Novel therapies reduce toxicity, improve outcomes

SAN FRANCISCO, August 1, 2009 The world’s top lung cancer specialists, medical professionals and researchers are convening this week in San Francisco, CA for the 13th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer (IASLC). According to a series of studies presented today at the WCLC, targeted therapies, as first-line treatment, have the potential to slow cancer growth and improve patient outcomes. Unlike traditional chemotherapy-based treatments, which destroy cancerous and non-cancerous cells alike, targeted therapies are designed to inhibit only cancer cell replication and tumor growth and are generally well tolerated by patients.

“The studies presented at the WCLC confirm that targeted therapies are on the forefront of treatment innovation and show improved efficacy and prolonged progression-free survival time compared to chemotherapy and combination treatments,” said David Gandara, M.D., WCLC program chair. “Moreover, since the medicines are orally administered, patients can receive treatment in-home versus in a hospital setting, easing the burden on patients and caregivers.”

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CLINICAL OUTCOMES OF PATIENTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN IPASS (IRESSATM PAN ASIA STUDY) (ABSTRACT # B9.5)

An epidermal growth factor receptor (EGFR) is a protein found on the surface of cells to which an epidermal growth factor (EGF) binds. When an EGF attaches to an EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. An EGFR is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively in the presence of an EGF. The drug gefitinib is intended to attach to the EGFR and, thereby, inhibit the attachment of EGF and stop cancer cell division.

IPASS is a randomized phase III study that compared oral gefitinib with chemotherapy as first-line therapy and analyzed the treatment efficacy by EGFR mutation status. Of 1,217 enrolled patients in IPASS, 437 samples were available to assess for EGFR mutation, and 261 were found to be EGFR mutation-positive. The study assessed the clinical outcomes of objective response rate and progression-free survival among patients with an EGFR mutation versus those without.

“Our findings show that gefitinib had longer progression-free survival and greater objective response rate compared to chemotherapy in patients with EGFR mutations,” said Tony Mok, M.D., lead author and professor of clinical oncology at the Chinese University of Hong Kong. “Most notably, we found that responses to both gefitinib and chemotherapy were observed in the small group of patients with T790M mutations, which have previously been reported to be associated with resistance to EGFR tyrosine kinase inhibitors.”

Dr. Mok will present this study on Saturday, August 1, 2009 at 3:20 pm PT in Moscone West, Room 2001-2005, Level 2.

EFFICACY AND SAFETY OF ERLOTINIB AS FIRST-LINE MAINTENANCE IN NSCLC FOLLOWING NON-PROGRESSION WITH CHEMOTHERAPY: RESULTS FROM THE PHASE III SATURN STUDY (ABSTRACT # A2.1)

Erlotinib is an effective and well-tolerated treatment for patients with advanced non-small cell lung cancer (NSCLC) whose disease has progressed after chemotherapy, aimed at extending survival. The phase III SATURN study was initiated to evaluate the efficacy and safety of erlotinib as a first-line maintenance therapy following chemotherapy for patients whose cancer had not progressed following initial treatment.

Erlotinib targets a protein called the epidermal growth factor receptor (EGFR). EGFR, which helps cells divide, is found at abnormally high levels on the surface of many types of cancer cells, including many cases of NSCLC.

The study enrolled 1,949 patients, and 889 of which did not have progressive disease following four cycles of chemotherapy and were randomized to 150 mg/day of erlotinib or placebo. Patients who received erlotinib experienced significantly prolonged progression-free survival (PFS) over those on placebo a 29 to 31 percent reduction in risk of progression with erlotinib or an increase of progression-free survival time of 41 to 45 percent. The disease control rate (including patients whose tumors disappeared or reduced in size or did not get larger) was 40.8 percent with erlotinib versus 27.4 percent with placebo. The study also met a key secondary endpoint of extending overall survival in patients who received erlotinib immediately after initial chemotherapy. A statistically significant improvement in overall survival was seen in this pre-planned final analysis of the total patient population.

Further, a PFS benefit was seen with erlotinib regardless of the patient’s gender, smoking history, ethnicity, or whether testing indicated the patient’s tumor expressed the EGFR.

“The results of this study broaden the patient population for whom erlotinib can be effective,” said Federico Cappuzzo, M.D., lead author and professor and vice director of the Department of Medical Oncology at Instituto Clinico Humanitas in Milan, Italy. “Given that lung cancer is the leading cause of cancer deaths worldwide and that NSCLC is the most common and deadly form of lung cancer, the PFS time that erlotinib can offer represents a significant advance in treatment of this disease.”

Dr. Cappuzzo will present this study on Saturday, August 1 at 2:30 pm PT in Moscone West, Room 2001-2005, Level 2.

MOLECULAR MARKERS AND CLINICAL OUTCOME WITH ERLOTINIB: RESULTS FROM THE PHASE III PLACEBO-CONTROLLED SATURN STUDY OF MAINTENANCE THERAPY FOR ADVANCED NSCLC (ABSTRACT # B9.1)

In another segment of the SATURN study, researchers further examined the efficacy of erlotinib as a maintenance therapy in non-progressive disease patients after first-line platinum-containing chemotherapy. Currently the indications for erlotinib are limited to its use as a second- or third-line agent after failure of first-line chemotherapy.

To expand the potential for the use of erlotinib, Wolfram Brugger, M.D., Ph.D., head of the Department of Hematology, Oncology and Immunology at Schwarzwald-Baar Clinic in Germany, and his team of researchers conducted the phase III, placebo-controlled SATURN study to evaluate the efficacy of erlotinib as a maintenance therapy.

Dr. Brugger enrolled a total of 889 non-small cell lung cancer (NSCLC) patients and treated them with either 150mg/day of erlotinib or placebo after four cycles of platinum-based doublet chemotherapy. Researchers evaluated molecular markers including EGFR protein and EGFR gene copy number, EGFR- and KRAS-mutations and EGFR polymorphism in order to potentially identify predictive markers for erlotinib therapy.

Both arms of the trial were well represented in patient and disease characteristics, specifically regarding biomarker status. Dr. Brugger and his team determined that the use of erlotinib provided a clinical benefit in terms of both progression-free and overall survival for all patients, regardless of the status of biomarkers.

“This study demonstrates the tremendous potential for erlotinib and the potential for its expanded use as a maintenance therapy,” says Dr. Brugger. “The addition of an effective tool physicians can use to maintain a cancer-free state in their patients is crucial to prolonged survival.”

Dr. Brugger will present this study on Saturday, August 1 at 2:30 pm PT in Moscone West, Room 2001-2005, Level 2.

VANDETANIB PLUS DOCETAXEL VERSUS DOCETAXEL AS SECOND-LINE TREATMENT FOR PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER: A RANDOMIZED, DOUBLE-BLIND PHASE III TRIAL (ZODIAC) (ABSTRACT # C2.2)

Vandetanib is an orally administered medication that targets two receptors already known to play a role in non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These receptors are targeted separately by other drugs, but vandetanib is the first drug designed to target both.

In previous research, the addition of vandetanib to chemotherapy was shown to prolong the progression-free survival (PFS) and improve response rate in patients with previously treated advanced NSCLC. To expand upon these findings, researchers conducted a phase III study to further evaluate whether vandetanib plus chemotherapy prolonged the PFS of advanced NSCLC patients when compared to chemotherapy alone.

Over two years, 1,391 patients were recruited to participate in the study. Patients were randomized to receive chemotherapy with vandetanib or chemotherapy with the placebo. A statistically significant difference in PFS was seen (HR = 0.79) in favor of vandetanib. The median PFS time was 17.3 weeks in the vandetanib arm versus 14 weeks in the control arm. While there was no statistical difference in overall survival, a significant improvement in objective response rate was observed. Vandetanib treatment was also associated with a statistically significant improvement in symptoms related to the underlying cancer.

“Clearly in a disease as heterogeneous as lung cancer, the need to target multiple pathways has become paramount. This agent, targeting two key pathways critical for non-small cell lung cancer growth and metastasis, is novel and could play a key role,” said Roy S. Herbst, M.D., Ph.D., chief of thoracic medical oncology at the University of Texas M.D. Anderson Cancer Center and the study’s lead author. “The fact that more patients had an improvement in the symptoms from their lung cancer suggests that the drug could be important for the future management of this disease.”

Dr. Herbst will present this study on Saturday, August 1, 2009 at 10:40 am PT in Moscone West, Room 2007-2011, Level 2. Please note that this research was also presented at the 2009 ASCO Annual Meeting.

A RANDOMIZED PHASE III STUDY OF GEFITINIB VERSUS STANDARD CHEMOTHERAPY (GEMCITABINE PLUS CISPLATIN) AS A FIRST-LINE TREATMENT FOR NEVER-SMOKERS WITH ADVANCED OR METASTATIC ADENOCARCINOMA OF THE LUNG (ABSTRACT # PRS.4)

Doctors are constantly on the look out for advancements to better treat and tailor cancer treatment to the individual. Targeted therapies have been introduced that have improved standard chemotherapy approaches. Combining targeted therapies in specific patients with lung cancer may reduce the need for chemotherapy, and increased understanding of the targets involved in the pathogenesis of lung cancer may help to individualize drug therapy. One of these targeted therapies is gefitinib, a tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR), a protein that causes cancer cells to divide. Gefitinib has shown high response rate and extended survival in never-smoker lung cancer patients, especially in those with an EGFR mutation.

In this randomized phase III trial, researchers sought to compare the efficacy of gefitinib as a first-line treatment with standard chemotherapy in patients who were never-smokers. Investigators randomized 309 never-smokers living with late-stage lung cancer into two groups. One group received gefitinib and the other group received chemotherapy.

While the gefitinib did not show an improved overall survival, results showed the group receiving gefitinib had a higher response rate and a significantly better progression-free survival (PFS, length of time during and after treatment when a patient’s disease does not worsen) than those receiving chemo. Also, high-grade toxicity was less common in the gefitinib group than in the chemotherapy group.

Additionally, in the gefitinib group, PFS in the mutation-negative subgroup was shorter than that of the mutation-positive group (with a median of 2.1 vs. 8.4 months). There was no difference between these two subgroups in the chemotherapy group.

“Gefitinib did not improve overall survival over the standard chemotherapy,” said Jin S. Lee, M.D. of the National Cancer Center Korea in Goyang, Korea. “However, a promising survival outcome along with high overall response rate and better toxicity profile suggests that gefitinib might be a reasonable first-line therapy for this group of never-smoker lung cancer patients.”

Dr. Lee will present this study on Monday, August 3 at 9:35 am PT in Moscone West, Ballroom, Level 3.

EFFICIENCY OF MAINTENANCE ERLOTINIB VERSUS PLACEBO IN PATIENTS WITH UNRESECTABLE STAGE III NON-SMALL LUNG CANCER (NSCLC) FOLLOWING CONCURRENT CHEMORADIATION (D0410, NCT00153803) (ABSTRACT # C6.1)

Currently, the role of maintenance therapy following concurrent treatment with chemotherapy and radiotherapy (cCRT) in patients with unresectable stage III non-small lung cancer (NSCLC) remains undefined, and concern has been noted with maintenance therapies. To examine alternative treatment options, this trial was designed to evaluate the effectiveness of maintenance erlotinib following cCRT in unresectable stage III NSCLC patients.

In this upfront, randomized, placebo-controlled phase III trial, scientists randomly assigned 243 patients with unresectable stage III NSCLC to receive erlotinib or placebo daily following their cCRT.

In the intent-to-treat analysis, there was no statistically significant difference in the primary endpoint of progression-free survival (PFS). In a retrospective, subset analysis of subjects dispensed erlotinib following cCRT, their median PFS rate was 13.5 months compared to 10.4 months for subjects randomized to placebo. Furthermore, the median overall survival rate was 30.4 months for erlotinib compared to only 25.1 months for the placebo.

Time to disease progression was delayed in the intent-to-treat analysis for participants randomized to erlotinib and significantly delayed in subjects dispensed erlotinib in the retrospective, subset analysis.

“Based on these trends NSCLC patients exposed to maintenance erlotinib after cCRT treatment, we can conclude that this maintenance therapy may prolong disease progression,” says James R. Rigas, M.D., lead author and Director of the Comprehensive Thoracic Oncology Program at Dartmouth-Hitchcock Norris Cotton Cancer Center. “While more research is needed, we are encouraged by these results and believe erlotinib could be a new maintenance therapy for high risk, stage III patients.”

Dr. Rigas will present this study on Monday, August 3 at 10:30 am PT in Moscone West, Room 2002-2004, Level 2.

ABOUT LUNG CANCER

Lung cancer is the uncontrolled growth of abnormal cells in one or both lungs. As they grow, the abnormal cells can form tumors and impede the function of the lung, which is to provide oxygen to the body via the blood. Approximately 1.3 million new cases of lung cancer will be diagnosed this year, and the disease remains the leading cause of cancer deaths worldwide.

Founded in 1972, the International Association for the Study of Lung Cancer (IASLC) is an international organization of 2,000 lung cancer specialists, spanning 53 countries. IASLC members work towards developing and promoting the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer. IASLC’s mission is to enhance the understanding and education of lung cancer to scientists, members of the medical community and the public. In addition to the biannual meeting, the IASLC publishes the Journal of Thoracic Oncology, a prized resource for medical specialists and scientists who focus on the detection, prevention, diagnosis and treatment of lung cancer.

Women who have premature menopause because of medical interventions are at an increased risk of developing lung cancer, according to a new study published in the International Journal of Cancer. The startling link was made by epidemiologists from the Universit de Montral, the Research Centre of the Centre Hospitalier de l’Universit de Montral and the INRSInstitut Armand-Frappier.

“We found that women who experienced non-natural menopause are at almost twice the risk of developing lung cancer compared to women who experienced natural menopause,” says Anita Koushik, a researcher at the Universit de Montral’s Department of Social and Preventive Medicine and a scientist at the Research Centre of the Centre Hospitalier de l’Universit de Montral. “This increased risk of lung cancer was particularly observed among women who had non-natural menopause by having had both their ovaries surgically removed.”

The scientists studied 422 women with lung cancer and 577 control subjects at 18 hospitals across Montreal, Quebec, Canada. They assessed socio-demographic characteristics, residential history, occupational exposures, medical and smoking history, and (among women) menstruation and pregnancy histories.

“A major strength of this study was the detailed smoking information which we obtained from all study participants; this is important because of the role of smoking in lung cancer and because smokers generally have lower estrogen levels than non-smokers,” says Dr. Koushik. “Although smoking is the dominant cause of lung cancer, we know other factors can play an important role in enhancing the impact of tobacco carcinogens; this research suggests that in women hormonal factors may play such a role.”

Women were considered menopausal if their menstrual periods had stopped naturally, surgically (by hysterectomy with bilateral surgical ovary removal) or because of radiation or chemotherapy. Women who had at least one remaining ovary and who still had their menstrual periods at the time of diagnosis/interview were classified as premenopausal. Among participants with natural menopause, the median age for attaining menopause was 50 years old; among those with non-natural menopause, it was at 43 years.

“Non-natural menopause, particularly surgical menopause, may represent an increased risk with younger age at menopause given that surgery is usually done before natural menopause occurs. It’s possible that vulnerability to lung cancer is caused by early and sudden decrease in estrogen levels or potentially long-term use of hormone replacement therapy and further research is needed to explore these hypotheses,” says Jack Siemiatycki a professor at the Universit de Montral’s Department of Social and Preventive Medicine and a scientist at the Research Centre of the Centre Hospitalier de l’Universit de Montral.

About the Study:
The article “Characteristics of menstruation and pregnancy and the risk of lung cancer in women,” published in the International Journal of Cancer, was authored by Anita Koushik and Jack Siemiatycki of the Universit de Montral and Research Centre of the Centre Hospitalier de l’Universit de Montral and Marie-Elise Parent of the INRSInstitut Armand-Frappier.

Partners in Research:
This study was funded by the Canadian Institutes of Health Research, the Fonds de la recherche en sant du Qubec and the Guzzo-SRC Chair in Environment and Cancer.

On the Web:
About cited article from International Journal of Cancer: http://www3.interscience.wiley.com/cgi-bin/fulltext/122380525/PDFSTART
About the Universit de Montral: http://ww.umontreal.ca/english
About the Research Centre of the Centre Hospitalier de l’Universit de Montral: http://www.chumtl.qc.ca/crchum.en.html
About the Environmental Epidemiology and Population Health Research Group: http://www.environepi.ca/
About INRSInstitut Armand-Frappier: http://www.iaf.inrs.ca/anglais/centre_bref.html

The University of Nottingham has developed a new way of scanning for lung cancer, a method which could revolutionize the way that the early stages are caught and treated.

The new scan uses antibodies to create a reaction on lung scans, which only occur when the presence of cancer within the lungs are detected.

The image that results are clear enough to allow doctors to treat cancer aggressively, long before tumors gave developed. This early catch has the potential to save thousands.

To see pictures of these scans, click here.

As soon as there is an immune system response to cancer, we can pick up the antibodies which teh body produces, chairman of the company Onicimmune, which was created to further develop this new technology, was quotes in the UK paper, The Daily Mail.

The overall performances of the test compared to a CT scan is better, because a scan produces so many false positives.

New data from several studies evaluating new techniques for early diagnosis and treatment of lung cancer are being presented at the first European Multidisciplinary Conference on Thoracic Oncology (EMCTO) in Lugano, Switzerland (1-3 May 2009).

“Lung cancer is the leading cause of cancer deaths worldwide and also in Europe. One of the reasons for this is that symptoms of lung cancer are very often lacking or occur only late in the course of the disease,” said Prof Rudolf M. Huber from the University of Munich in Germany.

“The prognosis of lung cancer patients is very dependent on how advanced their disease is. In stage I for example, where the tumour has not yet spread, 5-year-survival rates are about 70%; whereas in stage IV, where it has metastasised to other parts of the body, survival is about 1%. Even for patients with locally advanced tumours, survival over 5 years is only about 10%. Therefore every effort should be undertaken to diagnose early in the course of the disease.”

“Developing better tools for distinguishing between lung cancer and other lung diseases will help us offer greater hope for patients,” added Prof Huber.

In one study presented at the conference, Italian researchers compare two computed tomography techniques for diagnosing indeterminate lung lesions, finding that a form of single-photon emission computed tomography could offer an alternative method in situations where positron emission tomography is not available.

In another abstract, UK scientists report that a new approach to diagnosis that ensures a patient has had a chest CT scan before they attend a clinic has the potential to reduce the time between their first abnormal chest X-ray and final diagnosis.

Also during the conference, Greek investigators suggest that they may have found a new factor that will help indicate a patient’s prognosis at the time of diagnosis. Their work indicates that the expression of specific cell surface molecules on tumour cells correlates with clinical parameters. The results “could comprise a promising prognostic factor in lung carcinomas, thus presenting exciting possibilities for the future.”

The EMCTO Conference is co-organized by the European Society for Medical Oncology (ESMO), the European Society for Therapeutic Radiology and Oncology (ESTRO), the European Society of Thoracic Surgeons (ESTS) and the European Respiratory Society (ERS).

European Society for Medical Oncology

Relying on principles similar to those that cause Jell-O to congeal into that familiar, wiggly treat, University of Michigan researchers are devising a new method of detecting nitric oxide in exhaled breath.

Because elevated concentrations of nitric oxide in breath are a telltale sign of many diseases, including lung cancer and tuberculosis, this development could prove useful in diagnosing illness and monitoring the effects of treatment.

Assistant professor of chemistry Anne McNeil and graduate student Jing Chen will discuss the work at the spring meeting of the American Chemical Society in Salt Lake City, Utah.

McNeil and Chen work with molecular gels, which differ from Jell-O in being made up of small molecules, rather than proteins. But there are also key similarities, McNeil said.

“In both Jell-O and molecular gels, you can use heat to dissolve the material, which then precipitates out into a gel structure. This gel structure is basically a fibrous network that entraps solvent in little pockets,” she said.

The researchers wanted to design a material made up of molecules that would organize themselves into a gel when prompted by particular cue —in this case, the presence of nitric oxide and oxygen. Other research groups have achieved similar feats with materials whose solubility changes when exposed to triggers (for example, a change in pH). But McNeil had the idea of promoting the process, known as stimuli-induced gelation, by changing the stackability of the molecules that make up the material.

“We took the approach of designing a molecule that has a shape that won’t pack together with other, identical molecules very well, but will change into a more stackable shape on exposure to nitric oxide,” McNeil said. When the molecules stack together, gelation occurs.

Because it’s easy to see when the material stops flowing and turns into a gel, this method of nitric oxide detection is simpler and less subject to interpretation than other detection methods such as colorimetry and spectroscopy.

“I like the simplicity of not needing an instrument and just being able to flip the sample vial over and see if a gel has formed,” McNeil said. At this point, the new technique isn’t sensitive enough for clinical use, but McNeil and Chen are working to improve its sensitivity. They’re also extending the approach to design materials that would use stimuli-induced gelation to detect hazardous materials, such as explosives.

McNeil and Chen reported earlier stages of their work in a paper published in the Journal of the American Chemical Society in November 2008 at: http://pubs.acs.org/doi/full/10.1021/ja807651a

U-M provided funding for the research.

For more information:

Anne McNeil—http://www.umich.edu/~michchem/faculty/mcneil/index.html
American Chemical Society—http://portal.acs.org/portal/acs/corg/content

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