Pertuzumab –Cancer Therapy

Roche/Genentech's pertuzumab is a humanised monoclonal antibody (MAb) to the HER2 receptor that is currently in phase III development for the treatment of advanced breast cancer.

Progression to phase III clinical trials comes on the back of encouraging phase II data, which suggest that the addition of pertuzumab to trastuzumab (Herceptin) can benefit breast cancer patients no longer responsive to standard therapy (trastuzumab plus chemotherapy).

HER DIMERISATION INHIBITORS (HDIs) – A NEW THERAPEUTIC CLASS

The HER family of transmembrane tyrosine kinase receptors, most especially HER2, have been identified as an important therapeutic target in breast cancer. The HER signalling pathway is known to play a pivotal role in neoplastic cell growth, differentiation, malignant transformation and resistance to chemotherapy.

In patients with HER2-positive breast cancer, amplification of the HER2 oncogene leads to over-expression of the receptor on cancer cells and promotion of tumour cell growth. It affects about 20–30% of breast cancer patients and is associated with aggressive disease and poor prognosis.

Roche's trastuzumab (Herceptin), which targets the HER 2 receptor protein, is now an established treatment for patients with HER2-positive breast cancer. Pertuzumab also targets the HER2 receptor but as a HER dimerisation inhibitor, or HDI, it inhibits the dimerisation or 'pairing' of the HER2 protein with other members of the HER family of receptors: HER1/EGFR, HER3 and HER4.

For example, in response to mitogenic signals, HER1 and HER3 form heterodimers with HER2 and act as strong oncogenic signals.

WORKING IN COMBINATION WITH HERCEPTIN

With complementary modes of action, potential exists to combine pertuzumab with trastuzumab in the treatment of HER2-positive breast cancer.

Early results from a non-randomised phase II study have shown evidence of meaningful activity from pertuzumab in combination with trastuzumab in a cohort of patients with late-stage cancer whose disease had progressed during trastuzumab therapy. At study entry, all patients had measurable progressive HER2 positive breast cancer and had received up to three courses of prior chemotherapy plus trastuzumab.

Preliminary results showed that approaching 20% of patients responded to pertuzumab plus trastuzumab, while a further 21% experienced disease stabilisation lasting for at least six months.

Phase III trials will explore the effectiveness of pertuzumab in combination with trastuzumab as first-line therapy in metastatic disease as well as in the neoadjuvant setting in early breast cancer (prior to surgical removal of the tumour).

POTENTIAL IN OVARIAN CANCER

Encouraging preliminary results have been reported with pertuzumab in patients with ovarian cancer, in which HER2 over-expression also occurs.

A phase II double-blind, placebo-controlled trial enrolled 130 women with advanced ovarian, primary peritoneal or fallopian tube cancer who had experienced disease progression within six months of receiving platinum-based chemotherapy. Patients were randomised to pertuzumab plus gemcitabine or gemcitabine alone.

In this difficult-to-treat population, overall progression-free survival increased by 52% in the combination treatment arm. Median progression free survival was 3.0 months (0–8.7 months) versus 2.6 months (0–9+ months) and progression-free survival rate at four months 49% versus 34% in the combination and gemcitabine alone arms respectively.

Adverse events were consistent with previous clinical trials of pertuzumab and included fatigue, diarrhoea, back pain and neutropenia.

MARKETING COMMENTARY

Although there have been major advances in the treatment of breast cancer in the last ten to 15 years, it remains a disease for which additional treatments are still needed to improve outcome. It is still the leading cause of cancer mortality in women.

Roche/Genentech's pertuzumab derives from the companies' expertise in therapeutic MAb research and development, which has seen trastuzumab (Herceptin) become a standard therapy for different stages of HER2-positive breast cancer. Researchers suggest that the potential to exploit synergism by combining trastuzumab with pertuzumab may offer a more effective therapeutic approach to breast cancer than treatment with a single HER2 MAb.

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