For about half a century, outcomes for patients with solid tumors such as those of the lung and breast have improved by only 5%, despite a yearly investment of $5 billion in public sector funds for research. But targeted therapies are extending survival in patients with biomarkers such as EGFR mutations, and other biomarkers can predict chemotherapy sensitivity and toxicity.
Advances in tumor biomarkers signal true progress in the war against lung cancer, and many of these advances have already transitioned from the research lab to the clinic, according to an expert panel at the 2009 World Conference on Lung Cancer (WCLC) in San Francisco.
The panelists were:
|•||Thomas Lynch, MD, director, Yale Cancer Center in New Haven, Conn.|
|•||Vincent Miller, MD, associate attending physician, thoracic oncology service, Memorial Sloan-Kettering Cancer Center in New York.|
|•||Tony Mok, MD, professor, department of clinical oncology, Chinese University of Hong Kong.|
|•||Jean-Charles Soria, MD, PhD, professor, division of cancer medicine, Institut Gustave Roussy in Villejuif, France.|
|•||Joan Schiller, MD, chief of the division of hematology and oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center in Dallas.|
EGFR mutation testing
The success of erlotinib (Tarceva) and gefitinib (Iressa) for patients with EGFR mutations has ushered in an era of molecular medicine, according to Dr. Lynch. These drugs provide dramatic responses in a subset of patients, and EGFR mutations with exon 19 or exon 21 deletions best predict this response. In such patients, the response rate for these TKIs is about 70%, he said.
Yet patients treated with these drugs can develop resistance and researchers are only now beginning to understand the pathways that make the tumors resistant. Biomarkers that signal resistance to TKIs include the T790M mutation, mesenchymal epithelial transition (c-MET) amplification, KRAS mutations, and PTEN loss, Dr. Lynch said. All these pathways are now under study as potential targets for new therapies.
©ASCO/Todd Buchanan 2005
But in the meantime, the ability to test for EGFR mutation status is an important tool for clinicians. "I would argue that EGFR testing is ready for prime time," Dr. Lynch said. "Almost always, you can get an EGFR mutation test from a larger resection specimen, and as the technology gets better, we will get to the point of testing from fineneedle aspiration."
Dr. Lynch noted that because of the dramatic response seen in patients with EGFR mutations, TKIs should be considered as a first-line therapy in these patients. "It should be a care standard for certain patients who harbor these mutations," he said. For certain subsets of patients, including light and never smokers with adenocarcinoma—who are more likely to harbor the EGFR mutation— testing for the biomarker should be done as early in the course of therapy as possible, he added.
One study that has added to scientists' understanding of the role of EGFR mutation status in predicting response to TKIs is the Iressa Pan-Asia Study (IPASS), Dr. Lynch said. In this phase III, open-label study, first-line gefitinib was compared with carboplatin/paclitaxel in patients from East Asia who had advanced pulmonary adenocarcinoma and were former light smokers or had never smoked (New Engl J Med 361:947-957, 2009).
According to the results, the 12-month rate of progression-free survival (PFS) was 24.9% with gefitinib and 6.7% with standard chemotherapy. Those who had EGFR mutations fared significantly better on gefitinib than those who were negative for the mutation. In the mutation-positive group, PFS was longer among patients who received gefitinib than among those who received chemotherapy (P < .0001).
"The response rate of 70% in the mutation-positive patients [treated with gefitinib] was striking, compared with 1.1% in the mutation-negative patients," Dr. Mok said.
The IPASS researchers also analyzed whether the EGFR gene copy number by fluorescence in situ hybridization (FISH) was predictive of outcomes. FISH-positive status did seem to predict a better outcome on gefitinib, but 70% of the FISH-positive patients in the study population also had an EGFR mutation, Dr. Mok said.
They concluded that the treatment effect that seemed to derive from the EGFR gene copy number was actually motivated by the underlying EGFR mutation. "We've learned the importance of the EGFR mutations, and future studies on TKIs should be driven by patients with these mutations," Dr. Mok said.