Wednesday, April 30, 2008

Breast cancer update: will genotyping help select best patients?

Previously, pharmacogenetic studies have demonstrated that women with a certain genotype have a better response to tamoxifen. Now, a modeling study has shown that for postmenopausal breast cancer patients with this genotype, tamoxifen is as good or better at reducing the risk for relapse as aromatase inhibitors. This finding does have clinical implications, but routine genotyping for all women considering tamoxifen is not yet recommended until the results have been validated with further studies.

Mathematical models to explore how genotype information affects therapy recommendations have been employed to analyze clinical data collected in the Breast International Group Trial 1-98 (BIG 1-98). This trial, published last year (J Clin Oncol. 2007;25:486-492), compared an aromatase inhibitor with tamoxifen in the adjuvant setting in postmenopausal women with estrogen-receptor-positive breast cancer.

The gene, CYP2D6, codes for a cytochrome P450 enzyme involved in tamoxifen's metabolism. About 60% of individuals of European descent are homozygous for the active alleles of this gene, known as "wild type," and it is this group that shows the best response to tamoxifen.

The model showed that women with this genotype had an outcome with tamoxifen that was similar or superior to the outcome seen with aromatase inhibitors. This finding differs from the results in unselected populations, in which aromatase inhibitors have demonstrated statistically significant improvements in disease-free survival over tamoxifen. It is possible that women who are concerned about the relative toxicity or cost of an aromatase inhibitor could consider undergoing genetic testing; if they are found to be wild type for CYP2D6, they could then pursue treatment with tamoxifen instead.

Several studies have shown that in postmenopausal women, aromatase inhibitors are generally more effective than tamoxifen. This model suggests, however, that the majority of women with the wild-type genotype have better outcomes with tamoxifen than with an aromatase inhibitor and, therefore, tamoxifen would be a better choice for them. The model also suggests that women who are heterozygous for this gene respond less well to tamoxifen, and so they should be treated with an aromatase inhibitor.

Tuesday, April 29, 2008

Market intelligence - when NICE is not so nice

The National Institute for Health and Clinical Excellence (NICE) have announced their decision not to recommend the use of Tarceva (erlotinib) for the treatment of locally-advanced or metastatic non-small-cell lung cancer (NSCLC) in the National Health Service (NHS) in England and Wales.

NICE’s Final Appraisal Determination (FAD) on Tarceva last week concluded that the drug “could not be considered a cost-effective use of NHS resources” when compared with either docetaxel or best supportive care. People currently receiving Tarceva “should have the option to continue therapy until they and their clinicians consider it appropriate to stop.” The Appraisal Committee that assessed Tarceva, also indicated that it awaits the results of ongoing trials comparing the drug with docetaxel, and recommends further research into subgroups for whom Tarceva “may provide greater benefit.”

This is an interesting perspective, given the US approach of screening patients who are EGFR-positive with K-Ras mutations who would be suitable for Tarceva therapy. Taking a break from chemotherapy may also prolong survival across multiple lines of therapy. Docetaxel is well known for its severe myelosuppressive effects that cause cancer patients to feel exhausted and beaten up. Tarceva, a small molecule targeted therapy has been shown to be superior to placebo in efficacy, survival and quality of life, so the decision is somewhat surprising clinically.

To put it in context, chemotherapy is only somewhat effective for patients with advanced NSCLC, although there is some evidence for a benefit in terms of survival and symptom relief. Response times to treatment are brief, and the median time to cancer progression is three to five months. In patients who initially received platinum-based chemotherapy for NSCLC, docetaxel offers the chance to improve survival for those with disease progression. Data suggests, however, that third-line chemotherapy is similar to supportive care in terms of survival, and the response rates to such therapy are bleak.

A randomized, placebo-controlled, double-blind trial was recently conducted to determine whether the EGFR inhibitor erlotinib prolongs survival in non–small-cell lung cancer after the failure of first-line or second-line chemotherapy. It clearly demonstrated that erlotinib prolonged survival.

Eligible patients had stage IIIB or IV NSCLC, with performance status of between 0 and 3, and had undergone one or two prior rounds of chemotherapy. In a 2:1 ratio, 731 patients were randomized to receive either 150 mg of oral erlotinib daily or placebo, and they were stratified by center, performance status, response to prior chemotherapy, number of prior rounds of chemotherapy, and prior platinum-based therapy. Median age was 61.4 years, 49% had undergone two prior rounds of chemotherapy, and 93% had received platinum-based chemotherapy. Response rate was 8.9% with erlotinib and less than 1% with placebo (P < .001), with respective median durations of response being 7.9 and 3.7 months.

After adjustment for stratification categories, progression-free survival was 2.2 months with erlotinib and 1.8 months with placebo (hazard ratio [HR], 0.61; P < .001). Overall survival was 6.7 months with erlotinib and 4.7 months with placebo (HR, 0.70; P < .001). Only 5% of patients discontinued erlotinib because of toxic side effects.

The positive clinical data has been available in the public domain for a while now. This appears to be a financial decision rather than a clinical one. Given that the drug budget is a very small part of the overall NHS budget, one wonders why they don't attack the overinflated administrative staff budget with the same verve and vigour that they do with the relatively much smaller drug budgets.

Monday, April 28, 2008

New cancer therapy being market tested for gliobastoma?

Glioblastoma multiforme is by far the most common and most malignant of the glial tumors, yet prognosis remains poor. Less than 5% of patients survive 5 years after diagnosis.

Preliminary data was recently reported at a cancer conference on an investigational compound has shown promise in prolonging survival among patients with recurrent glioblastoma. This compound, cediranib, was found to positively influence the outcome of the trial. The lead author, Dr. Batchelor (Massachusetts General Hospital Cancer Center in Boston), said that the primary outcome of this phase II study, a standard metric in this disease, is the proportion of patients who are alive without disease progression at 6 months, "Our percentage was 25.8%, and this compares favorably with historic controls, which are about 15%." The study cohort consisted of 31 patients with glioblastoma who had failed previous therapy with radiation, surgery, and chemotherapy.

Cediranib (AZD2171), from AstraZeneca, is an oral potent panvascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. It is a selective VEGF-signaling inhibitor that targets all 3 VEGF receptors.

AZD2171 has a half-life of 20 hours, which makes it compatible with once-daily dosing, and its primary target, VEGFR2, is expressed on glioblastoma endothelium. The researchers have observed the normalization of tumor vessels in patients with recurrent glioblastoma who received AZD2171 on a daily basis.