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EGFR biomarkers turn NSCLC decision-making in a new direction
The ability to test patients for EGFR mutations has given physicians treating lung cancer new options.
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Until recently, cytotoxic chemotherapy was the standard of care for patients with advanced non–small cell lung cancer, despite its limited effectiveness and severe adverse effects. Within the past five years, new advances in the use of targeted therapies, specifically, those targeting the epidermal growth factor receptor, have changed the landscape of advanced lung cancer treatment.
Findings from several major studies indicated that patients with lung cancer who also had EGFR gene mutations had improved PFS and response rates when treated with an oral EGFR tyrosine kinase inhibitor vs. standard chemotherapy.
“Findings from several key studies have shown it is reasonable to initially treat a patient, who has certain EGFR mutations, with a pill. This is a somewhat foreign concept in the lung cancer field,” Edward S. Kim, MD, associate professor of medicine, chief of the section of head and neck medical oncology, and director of clinical research operations in the department of thoracic/head and neck medical oncology at The University of Texas M.D. Anderson Cancer Center, told HemOnc Today.
“In the past, most clinicians believed heavy chemotherapy was the best treatment for patients with advanced lung cancer, but as we find unique characteristics in an individual’s tumor, we realize there are effective treatments that will work specifically with that unique characteristic or biomarker,” Kim said.
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EGFR, which is often overexpressed in NSCLC, is linked to cancer proliferation. EGFR inhibitors improve outcome in select patients by inhibiting the activity of certain molecules involved in tumor growth and metastasis.
Currently, EGFR pathway inhibition using TKIs is established as a first-, second- and third-line treatment for NSCLC. In Europe, the EGFR TKI gefitinib (Iressa, AstraZeneca) is approved for all lines of therapy for patients with certain EGFR mutations; typically those found on exons 19 and 21. Globally, gefitinib and erlotinib (Tarceva, OSI Pharmaceuticals), another EGFR TKI, are approved as second- and third-line therapies.
Despite these new findings, many questions remain unanswered regarding how EGFR biomarkers should be incorporated into clinical decision-making when treating NSCLC. Individualized treatment for patients with EGFR mutations has been shown to improve certain outcomes in NSCLC, but there is still much to consider, according to the experts interviewed by HemOnc Today.
Landmark study
Initially, selecting patients with NSCLC for treatment with an EGFR TKI was unfamiliar territory for clinicians, according to Adi Gazdar, MD, professor of pathology and deputy head at the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas.
Predicting response was based mainly on identifying mutations that resulted in ligand-independent gene activation. It was realized later that the relationship between response to EGFR inhibitors and EGFR mutations was more complex because not all EGFR mutations are alike. Some confer resistance to tumor cells and, of considerable importance, mutation status is a strong predictor for selecting patients for appropriate treatment.
A key study contributing to the understanding of the use of EGFR TKIs is the Iressa Pan-Asia Study (IPASS), which reported beneficial outcomes among Asian populations with specific characteristics.
Results of IPASS, published in The New England Journal of Medicine in September, demonstrated that treatment with gefitinib was superior to treatment with carboplatin (Paraplatin, Bristol-Myers Squibb) plus paclitaxel (Taxol, Bristol-Myers Squibb) chemotherapy, when given as first-line treatment in East Asian patients with adenocarcinoma who were nonsmokers or former light smokers and who also had an EGFR mutation.
In the phase-3 study, Tony S.K. Mok, MD, professor in the department of clinical oncology at The Chinese University of Hong Kong, and colleagues enrolled patients from 87 centers in Hong Kong, elsewhere in China, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan and Thailand. Six hundred nine patients were randomly assigned gefitinib 250 mg and 608 patients were assigned chemotherapy with carboplatin and paclitaxel.
Among patients with the EGFR mutation, PFS was longer for those treated with gefitinib than for those treated with chemotherapy (HR=0.48; 95% CI, 0.36-0.64). Conversely, among patients without EGFR mutations, PFS was longer for those assigned chemotherapy vs. those assigned gefitinib (HR=2.85; 95% CI, 2.05-3.98).
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According to Mok and colleagues, EGFR-mutation status should be determined before the initial treatment of patients with pulmonary adenocarcinoma. “Ethnic origin, smoking status and histologic findings help to identify patients who have a high likelihood of having an EGFR mutation,” they wrote in the study.
“This biomarker allows us to safely administer a therapy that is oral and has fewer side effects,” Kim said. “We are no longer shot-gunning the treatment approach and giving everyone the same drugs. Now, we can individualize treatment for certain patients.”
In its September issue, The New England Journal of Medicine also published the results of a prospective study of screening for EGFR mutations in patients with NSCLC. The study, conducted by the Spanish Lung Cancer Group, Rosell and colleagues, demonstrated the usefulness of selecting patients for TKI therapy based on large-scale, EGFR-mutation screening.
From April 2005 through November 2008, the researchers screened 2,105 patients from 129 institutions in Spain; 350 patients had mutations.
Mutations were found more frequently in women (69.7%), never smokers (66.6%) and patients with adenocarcinomas (80.9%). Based on mutation status, 217 patients were assigned erlotinib 150 mg daily, of whom 197 were evaluable. The median follow-up was 14 months.
The median PFS was 14 months (95% CI, 11.3-16.7) and the median OS was 27 months (95% CI, 22.7-31.3) for patients assigned treatment with erlotinib, which was “an improvement over findings in patients with lung cancer that have been reported previously,” Rosell and colleagues wrote.
These findings suggested that large-scale screening was feasible and should play a role in clinical decision-making, said Gazdar, who wrote an editorial to accompany these two studies.
Additional evidence
In December, in the Journal of Clinical Oncology, results of another study that supported the IPASS findings were published. Data from the phase-3 Iressa in NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) trial indicated that patients positive for EGFR mutations had improved PFS and objective response rates when treated with an EGFR TKI compared with treatment with docetaxel (Taxotere, Sanofi-Aventis).
In the study, Douillard and colleagues examined several EGFR biomarkers and KRAS mutation status in 1,466 pretreated patients with NSCLC.
Patients were randomly assigned gefitinib 250 mg (n=733) or IV docetaxel 75 mg/m2 (n=733). As with other studies of EGFR mutations, the frequency of mutation-positive tumors was higher in women, those with adenocarcinoma histology, never smokers and Asians.
The researchers found no differences between treatment groups in patients negative for EGFR mutation. However, PFS (HR=0.16; 95% CI, 0.05-0.49) and overall response rate (42.1% vs. 21.1%; P=.04) were better in patients positive for an EGFR mutation treated with gefitinib vs. docetaxel.
KRAS mutation was not predictive of a difference in survival between the gefitinib group and the docetaxel group. No differences were observed for OS, PFS or response rates based on KRAS mutation status.
KRAS mutations
EGFR biomarker profiling primarily focuses on the selection of patients who are most likely to benefit from EGFR inhibitors, but of equal importance is the selection of patients for whom EGFR inhibitor therapy is not appropriate, namely those with KRAS mutations.
KRAS mutations, a downstream effector of the EGFR pathway, are seen in 20% to 30% of patients with NSCLC and are mutually exclusive to EGFR mutations. Study findings have shown that KRAS mutations are associated with a lack of sensitivity to EGFR TKIs and are a poor prognostic factor, according to Tarek Mekhail, MD, MSc, associate professor, University of Central Florida, and medical director, Thoracic Cancer Program at Florida Hospital Cancer Institute, Orlando.
“Patients with KRAS mutations do poorly regardless of whether they are treated with TKIs or with standard chemotherapy,” Mekhail said in an interview.
The use of cetuximab (Erbitux, ImClone) to treat colorectal cancer has been shown to be ineffective in patients with KRAS mutations. However, findings from a substudy of BMS099, conducted by Khambata-Ford and colleagues, indicated that the same may not be true in patients with KRAS mutations and NSCLC.
BMS099 was designed to be a supportive study to First-line in Lung Cancer with Erbitux, or FLEX, but with a primary endpoint of PFS.
FLEX study results were published in 2009 in The Lancet. The study assigned 1,125 patients with EGFR-positive advanced NSCLC to cetuximab plus cisplatin/vinorelbine or chemotherapy alone. The primary endpoint was OS. Results indicated that those patients assigned cetuximab plus chemotherapy had an improved OS vs. patients assigned chemotherapy alone (median 11.3 months vs. 10.1 months; P=.044).
In the BMS099 study, Lynch and colleagues assigned 338 patients to taxane/carboplatin plus cetuximab and 338 patients to taxane/carboplatin alone. The difference in PFS for cetuximab with chemotherapy (4.4 months) and chemotherapy alone (4.24 months) was small and not statistically significant.
OS was slightly higher (9.69 months) with the addition of cetuximab vs. chemotherapy alone (8.38 months); however, these results did not reach statistical significance either. The endpoint reaching statistical significance was overall response rate, which was improved in the combination therapy group (25.7%) vs. the chemotherapy alone group (17.2%; P=.007).
To further examine the negative results of the study, Khambata-Ford and colleagues conducted a retrospective analysis of BMS099 to assess the relationship between KRAS mutation and EGFR biomarker status and PFS, OS and overall response rate.
No significant associations were found between biomarker status, including KRAS and EGFR, and PFS, OS or overall response rate, according to the researchers.
“The problem is (that) collecting tissue samples has not been the focus of many lung cancer trials,” Kim said. “Here, they tested for KRAS and EGFR with [fluorescent in situ hybridization] and found no associations with outcomes. People thought they might see an association with KRAS because cetuximab and KRAS in colon cancer have an association, but these are two different cancers.”
In their conclusion, the researchers wrote that “despite low numbers that preclude firm conclusions, the consistency between BMS099 and other recent correlative studies is noteworthy, which indicated that cetuximab benefit is not likely to be associated with any of the markers initially considered obvious candidates.”
Standard mutation testing
Although a relationship between EGFR biomarkers and cetuximab has not been firmly established, there is evidence to support a relationship between EGFR mutations and TKIs. The experts who spoke with HemOnc Today said standardized EGFR biomarker testing is needed, but implementing it may be challenging.
Currently, there are no FDA guidelines on using EGFR mutations to prescribe these drugs, Kim said. In addition, although major cancer associations, such as the National Comprehensive Cancer Network, have released guidelines acknowledging the role of EGFR mutations in TKI treatment, they only say that clinicians should “consider using erlotinib for patients with advanced or metastatic cancer who have never smoked and whose tumors have a known active EGFR mutation.”
Although the National Comprehensive Cancer Network acknowledges the efficacy of using TKIs in EGFR-positive patients, there is still a struggle to get the EGFR mutations testing done in a timely manner. “Getting results can take as long as three weeks, which is too long for patients to wait for treatment,” Kim said.
A lack of action from the FDA may be due to the lack of improvement in OS in the major phase-3 studies on EGFR mutations.
“In a general population, these drugs have been proven to be similar to chemotherapy, as far as overall activity. … Although there may be no improvement in OS, if you give the TKIs to a patient with an EGFR-positive tumor, they will have higher response, longer PFS and a delay in the time until recurrence, not to mention the improved side effects and quality of life,” Kim said.
The ideal scenario for testing for EGFR mutations is similar to what is already standard for breast cancer tissue samples. “In breast cancer, tests are automatically done to test for hormonal status and HER-2 status,” Kim said.
“Clinicians would like pathologists, from a lung cancer standpoint, to automatically run EGFR-mutation tests. The test is essential and needed on the pathology report for making decisions about treatment.”
Another biopsy
M.D. Anderson Cancer Center’s thoracic program currently tests all patients enrolled into the BATTLE Program: Umbrella Protocol for Patients with NSCLC for mutation status in their thoracic molecular pathology research lab. BATTLE is a phase-2 study in which clinicians biopsy tissue in all patients upfront, then select a treatment that is best suited to the patient’s profile.
“BATTLE is special because clinicians often meet resistance in performing yet another biopsy in patients with lung cancer; but, in this study, we enrolled over 300 patients in less than three years and were able to successfully complete the trial,” Kim said.
Kim reported findings from this study at the recent American Association for Cancer Research Annual Meeting in Washington, D.C.
Kim and colleagues found that among patients treated with erlotinib in the EGFR-mutation–positive exploratory subgroup, there was a disease control rate of 71%. Kim said these results confirmed what was already known, but more importantly, the BATTLE study changes the standard of how lung cancer trials can be designed moving forward, proving that biopsy-required trials can be performed successfully in lung cancer.
Despite the complications and morbidity associated with lung cancer biopsies, many patients are willing to undergo them, provided it will influence their individual therapy, Gazdar told HemOnc Today. “If you explain this to patients, a surprisingly high percentage are willing to undergo another biopsy.”
Few would argue against making testing for mutation status standard practice, but standardization relies on having the ability to perform the test, which will come with time, according to Roy S. Herbst, MD, PhD, professor of medicine and the chief of thoracic medical oncology in the department of thoracic/head and neck medical oncology at M.D. Anderson Cancer Center.
“We are entering an era of lung cancer, when clinicians may have a specific treatment for 15% to 20% of patients,” he told HemOnc Today.
Standardization of testing for mutation status raises many issues, including experimenting with alternative techniques for testing and making treatment decisions.
Blood-based testing on horizon
Due to the hurdles clinicians face when testing tissue for mutation status, there is a movement toward faster and more accessible testing. One technique currently being explored is obtaining circulating tumor cells to test for EGFR mutations.
Clinicians aim to tailor treatment for patients with NSCLC based on their mutation status, which currently requires obtaining tissue samples to determine EGFR-mutation status. Yet, biopsying these samples is invasive and often results in complications. A potential alternative may be to perform a blood test to look for gene mutations.
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Researchers have found circulating tumor cells in the blood, but getting a sufficient amount in the proper form can be problematic, according to Gazdar.
“There are some promising research findings, and obviously a blood test is preferable to a biopsy, as complications and morbidity are much less, but this method is not state of the art and not ready for prime time,” Gazdar said.
However, a group from the Massachusetts General Hospital, Boston, led by Daniel A. Haber, MD, PhD, director of its cancer center, have published their results identifying EGFR mutations from the blood of NSCLC patients and also using circulating tumor cell technology to try to understand how these patients eventually become resistant to drugs such as erlotinib and gefitinib.
Their study, published in The New England Journal of Medicine in July 2008 by Shyamala Maheswaran, PhD, associate professor in the department of surgery at Harvard Medical School, Boston, and colleagues isolated circulating tumor cells from patients with metastatic NSCLC and known EGFR mutations. The correct mutation was identified from the circulating tumor cells in 19 of 20 cases, and in a few patients followed with serial analyses over time, the T790M resistance mutation was detected shortly before patients clinically became resistant to EGFR-directed treatment.
“This new technique is exciting but is not yet ready for general use in oncology clinics. We are currently embarking on a major project to collaborate with other centers around the country to collect circulating tumor cells from the blood stream and perform genetic testing. We hope our work will bring genotyping of cancers to the treating oncologist’s office faster and easier than existing technology,”
Lecia van dam Sequist, MD, MPH, assistant professor of medicine, at Harvard Medical School, told HemOnc Today.
Although many obstacles still exist within the framework of decision-making based on EGFR-mutation status in patients with NSCLC, the current findings, particularly from studies such as IPASS, represent progress toward standard testing for mutation status. If testing could be standardized it would result in more individualized therapy, ultimately leading to outcomes that are more beneficial for these select patients, according to the experts interviewed by HemOnc Today. – by Christen Cona
Are EGFR mutations primarily a concern among Asian populations?
For more information:
- Bell DW. Clin Cancer Res. 2006;doi:10.1158/1078-0432.CCR-06-0670.
- Douillard JY. J Clin Oncol. 2010;28:744-752.
- Gazdar AF. N Engl J Med. 2009;doi:10.1056/NEJMe0905763.
- Inoue A. PLoS Med. 2005;doi:10.1371/journal.pmed.0020013.
- Khambata-Ford S. J Clin Oncol. 2010;doi:10.1200/JCO.2009.25.2890.
- Kim ES. Lancet. 2008;372:1809-1818.
- Lynch TJ. J Clin Oncol. 2010;doi:10.1200/JCO.2009.21.9618.
- Maheswaran S. N Engl J Med. 2008;359:366-377.
- Mok TS. N Engl J Med. 2009;361:947-957.
- Rosell R. N Engl J Med. 2009;361:958-967.
- Shepherd FA. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.3996.