from 75 mg/m² to 55 mg/m² or from 100 mg/m² to 75 mg/m²), delayed, or discontinued if there was unacceptable toxicity.¹

The post-hoc analysis of CLEOPATRA included the 804 patients in the safety population who received ≥1 doses of any drug. Among these patients, 475 received >6 cycles of docetaxel, 210 received 6 cycles, and 119 received <6 cycles. Patients who received <6 cycles received a median of 3 cycles of docetaxel. The median docetaxel dose intensity was 24.5 mg/m² to 25.0 mg/m² per week. In the cohort of patients who received <6 cycles of docetaxel, the most frequently cited reason for discontinuation of the agent was adverse event or intercurrent illness. In the cohort of patients who received >6 cycles of docetaxel, 73.8% in the control arm and 80.3% in the pertuzumab arm continued targeted therapy after discontinuing docetaxel.⁶

Miles and colleagues found no statistically significant improvement in PFS or OS associated with >6 cycles of docetaxel compared with 6 cycles of docetaxel, after adjusting for the effect of pertuzumab. They also noted that patients who received <6 cycles of docetaxel had poorer PFS and OS compared with those who received 6 cycles of the drug.⁶

“Compared with placebo, the addition of pertuzumab to trastuzumab plus docetaxel significantly improved PFS,” regardless of whether patients received <6, 6, or >6 cycles of docetaxel, the investigators concluded. In addition, they stated that receiving “more than six cycles of docetaxel was not associated with statistically significant additional clinical benefit compared with the recommended minimum of six cycles.”

References
1. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
2. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.
3. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-734.
4. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2078-2099.
5. Al-Batran SE, Hozaeel W, Tauchert FK, et al. The impact of docetaxel-related toxicities on health-related quality of life in patients with metastatic cancer (QoliTax). Ann Oncol. 2015;26:1244-1248.
6. Miles D, Im YH, Fung A, et al. Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial. Ann Oncol. 2017;28:2761-2767.