perjetaPertuzumab (Perjeta) became the first drug to ever be approved by the FDA for use prior to surgery for non-metastatic breast cancer on September 30, 2013. This development further signals a paradigm shift away from chemotherapy and towards targeted therapy – specifically in the now increasingly target-rich environment of HER2-positive breast cancer.

What is Perjeta?

Pertuzumab is a monoclonal antibody, which works by preventing a molecular interaction between the HER2 receptor and other related receptors on the breast cancer cell’s surface. We’ve known about the effectiveness of pertuzumab based on a prior trial with over 800 patients (CLEOPATRA).

What is HER2 positive breast cancer

Courtesy of Genentech.

  • This phase III trial compared pertuzumab, the anti-HER2 drug herceptin and the chemotherapy drug docetaxel with a placebo / herceptin / docetaxel combination as first-line therapy in patients with metastatic breast cancer.
  • The combination with pertuzumab demonstrated a clear advantage – 18.5 months until the time of disease progression compared with 12.4 months for the placebo regimen.
  • This trial led to the FDA’s approval of pertuzumab in combination with herceptin and chemotherapy in 2012 for treatment of metastatic, HER2-positive breast cancer.

Two additional trials support the FDA’s decision to grant accelerated approval of Perjeta in the pre-surgery setting. Both the phase II TRYPHAENA and the phase II NeoSphere trials demonstrated an improved complete response rate with patients receiving pertuzumab compared to those who had not. Specifically, the Neosphere trial compared the outcomes of patients who received:

a)    trastuzumab plus docetaxel.

b)    pertuzumab, trastuzumab plus docetaxel.

c)    pertuzumab plus trastuzumab.

d)    pertuzumab plus docetaxel.

Of the patients who received pertuzumab, trastuzumab and docetaxel, 45.8 percent of them experienced a complete response. In other words, at the time of surgery, the disease was undetectable. This surpassed the 29 percent, 16.8 percent and 24 percent complete response rates associated with the other drug combinations, respectively.

The most common side effects with this treatment included low white blood counts as well as fever with low white blood counts (febrile neutropenia). With pertuzumab, like trastuzumab, effect on heart function is a significant concern, which warrants continued monitoring during treatment.

Perjeta FDA Approval

How-Perjeta-Works

Courtesy of Genentech.

So what has led to the accelerated FDA approval of pertuzumab-based chemotherapy in the upfront setting prior to surgery? In May 2012, the FDA issued a draft guidance allowing the use of “complete response rate,” as mentioned above, to be an endpoint allowing accelerated approval.

We know from clinical experience that in patients who experience a disappearance of their tumor while receiving chemotherapy have an overall better prognosis compared with those who do not.

But what is needed is a confirmatory trial – involving many more patients than the 417 enrolled in the NeoSphere study. The larger, phase III APHINITY trial (4,800 plus patients) will compare Perjeta, trastuzumab and chemotherapy with trastuzumab plus chemotherapy. This will provide further information regarding safety and efficacy – with the possibility of further shaping Perjeta’s role in the treatment of HER2-positive breast cancer. At this time, however, Perjeta is not approved for use in the “after surgery” setting.

Breast Cancer Targeted Therapies

In this new era of targeted therapies, it’s clear that the anti-HER2 front in the war against breast cancer has borne out some of the greatest benefits. In addition to improved complete response rates (with resultant improved survival), we can also expect enhanced tolerability due to the minimization of the role for cytotoxic chemotherapy in these newer regimens.