Unprecedented Survival Benefit Cements Perjeta Regimen for Newly Diagnosed HER2 Metastatic Breast Cancer

The addition of Perjeta (pertuzumab) to Herceptin (trastuzumab) and docetaxel as a first-line therapy for metastatic HER2-positive breast cancer improved overall survival (OS) by nearly 16 months, according to findings from the phase 3 CLEOPATRA study. The results, which were initially reported at the 2014 Congress of the European Society for Medical Oncology 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, medical director, Washington Cancer Institute at MedStar Washington Hospital Center.

The trial randomized 808 patients with unresectable or metastatic HER2-positive breast cancer to frontline therapy with Herceptin and docetaxel plus either Perject or placebo. 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 Perjeta arm and 50.6 months in the control group, the median OS was 56.5 months and 40.8 months, respectively. Investigator-assessed median PFS was 18.7 months in patients receiving pertuzumab and 12.4 months in the placebo arm. 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 were minor and occurred during docetaxel administration and declined after discontinuation. The most common side effects of any grade in the Perjeta arm were diarrhea, rash and upper respiratory tract infection. Cardiac toxicity was not increased in the Perjeta arm compared with the placebo group. The rate of left ventricular dysfunction in the two arms was 6.6 percent and 8.6 percent, 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 Perjeta/Herceptin. It is also important to determine whether hormonal therapy plus Perjeta and Herceptin is more effective than hormonal therapy plus Herceptin 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 Kadcyla (ado-trastuzumab emtansine) in the phase 3 MARIANNE trial, which randomized women with previously untreated advanced HER2-positive breast cancer to Kadcyla plus or minus Perjeta compared with Herceptin plus either docetaxel or paclitaxel.

Although positive phase 2 data had indicated that Kadcyla would succeed in the frontline setting, the phase 3 results showed that neither Kadcyla arm improved outcomes versus standard Herceptin plus chemotherapy.

With the negative Kadcyla MARIANNE results, the Perjeta/Herceptin 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.