Slowing final approval, GlaxoSmithKline's breast cancer drug Tyverb (lapatinib) was sent back to the Committee for Medicinal Products for Human Use (CHMP) for further discussion, after receiving new data from GSK observed during a standard pharmacovigilance review of clinical trial and post-marketing data.
The CHMP is requested to discuss these new data prior to the Commission issuing its adoption of the CHMP's opinion and releasing the marketing authorisation, GSK said confirming that the European Union Commission has referred back the drug to CHMP.
It is expected that Tyverb will be discussed at the next meeting of the CHMP, probably during its April 21-24 meeting. GSK believes that these data do not change the positive benefit-risk profile for Tyverb in the proposed indication and will work closely with the CHMP and the Commission to make Tyverb available to patients in Europe as quickly as possible following final authorisation.
Tyverb is the first oral, small molecule dual targeted therapy that works by getting inside the cancer cell to inhibit both ErbB1 (EGFR) and ErbB2 (HER2), two receptor proteins which are responsible for tumour growth. This novel mechanism of action is a new way to treat breast cancer, claimed the company.
GSK observed in the review of clinical trial and post-marketing data, that hepatotoxicity (predominately elevated liver enzymes) may occur during treatment with Tyverb. The overall incidence of these events has been 0.4 per cent (or four per 1,000 patients) and the events were generally identified through a routine blood test. Severe hepatotoxicity has been uncommon. Elevated liver enzymes generally returned to normal when the patients stopped taking Tyverb. GSK has informed investigators in ongoing clinical trials, and healthcare providers in those countries where Tyverb is approved, to recommend increased frequency of blood tests to monitor liver function.
In December 2007, the CHMP issued a positive opinion recommending conditional marketing authorisation for Tyverb and final marketing authorisation was expected from the EU Commission between 22nd February and 8th March 2008. If approved by the Commission, Tyverb, in combination with capecitabine, will be indicated for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy which must include anthracyclines, taxanes and therapy with trastuzumab in the metastatic setting.
The CHMP positive opinion issued in December was based on a pivotal phase III trial (EGF100151) in which women with locally advanced or metastatic ErbB2-positive breast cancer whose disease had progressed following prior treatment with anthracyclines, taxanes and trastuzumab were given either the combination of lapatinib and capecitabine, or capecitabine alone. The data showed that the investigator assessed median time to progression was 5.5 months (23.9 weeks) in the lapatinib and capecitabine arm versus 4.2 months (18.3 weeks) in the capecitabine arm alone. The independent assessment demonstrated that lapatinib when given in combination with capecitabine significantly increased time to progression by 6.2 months (27.1 weeks) compared to 4.3 months (18.6 weeks) with capecitabine alone.
Central nervous system metastases are a major burden for breast cancer patients. In addition to the achievement of the primary endpoint in the pivotal phase III trial, results from an unplanned exploratory analysis demonstrated a reduced incidence of brain metastases as the first site of disease recurrence. In this retrospective exploratory analysis, 2 per cent of patients in the combination arm had relapse to the brain compared with 6 per cent in the capecitabine alone arm. These preliminary results with lapatinib are encouraging and are the basis of ongoing research in this area.
The most common adverse events during therapy with lapatinib plus capecitabine during the pivotal Phase III trial were gastrointestinal (diarrhoea, nausea and vomiting) or skin disorders (rash and hand and foot syndrome). Diarrhoea and rash were more common with the combination than with capecitabine alone. The majority of adverse events were mild to moderate in severity, and the incidence of grade 3 and 4 events was low and similar in both treatment groups. Lapatinib has also been associated with reports of decreases in left ventricular ejection fraction (LVEF) and also with reports of pulmonary toxicity. The prescribing information will contain appropriate advice for doctors.
A marketing authorisation under conditional approval means that further evidence on the medicinal product is awaited. In the case of Tyverb this relates to provision of further data from the pivotal study and additional demonstration of decreased incidence of relapse in the central nervous system, for which a study will be conducted. If Tyverb receives conditional approval, the European Medicines Agency will review new information annually and update the product information as necessary.