CLEOPATRA Closes Landmark Survival Analysis in HER2-Positive Metastatic Breast Cancer

Previously reported improvements in overall survival (OS) with dual HER2 receptor blockade plus docetaxel in HER2-positive metastatic breast cancer have been maintained over a median follow-up of over 8 years, the end-of-study analysis of the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study has confirmed.

In the previously published primary analysis of the CLEOPATRA study, adding pertuzumab to trastuzumab and docetaxel in the first-line treatment of HER2-positive metastatic breast cancer extended median progression-free survival (PFS) by 38% compared with the combination of trastuzumab and docetaxel alone, at a Hazard Ratio (HR) of 0.62 (95% CI, 0.51-0.75; P<0.001), Sandra Swain, MD, Georgetown University Medical Center, Washington, DC, and colleagues reported in the Lancet Oncology.

A second interim analysis showed that OS was also significantly improved by 34% in patients who received additional pertuzumab and the same backbone doublet at a HR of 0.66 (95% CI, 0.52-0.84; P=0.0008), investigators observed.

In this final analysis of the same data set, median OS was 31% longer at 57.1 months (95% CI, 50-72 months) in patients who received additional pertuzumab compared with 40.8 months (95% CI, 36-48 months) in the non-pertuzumab group at a HR of 0.69 (95% CI, 0.58-0.82), the study authors reported.

“To our knowledge, this is the longest follow-up of patients for first-line treatment of HER2-positive metastatic breast cancer (maximum of 120 months),” Swain and colleagues pointed out.

“This end-of-study analysis of CLEOPATRA showed that the overall survival improvement with first-line pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel for HER2-positive, metastatic breast cancer was maintained at a median follow-up-of 99 months,” they stated.

Study Entry

A total of 808 patients with HER2-positive metastatic breast cancer who had not received previous treatment for metastatic disease were eligible for study entry.

“Study drugs were given intravenously every 3 weeks,” the authors observed.

Specifically, pertuzumab was given on day 1 of each cycle, at a loading dose of 840 mg in the first cycle, followed by 420 mg given as a maintenance dose in subsequent cycles.

Trastuzumab was given on day 2 of the first cycle at a loading dose of 8 mg/kg, which was reduced to a maintenance dose of 6 mg/kg for subsequent cycles.

Docetaxel was also given on day 2 of the first cycle at 75 mg/m2, which was increased to 100 mg/m2 if patients could tolerate an increase in dose.

“If chemotherapy was discontinued due to toxic effects, pertuzumab, placebo or trastuzumab was continued until disease progression, unacceptable toxic effects, or withdrawal of consent,” Swain and colleagues observed.

They found:

• At 5 years, landmark OS rates were 49% (95% CI, 44-54 months) in the additional pertuzumab group versus 35% (95% CI, 30-40 months) in the control arm.
• At 6 years, landmark OS rates were 45% (95% CI, 40-50 months) in the additional pertuzumab arm versus 28% (95% CI, 24-33 months) in the control arm.
• At 7 years, landmark OS rates were 40% (95% CI, 35-46 months) in the additional pertuzumab group versus 26% (95% CI, 26% (95% CI, 21-31 months) in the control arm.
• At 8 years, the landmark OS rates were 37% (95% CI, 31-42 months) in the additional pertuzumab arm versus 23% (95% CI, 19-28 months) in the control arm.

Investigators also noted that median PFS was 31% longer for patients in the additional pertuzumab arm at 18.7 months (95% CI, 17-22 months) compared with 12.4 months (95% CI, 10-14 months) in the control arm at a HR of 0.69 (95% CI, 0.59-0.81).

Safety Population

In the safety population, there was a higher incidence of diarrhea and rash in patients who received additional pertuzumab than in those who did not—both any grade and grade 3 or higher.

This was again true for patients who crossed over to pertuzumab (n=50) by the end of the study interval, although in this small subgroup, diarrhea and rash were generally grades 1 and 2.

However, the most common grade 3 to 4 adverse event (AE) was neutropenia which occurred in similar proportions of patients at 49% in the pertuzumab group and 46% in the non-pertuzumab group, as investigators pointed out.

“Since the previous analysis, there was only one new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular dysfunction (pertuzumab group post-crossover),” study authors observed.

Two percent of patients died due to AEs during the treatment phase in the pertuzumab arm compared with 3% of those who did not receive pertuzumab, researchers also pointed out.

“Thirty seven percent (37%) of patients on continued pertuzumab and trastuzumab-based therapy in CLEOPATRA were still alive with more than 8 years of follow-up, and 165 did not progress,” Swain and colleagues noted.

“[This suggests] that these patients could continue to maintain clinical benefit over time,” they emphasized.

Commenting on these findings, Matteo Lambertini MD, University of Genova, Italy, and Ines Vaz-Luis, MD, Universite Paris-Saclay, Inserm, Villejuif, France,observed that dual anti-HER2 blockade added to docetaxel is “an unquestionable step forward” in the treatment of HER2-positive metastatic breast cancer.

Indeed, prior to the introduction of anti-HER2 targeted therapies, “median overall survival for patients with HER2-positive metastatic breast cancer was less than 2 years,” they wrote.

The results of this updated final analysis “challenge the concept of HER2-positive metastatic breast cancer being an incurable disease,” the editorialists suggested

However, Lambertini and Vaz-Luis cautioned that when translating final results from CLEOPATRA into clinical practice, physicians need to consider that over half of patients in the study did not receive any prior adjuvant or neoadjuvant treatment.

Moreover, only 11% had been previously exposed to trastuzumab.

In current practice, “most [patients] have been previously exposed to single-agent or dual anti-HER2 blockade in the early setting,” they pointed out.

“[So] the performance of the current standard pertuzumab-based first-line treatment in patients previously exposed to adjuvant or neoadjuvant anti-HER2 therapy remains to be clarified,” the editorialists noted.

1. Dual HER2 blockade with pertuzumab and trastuzumab plus docetaxel maintained its earlier survival advantage over trastuzumab plus docetaxel alone for a median follow-up of 8 years in HER2-positive, metastatic breast cancer.

2. Over one-third of women treated with first-line pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer were still alive at a median follow-up of over 98 months and 16% of them had not progressed at the end-of-study analysis, a remarkable outcome given the once deadly nature of this disease.

Pam Harrison, Contributing Writer, BreakingMED™

Cat ID: 22

Topic ID: 78,22,730,22,691,192