Tykerb - Dual Tyrosine Kinase Inhibitor for the Treatment of Solid Tumours

Tykerb (lapatinib ditosylate) is an epidermal growth factor receptor (EGFR) and ErbB-2 (Her2/neu) dual tyrosine kinase inhibitor, under development by GlaxoSmithKline as a treatment for solid tumours such as breast and lung cancer. This novel investigational agent has attracted considerable interest, as it appears to arrest the development of breast cancer in some patients with metastatic, treatment-refractory disease.

In 2006, GSK filed for regulatory approval with both the US FDA and the European EMEA for Tykerb (lapatinib ditosylate) to be used in combination with capecitabine as a treatment for metastatic (advanced) HER2 positive breast cancer in patients previously treated with other anti-cancer drugs including trastuzumab (Herceptin).

Regulatory filing followed the release of positive data from a pivotal open-label phase III trial that showed treatment with Tykerb (lapatinib ditosylate) almost doubled the time to progression in patients with HER2 (erbB2) positive advanced breast cancer.

In March 2007, the FDA approved Tykerb (lapatinib ditosylate) for its primary indication. A decision from the EMEA is expected soon. Later that year, European regulators followed suit. In Europe, lapatinib ditosylate, which is to be used in conjunction with other chemotherapeutic agents, will be marketed under the brand name, Tyverb.

TYROSINE KINASE INHIBITORS (TKI) REPRESENT A GROWING CLASS OF ANTI-CANCER AGENTS

Protein tyrosine kinases are enzymes that provide a central switch mechanism in cellular signal transduction pathways. As such they are involved in many cellular processes such as cell proliferation, metabolism, survival and apoptosis. Several protein tyrosine kinases are known to be activated in cancer cells and to drive tumour growth and progression.

Blocking tyrosine kinase activity therefore represents a rational approach to cancer therapy. Therapeutic strategies include blocking kinase-substrate interaction, inhibiting the enzyme's adenosine triphosphate (ATP) binding site and blocking extracellular tyrosine kinase receptors on tumour cells. Already several TKIs have been approved as anti-cancer agents.

The erbB or HER family of transmembrane tyrosine kinase receptors, especially receptors erbB1 (or EGFR) and erbB2 (or Her2/neu), has been identified as an important therapeutic target in a number of cancers. Her2/neu, for example, is overexpressed in around 20% to 30% of patients with aggressive breast cancer, while EGFR is overexpressed in several solid tumours.

GSK’s Tykerb (lapatinib ditosylate) is a small molecule, orally-active TKI that targets both erbB receptors. Its dual mode of action distinguishes it from existing TKIs such as gefitinib (Iressa) and trastuzumab (Herceptin), which are single EGFR and Her2/neu receptor inhibitors respectively. It is hoped that dual TKIs may help to address the problem of drug resistance that can arise following treatment with single receptor inhibitors.

TYKERB EXPANDS TREATMENT OPTIONS FOR BREAST CANCER PATIENTS

Data from clinical trials provide evidence of the clinical effectiveness of GSK’s Tykerb (lapatinib ditosylate) in advanced breast cancer. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine (Xeloda), Tykerb (lapatinib ditosylate) almost doubled time to progression when compared with capecitabine alone (36.9 vs. 19.7 weeks respectively).

In this trial, in which patients were randomised to combination therapy or to capecitabine alone, all patients had metastatic breast cancer that had progressed following treatment with trastuzumab (Herceptin) or other anti-cancer drugs. Additional analyses of trial data showed that the incidence of CNS or brain metastases, a common site of metastatic disease, was also much lower in patients in the combination treatment arm. Only 4 patients on combination therapy experienced CNS relapse compared with 11 of those on capecitabine alone.

There is also some encouraging evidence to suggest that Tykerb (lapatinib ditosylate) may have efficacy in inflammatory breast cancer, a highly aggressive form of the disease that has a particularly poor prognosis.

Based on the available data, once-daily oral Tykerb (lapatinib ditosylate) appears generally well tolerated with rash, fatigue and diarrhoea – the most common treatment-related adverse events to be reported among patients treated to date.

NEW THERAPEUTIC PARADIGMS FORPATIENTS WITH SOLID TUMOURS

The recent introduction of several new classes of anti-cancer drugs, such as the TKIs, has opened the door to new approaches to cancer treatment, in which the goals of therapy are to halt disease progression, ameliorate symptoms and improve patient quality of life.

Often described as targeted cancer therapies, these new agents have the potential to prolong life without the serious side effects associated with cytotoxic drugs that have traditionally underpinned the treatment of most solid tumours. Many of the new targeted anti-cancer agents possess cytostatic rather than cytotoxic properties. Increasingly, oncologists envisage a time when cancers will be turned from life-threatening diseases into manageable chronic conditions.

MARKETING COMMENTARY

Although there have been major advances in the treatment of breast cancer in the last 10–15 years, it remains a disease for which new treatments are still urgently needed. This is especially true for patients whose disease recurs and progresses following treatment.

Among currently available TKIs, trastuzumab (Herceptin) has made a significant contribution to the treatment of metastatic breast cancer. However, eventually most patients with metastatic breast cancer receiving trastuzumab-containing regimens experience disease progression, with salvage chemotherapy effective in about 10% of cases.

Approval of Tykerb/Tyverb (lapatinib ditosylate) in HER2 positive metastatic breast cancer offers an important advance for patients with this type of breast cancer who fail to benefit from continued trastuzumab-based therapy.

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