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Advanced Targeted Therapies Effective As First-line Treatment For Lung Cancer

August 11, 2009
International Association for the Study of Lung Cancer
Several new studies show that targeted therapies, as first-line treatment, have the potential to slow cancer growth and improve patient outcomes.

The world's top lung cancer specialists, medical professionals and researchers are convening in San Francisco, CA for the 13th World Conference on Lung Cancer (WCLC), July 31- August 4, organized by the International Association for the Study of Lung Cancer (IASLC). According to a series of studies presented August 1 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."

Clinical Outcomes Of Patients With Epidermal Growth Factor Receptor (egfr) Mutations In Ipass

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 presented this study August 1, 2009.

Efficacy And Safety Of Erlotinib As First-line Maintenance In Nsclc Following Non-progression With Chemotherapy

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 presented this study on August 1.

Molecular Markers And Clinical Outcome With Erlotinib: Results From The Phase Iii Placebo-controlled Saturn Study Of Maintenance Therapy For Advanced Nsclc

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 presented this study on August 1.

Vandetanib Plus Docetaxel Versus Docetaxel As Second-line Treatment For Patients With Advanced Non-small Cell Lung Cancer

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 presented this study on August 1.

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 

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 presented this study on August 3.

Efficiency Of Maintenance Erlotinib Versus Placebo In Patients With Unresectable Stage Iii Non-small Lung Cancer (nsclc) Following Concurrent Chemoradiation

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 presented this study on August 3.

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International Association for the Study of Lung Cancer. "Advanced Targeted Therapies Effective As First-line Treatment For Lung Cancer." ScienceDaily. ScienceDaily, 11 August 2009. <>.
International Association for the Study of Lung Cancer. (2009, August 11). Advanced Targeted Therapies Effective As First-line Treatment For Lung Cancer. ScienceDaily. Retrieved May 23, 2017 from
International Association for the Study of Lung Cancer. "Advanced Targeted Therapies Effective As First-line Treatment For Lung Cancer." ScienceDaily. (accessed May 23, 2017).