Originally published April 8.
Formal guidelines from professional medical societies now recommend that all patients with advanced lung adenocarcinomas should be tested for alterations in EGFR and ALK genes, which can help doctors then decide whether these patients will benefit from certain targeted tyrosine kinase inhibiting drugs.
The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology released on April 3 a document, entitled "Molecular Testing Guidelines for the Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors." The guidelines have been published in the Archives of Pathology & Laboratory Medicine, the Journal of Thoracic Oncology, and The Journal of Molecular Diagnostics.
"The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an EGFR or ALK inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests," wrote Neal Lindeman of Brigham & Women's Hospital and other colleagues from the three professional societies in the collaboratively developed, published guidelines.
Personalized medicine advocates lauded the release of the guidelines as a step toward standardizing molecular testing practices in lung cancer treatment. "We commend AMP, CAP, and IASLC for their multidisciplinary approach on this impressive effort," Amy Miller, VP of public policy at PMC, said in a statement. "The guidelines will provide meaningful answers to clinical questions that will ensure a uniform approach to molecular testing for lung cancer which will improve patient care."
Clearer guidance on when and how molecular testing should be performed and which markers should be gauged in lung cancer patients will help oncologists personalize treatment with pharmacogenetically targeted drugs. The US Food and Drug Administration in 2011 approved Xalkori, a treatment for non-small cell lung cancer patients with ALK rearrangements.
Although the FDA has not yet approved any drugs specifically for NSCLC patients with EGFR mutations, many physicians at academic cancer centers in the US are already testing patients for these mutations and prescribing EGFR inhibitors, such as Roche/Genentech's Tarceva, to those who have a shot at response. Boehringer Ingelheim, meanwhile, has reported impressive progression-free survival in advanced adenocarcinoma patients with EGFR-mutated tumors after being treated with the investigational drug afatinib (PGx Reporter 6/6/2012).
These latest guidelines, however, are somewhat counter to a paper published last year that suggested it may be more cost effective to administer ALK testing with the help of enrichment strategies to hone in on patients who are more likely to harbor such rearrangements. In a paper published in the British Journal of Cancer, University of Colorado researchers Adam Atherly and Ross Camidge wrote that broadly testing all advanced NSCLC patients in order to identify the between 3 percent and 5 percent of those with ALK rearrangements did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained. However, by applying an enrichment strategy, where clinicians target testing to patients with certain characteristics that make them more likely to harbor ALK mutations — such as patients with adenocarcinomas who have EGFR-negative mutations, and were low or non-smokers — the researchers found that oncologists could decrease the cost per QALY gained to around $4,756 (PGx Reporter 3/28/2012).
Test makers and personalized drug developers have criticized this economic analysis on a number of fronts, however, most importantly pointing out that histology-driven or phenotype-based enrichment strategies would still miss patients who would benefit from targeted treatment.
From Graded Evidence to Guidelines
In order to develop the guidelines, representatives from AMP, CAP, and IASLC came together and screened more than 1,500 articles published from January 2004 to February 2012 and identified more than 500 articles of interest. The co-chairs and the members of the writing and advisory panels then developed draft recommendations based on information culled from these articles and held a public meeting to discuss them. Finally, the experts issued 37 guideline items addressing 14 subjects, of which 15 of the items received an A or B grade.
The published guidelines explain that experts only used evidence they deemed to have an A or B grade to issue "recommendations." The groups gave an A or B grade to evidence "that can be trusted to guide clinical practice in all or in most situations," the published guidelines state. The groups used grade C evidence, meanwhile, to support "suggestions" that doctors should consider more carefully before applying. Evidence to which the experts gave a D grade was considered "weak" and was not used to support recommendations or suggestions. For topics where Grade C or above evidence was not available, the groups issued an "expert consensus opinion."
For example, the experts recommended that doctors test patients for EGFR mutations at the time they are diagnosed with advanced-stage disease (stage IV), if they are "suitable for therapy," or when patients who previously had lower-stage disease experience recurrence or progression and haven't been tested yet. The guidelines give the same testing timeframe when it comes to assessing ALK rearrangements, but only as a suggestion.
The expert consensus opinion is that doctors should test for EGFR mutations and ALK rearrangements when patients are diagnosed with Stage I, II, or III disease, but the group noted that "the decision to [test] should be made locally by each laboratory, in collaboration with its oncology team."
The experts are of the opinion that testing labs should issue results from EGFR and ALK tests within 10 working days. Furthermore, the guidelines prefer that labs use any validated EGFR testing method "with sufficient performance characteristics." For selecting patients for treatment with an ALK inhibitor, they recommended fluorescence in situ hybridization testing that utilizes dual-labeled break-apart probes.
Ultimately, the guidelines recommended healthcare providers prioritize limited tissue samples from patients for EGFR and ALK testing over other molecular markers. Specifically, the experts recommended doctors prioritize EGFR mutation testing for patients with lung adenocarcinomas and that physicians test for ALK rearrangements after the patient has been tested for EGFR mutations.
As to whether labs must test all adenocarcinomas for alterations in both EGFR and ALK, the experts issued the consensus view that labs "may implement testing algorithms to enhance the efficiency of molecular testing of lung adenocarcinomas, provided the overall turnaround time requirements are met."
Lung adenocarcinomas are the most common type of lung cancer, in which the disease is commonly found in the outer regions of the organ and starts in cells that secrete mucus-like substances. Approximately 20 percent of patients with lung adenocarcinomas, which are a type of non-small cell lung cancer, harbor abnormalities in the ALK and EGFR genes. Most of the time, alterations in ALK and EGFR are mutually exclusive in a patients' tumor.
Market Impact
If these guidelines lead to standardized testing methods for alterations in EGFR and ALK genes, it will likely help stabilize markets for pharmacogenetically targeted drugs such as Tarceva, Xalkori, and afatinib, which is currently undergoing priority review at the FDA.
Anticipating the market launch of afatinib, sponsor Boehringer Ingelheim launched the "Let's Test" campaign last year (PGx Reporter 10/24/2012). Through this effort, the drug developer is hoping to encourage healthcare providers to collect tissue samples from their lung cancer patients early on and more readily test patients for EGFR mutations and ALK rearrangements.
Before launching the campaign, Boehringer's own research showed that many lung cancer patients who do receive ALK or EGFR testing don't receive test results early enough to influence a personalized treatment strategy. Furthermore, data collected by Ipsos US Oncology Monitor suggest that only 50 percent of NSCLC patients are being tested for EGFR mutations.
Lee James, Pfizer's senior medical director for Xalkori, noted that ALK testing rates among physicians have risen from 11 percent when the drug was first launched in 2011, to 60 percent currently. Most academic centers routinely test for ALK rearrangements and EGFR mutations, James said, adding that molecular testing in community oncology practices is also increasing.
"We believe these new guidelines will serve as a helpful resource to the lung cancer community by clarifying how and when testing should be conducted and reinforcing the importance of routine molecular testing as part of the lung cancer treatment paradigm," James said.
Lung tumor tissue samples are a precious resource when conducting molecular analysis in lung cancer patients. Since the guidelines tell doctors to prioritize testing for EGFR mutations and ALK rearrangements, "this guidance may help reduce the likelihood that a biopsy specimen might be used up by performing other molecular tests before an ALK or EGFR test is performed," James added.