Unprecedented OS Benefit Cements Pertuzumab Regimen as Frontline Standard in HER2-Positive MBC


Frontline pertuzumab plus trastuzumab and docetaxel improved survival by nearly 16 months in metastatic HER2-positive breast cancer, according to results from the phase III CLEOPATRA study that are now published in The New England Journal of Medicine.

Sandra M. Swain, MD

The addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and docetaxel as a first-line therapy for metastatic HER2-positive breast cancer improved overall survival (OS) by nearly 16 months versus trastuzumab plus docetaxel, according to findings from the phase III CLEOPATRA study. The results, which were initially reported at the 2014 ESMO Congress, have now been published in The New England Journal of Medicine.

“We’ve never really seen this kind of survival in such an aggressive form of breast cancer before,” said lead author Sandra M. Swain, MD, medical director, Washington Cancer Institute at MedStar Washington Hospital Center, in an interview with OncLive.

The double-blind, phase III CLEOPATRA trial randomized 808 patients with unresectable or metastatic HER2-positive breast cancer to frontline therapy with trastuzumab and docetaxel plus either pertuzumab (n = 402) or placebo (n = 406).

Patients received either placebo or pertuzumab, given as an 840-mg loading dose followed by a 420-mg maintenance dose, plus trastuzumab, given as an 8-mg/kg loading dose followed by a 6-mg/kg maintenance dose, and 6 cycles of docetaxel, 75 mg/m2 with escalation to 100 mg/m2 if tolerated. Treatments were administered every 3 weeks until disease progression or unacceptable toxicity.

Enrolled patients were required to have an ECOG performance status of 0 or 1. One hormonal treatment for metastatic disease, as well as adjuvant or neoadjuvant chemotherapy with or without trastuzumab were allowed.

The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS, overall response rate (ORR), and duration of response.

At a median follow-up of 49.5 months in the pertuzumab arm and 50.6 months in the control group, the median OS was 56.5 months and 40.8 months, respectively (HR = 0.68; 95% CI, 0.56-0.84; P <.001).

Investigator-assessed median PFS was 18.7 months in patients receiving pertuzumab and 12.4 months in the placebo arm (HR = 0.68; 95% CI, 0.58-.80; P <.001). The median duration of response was 20.2 months and 12.5 months, respectively.

The OS and PFS benefits with pertuzumab were consistent in predetermined subgroup analyses.

“I think the exciting thing is that the patients are living much longer, and even if in the advanced stage they eventually have progression of their disease, there are many more studies ongoing [that are] looking at trying to improve [outcomes],” Swain said.

Most adverse events (AEs) were grade 1 or 2 and occurred during docetaxel administration and declined after discontinuation.

The most common AEs of any grade in the pertuzumab arm were diarrhea (28.1% vs 14.2%), rash (18.3% vs 8.0%), upper respiratory tract infection (18.3% vs 12.3%), headache (17.0% vs 12.3%), pruritus (13.7% vs 5.7%), asthenia (13.4% vs 8.8%), and fatigue (13.4% 9.6%).

Cardiac toxicity was not increased in the pertuzumab arm compared with the placebo group. The rate of left ventricular dysfunction in the two arms was 6.6% and 8.6%, respectively.

In their discussion, the authors noted some of the challenges that remain in this setting, including the need for biomarkers to identify who will benefit most from dual-HER2 blockade with pertuzumab/trastuzumab. It is also important to determine whether hormonal therapy plus pertuzumab and trastuzumab is more effective than hormonal therapy plus trastuzumab alone in patients with hormone receptor—positive disease, according to the authors.

The significance of the CLEOPATRA outcomes has become even more significant since the disappointing results were reported for frontline T-DM1 (ado-trastuzumab emtansine; Kadcyla) in the phase III MARIANNE trial.

MARIANNE randomized women with previously untreated advanced HER2-positive breast cancer to T-DM1 plus or minus pertuzumab compared with trastuzumab plus either docetaxel or paclitaxel.

Although positive phase II data had indicated that T-DM1 would succeed in the frontline setting, the phase III results showed that neither T-DM1 arm improved outcomes versus standard trastuzumab plus chemotherapy.

With the negative T-DM1 MARIANNE results, the pertuzumab/trastuzumab regimen that succeeded in the CLEOPATRA trial is now firmly established as the first-line standard of care for patients with HER2-positive metastatic breast cancer.

Additional reporting by Gina Columbus.


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.

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