Cervical cancer vaccines

The UK has recently approved a second vaccine that protects against HPV called Cervarix from GSK, in addition to Gardasil from Merck. Both vaccines protect against HPV, but Gardasil also protects against gentical warts, which Cervarix does not.

Male with genital warts - image courtesy of Wikipedia

The wholesale price for the two is exactly the same, £80.50, and the formal list price is also comparable at £240 per vaccination. Other European countries appear to have chosen Gardasil, for it's extra protective effects. Genital warts are, of course, far more common than cervical cancer in Western Europe. Most women over 40 receive a regular annual Pap smear to screen for HPV and cervical cancer, hence the low rates compared to Latin America and Africa, where the smear test is considerably less common.

Guess which vaccine the NHS chose in it's wisdom? Yes, Cervarix. Any parent wanting to innoculate their daughter with Gardasil will therefore have to get it on private health plans at a much greater cost.

Meanwhile, although a small number of boys were included in the trial, there were insufficent numbers to gain approval for use in the male population. If you are going to reduce the spread of genital warts and HPV in the population, it makes sense to innoculate both surely?

Are Her2 inhibitors an alternative to chemo in breast cancer?

Image via WikipediaSeveral studies exploring the use of lapatinib (Tykerb, GlaxoSmithKline) in metastatic breast cancer have suggested that it may offer an alternative to chemotherapy in this setting, both as monotherapy, and in combination with other targeted therapies.

One study explored the use of lapatinib alone, whereas others investigated combinations with trastuzumab (Herceptin, Genentech/Roche), with bevacizumab (Avastin, Genentech/Roche), and with the investigational agent pazopanib (under development by GlaxoSmithKline).

Studies presented at American Society of Clinical Oncology opened up an interesting debate regarding whether biological therapy without chemotherapy for metastatic breast cancer is feasible.

The efficacy of these targeted agents is higher when they are combined with chemotherapy, and the toxicity of these agents in combination needs to be explored further. Hence, the preferred front-line choice for metastatic breast cancer is presently trastuzumab with chemotherapy, and the evidence suggests that continuation of trastuzumab is the best option for patients who progress. Combining drugs that have different targets is also a promising option.

Lapatinib is currently approved in the US for a very narrow indication in combination with capecitabine (Xeloda, Roche) for advanced metastatic HER2+ breast cancer in women who have received previous chemotherapy, including an anthracycline, a taxane, and trastuzumab. A similar approval in Europe is pending with the EMEA.

The largest of the new trials presented was a phase 3 study of lapatinib monotherapy compared with a combination of lapatinib and trastuzumab (EGF104900). Both of these drugs target HER2+ breast cancer, but trastuzumab (a monoclonal antibody) is a large-protein molecule that targets the part of the HER2 protein on the outside of the cell; lapatinib (an oral drug) is a smaller molecule that enters the cell and blocks the function of this and other proteins intracellularly. The combination effectively attacks HER2 from multiple angles.

The trial involved 269 patients with HER2+ breast cancer who had documented progression on trastuzumab in the metastatic setting. The combination of lapatinib plus trastuzumab showed a significant increase in progression-free survival, compared with lapatinib alone (12 weeks vs 8.1 weeks). This translates into a 27% reduction in the risk for disease progression (hazard ratio [HR], 0.73; P = .008). The overall clinical-benefit rate (the response rate and the rate of durable stable disease) for the combination was double that for monotherapy (24.7% vs 12.4%; P = .01). There was a trend toward improved overall survival.

More data on the role of combined HER2+ therapy in combination with chemotherapy will be available soon from the ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study. ALTTO is being conducted in less-heavily pretreated patients with early-stage disease.

A trial of lapatinib plus bevacizumab was reported in a small phase 2 single-group study, conducted in 32 patients who had received a median of 5 previous metastatic breast cancer therapies. 28 of these 32 patients had received prior treatment with trastuzumab.

The combination resulted in a 34.4% clinical-benefit rate (defined as complete response plus partial response plus stable disease at 24 weeks or more), and 62.5% of patients were progression free at week 12.

The most common adverse events were diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and vomiting (46%). There were 2 grade 2 asymptomatic LVEF decreases, 1 grade 3 gastrointestinal hemorrhage, and 1 grade 3 hypertensive event.

Overall, blocking both the HER2 and the VEGF pathways led to anticancer activity for even heavily pretreated patients with metastatic breast cancer that could potentially advance the treatment of this high-risk disease.

A combination study of lapatinib plus pazopanib, where both drugs were taken orally once daily, suggested that they might provide a potential future treatment option for HER2+ breast cancer. It involved 141 patients and compared the combination with lapatinib monotherapy.

The results confirmed the efficacy of lapatinib monotherapy and showed a trend toward better outcomes with the combination. At 12 weeks, 36.2% of patients taking the combination and 38.9% taking the monotherapy experienced disease progression (P=.37). The response rate was 44.9% with the combination and 28.8% with the monotherapy according to investigator assessment, and 36.2% vs 22.2%, respectively, according to independent assessment.

Erbitux extends overall survival by 5 weeks in lung cancer

ImClone announced that late-stage study data showed that first-line treatment with Erbitux (cetuximab) plus standard chemotherapy significantly increased overall survival by about five weeks in patients with advanced non-small cell lung cancer (NSCLC), compared with chemotherapy alone. The results were presented at the American Society of Clinical Oncology (ASCO) meeting this weekend.

To put things in context, the American Cancer Society estimates that in the United States, more than 215,000 people will be diagnosed with lung cancer in 2008, which accounts for about 15 percent of all cancer diagnoses. Approximately 87 percent of these patients will be diagnosed with NSCLC, with many being diagnosed with locally advanced or metastatic disease. Lung cancer is the leading cause of cancer-related death in men and women, with more than 161,000 deaths expected to occur in 2008 – accounting for about 29 percent of all cancer deaths. In 2008, it is estimated that more Americans will die from lung cancer than breast, prostate, and colorectal cancers combined. Studies showing a significant improvement in survival will therefore impact the course of disease and affect large numbers of patients.

The randomised FLEX study involved 1125 patients with advanced non-small cell lung cancer (NSCLC) who had not previously received chemotherapy. The data demonstrated that those who received ImClone announced that Erbitux combined with chemotherapy resulted in a median overall survival of 11.3 months, compared with 10.1 months for chemotherapy alone, a significant difference. The findings also showed that tumours shrank in 36.3 percent of patients who received the Erbitux regimen, compared with 29.2 percent of patients who only received standard chemotherapy.

It is unlikely that the findings are impressive enough to significantly affect the position of Genentech's Avastin for patients with lung cancer who can be treated with the product in the short term. However, doctors treating patients with NSCLC who cannot take Avastin may opt to prescribe Erbitux, which could lead to an additional $700 million in annual sales in the US.

Overall, probably one in five patients or less get Avastin, so there's a huge opportunity outside of that in the long run, and the data are very competitive. Erbitux is expected to be filed for expanded US approval in NSCLC in the second half of this year, and the new indication could be added to the label by mid-2009. If approved, this will open new first-line treatment options for patients with non-small cell lung cancer regardless of histological subtypes, and potentially set a new standard in the first-line treatment of this disease.

Study showed Alimta improved survival in certain types of Non-Small Cell Lung Cancer

The type of non-small cell lung cancer (NSCLC) patients have may now influence their treatment regimen and, in turn, survival outcome according to the results of a major study published online in the Journal of Clinical Oncology.

NSCLC is the most common type of lung cancer and represents 85 to 90 percent of all lung cancers. According to the World Health Organization (WHO) Cancer Report, lung cancer is the world's most common cancer and the leading cause of cancer death for both men and women. More than 1 million people die from lung cancer each year.

NSCLC is defined as a group of histologies i.e. tumour types differentiated by cellular structure. The most common NSCLC histology types are squamous (or epidermoid) carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because, to date, approaches to diagnosis, staging, prognosis, and treatment have been similar.

The study, the largest Phase III clinical trial in the first-line NSCLC setting, evaluated ALIMTA® (pemetrexed for injection) plus cisplatin versus GEMZAR® (gemcitabine HCl for injection) plus cisplatin, a standard of treatment in this setting. The trial met its primary endpoint of non-inferiority relative to overall survival.

Additionally, in a pre-planned histological analysis, patients with either adenocarcinoma or large-cell carcinoma had a statistically superior and clinically relevant improvement in overall survival when treated with the pemetrexed regimen in the first-line setting.

In comparison, patients with squamous cell histology were found to have a more favorable overall survival when treated with the gemcitabine regimen.

The overall survival of patients treated with either the pemetrexed regimen or gemcitabine regimen was found to be non-inferior, with a median survival of 10.3 months. However, when researchers reviewed survival rates according to histological analysis, it was found that patients with adenocarcinoma achieved 12.6 months of overall median survival when treated with the pemetrexed regimen compared to 10.9 months for those treated with the gemcitabine regimen. Patients with large cell carcinoma who were treated with the pemetrexed regimen achieved 10.4 months of overall median survival versus 6.7 months for those treated with the gemcitabine regimen. Both findings are statistically significant.

Patients with squamous cell histology were found to have a more favorable rate of survival when treated with the gemcitabine regimen, achieving 10.8 months of median survival, compared to the 9.4 months for those treated with the pemetrexed regimen. This finding was statistically significant.

The Phase III, randomized study compared the overall survival between pemetrexed+cisplatin versus gemcitabine+cisplatin in chemonaive patients (1,725) with stage IIIB or IV NSCLC who also exhibited a performance status of 0-1. Patients on the pemetrexed arm (862) were treated with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day one every three weeks for up to six cycles. Patients on the gemcitabine arm (863) were treated with cisplatin (75 mg/m2) on day one and gemcitabine (1250 mg/m2) on days one and eight every three weeks for up to six cycles.

Hematologic grade 3/4 drug-related toxicities including neutropenia, anemia and thrombocytopenia were significantly lower for patients on the pemetrexed arm. Drug-related grade 3/4 febrile neutropenia and alopecia (all grades) were also significantly less on the pemetrexed arm. Drug-related grade 3/4 nausea was more common in patients treated with pemetrexed. Safety data by histology was generally consistent with the overall safety results.

Overall, patients with adenocarcinoma or large cell carcinoma histologies achieved improvement in overall survival when treated with Alimta (pemetrexed) based regimens.

While non-small cell lung cancer has typically been treated as one disease, this study confirms that histology, or tumour type, can provide a clue as to which treatment regimen works best for a particular tumor type. It suggests that if we can select the therapy for better results, we are closer to improving outcomes for lung cancer.

Oncology: Renal cell cancer slowed by Novartis' RAD001

Nearly two-thirds of renal cell cancer patients taking Novartis AG's RAD001 (everolimus) had progression of their disease delayed by a year, a significantly better result than in those taking placebo. Everolimus may offer potential new treatment option for patients with advanced kidney cancer who have failed standard therapies. The study assessed patients whose cancer had worsened despite receiving approved treatments for renal cancer, such as Bayer AG's Nexavar or Pfizer Inc's Sutent, or both.

Amazingly, the disease did not progress for one year in 65 percent of patients taking the once-daily RAD001 tablet, compared to 37 percent in those taking placebo, according to detailed results from a late-stage trial, which was stopped early because it met its main target.

The drug works by blocking a protein known as mTOR and disrupts the growth, division and metabolism of cancer cells.

Full results of the trial are due to be presented in an oral session at ASCO later this month (Abstract #LBA5026: Saturday, May 31, 2008; 4:30 PM-4:45 PM CDT).

There were 410 patients in the trial, 272 taking RAD001 and 138 placebo. Novartis announced it intends to file the drug for regulatory approval later this year.

Market trends: cancer vs. ophthalmology drugs

Today I was at the ophthalmologists office getting my eyes tested for some new glasses. The technician and I were chatting convivially about the pros and cons of Avastin versus Lucentis for wet age-related macular degeneration (AMD).

Later, while looking at the National Institutes of Health (NIH) site on the internet, I noticed they have finally started an independent trial that is designed to show how the two drugs stack up against each other. Both inhibit Vascular Endothelial Growth Factor (VEGF) but have different approved uses and indications.

Lucentis has been FDA-approved for use against wet AMD. Avastin isn't,it's approved for treatment of cancers such as colorectal carcinoma. Ophthalmologists and retinal surgeons have, however, commonly used it off-label, saying it's almost as effective as Lucentis, if not as effective. And Avastin also costs much less, i.e. $50 rather than $2,000. The challenge was that Avastin needed to be compounded by pharmacies and last year Genentech moved to restrict sales of Avastin to those pharmacies who were compounding Avastin for ophthalmology use, stating that there was a risk of microbial contamination from compounding and the FDA were concerned about the re-packaging.

The NIH decided to take matters into its own hands and perform a trial to answer the question. Time will tell. If the trial shows no difference between the two, expect Avastin to cannibalise sales of Lucentis and insurers/payers to exert their muscle in favour of the cheaper alternative.

AZ and Iressa attempting a comeback in lung cancer?

Last week, AstraZeneca announced the submission of a marketing authorisation application to the European Medicines Agency (EMEA) for its oral anti-cancer drug, gefitinib (IRESSA™) as a treatment for locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) in patients who have been pre-treated with platinum-containing chemotherapy.

The application was based on data from the Phase III INTEREST study, which showed that patients with pre-treated advanced NSCLC who received gefitinib had non-inferior overall survival to those treated with intravenous chemotherapy with a taxane (docetaxel). Gefitinib apparently had a more favourable tolerability profile than docetaxel and significantly more patients receiving gefitinib had an improvement in quality of life. In other words, they are attempting to do what Lilly did with Alimta in second-line treatment of NSCLC with their comparative trial against docetaxel.

This is the first time an Epidermal Growth Factor Receptor - Tyrosine Kinase Inhibitor (EGFR-TKI) has proven non-inferiority for overall survival relative to chemotherapy in patients with pre-treated advanced NSCLC. If the EU approve the therapy, it will be interesting to see how the US view the data.

The announcement represents a return to the spotlight for gefitinib, which had first-quarter sales of $58 million and is available in 36 countries. It was previously touted as a potential blockbuster, but those hopes collapsed in 2004 when results from a 1,700-patient study in people with advanced NSCLC who had failed previous chemotherapy, revealed that at the end of one year, just 27% of the Iressa group were still alive compared to 21% of placebo, a non-significant result.

AstraZeneca was allowed to keep the drug on the market in the USA, but its use was heavily restricted and no new patients were allowed access to the therapy unless they were taking part in a clinical trial. The company withdrew its application to market Iressa in Europe shortly after.

Does aspirin lower the risk of breast cancer?

A daily aspirin may give women modest protection against the most common type of breast cancer according to a study published in Breast Cancer Research. The finding reinforced earlier research indicating regular use of aspirin might reduce the risk of so-called estrogen receptor-positive breast cancer, which makes up about three quarters of breast cancer cases.

Estrogen receptor or ER-positive breast cancer is fueled by estrogen and aspirin may interfere with this hormone's activity. Researchers led by Gretchen Gierach of the National Cancer Institute, part of the National Institutes of Health, found that women who took aspirin daily cut their risk of developing this type of breast cancer by 16 percent.

The research involved about 127,000 women aged 51 to 72 from around the United States who were cancer-free when the study began. About 18 percent of the women were daily aspirin users. They were tracked for seven years and about 4,500 of them developed breast cancer.

The study did not find any relationship between aspirin and the less-common estrogen receptor-negative breast cancer. It also did not find any protective effect in women who took aspirin less than daily.

The study is the latest to suggest aspirin offers benefits beyond relieving headaches and body aches and reducing fevers. Aspirin is a common anti-inflammatory painkiller that can be used to relieve symptoms of arthritis and prevent second heart attacks and other ailments. Previous research has indicated it also may protect against colorectal cancer. It is possible that aspirin acts to reduce inflammation in cancer, which can trigger tumour growth.

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.

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.