Global Survey Reveals Suboptimal Molecular Testing Access in Lung Cancer Despite Broad Guidelines

NEW YORK – A new international survey of experts involved in the care of cancer patients suggests that the incorporation of molecular testing is lagging in lung cancer around the world due to a variety of factors, especially cost. 

The survey results point to the need to increase provider education that emphasizes the importance of molecular testing, according to the University of Memphis' Matthew Smeltzer, who recently presented the data at a lung cancer meeting hosted by the International Association for the Study of Lung Cancer (IASLC). 

In updated guidelines published last year, the College of American Pathologists (CAP), the IASLC, and the Association for Molecular Pathology (AMP) recommended that before prescribing targeted therapies, at a minimum, all patients should be tested for mutations in EGFR, ALK, and ROS1. The expert groups now also support the use of next-generation sequencing multi-gene panels over single-gene testing, and if NGS panels are performed, they recommend it may be useful to also gauge BRAF, ERBB2, MET, RET, and KRAS. There needs to be more evidence on these genes before a stronger recommendation can be made.  

However, the survey conducted by the IASLC showed that molecular testing is not being performed as widely as expert groups recommend, which means that only a minority of lung cancer patients are benefiting from targeted precision oncology drugs. According to the survey, presented at IASLC's 2019 World Conference on Lung Cancer earlier this month, although two-thirds of those ordering testing and treating patients indicated they were aware of the CAP/IASLC/AMP guidelines, 61 percent of respondents estimated that less than 50 percent of lung cancer patients were getting recommended testing. 

The survey, funded by AstraZeneca, contained more than 100 questions and was distributed online to around 34,600 IASLC members and providers worldwide in seven languages. Around 2,500 providers from more than 100 countries responded –- 56 percent from developing and 44 percent from developed countries. 

Among the respondents, most were oncologists, followed by scientists, thoracic surgeons, pulmonologists, and pathologists. Fifty-two percent of the respondents were from Asia, 19 percent from Europe, 11 percent from Latin America, 11 percent from the US or Canada, and 7 percent were from other regions. 

Around 40 percent of respondents said they weren't satisfied with the conditions of molecular testing in their country, noting that it takes too long to get results, issues with sample quality, and difficulty understanding results. 

Specifically, more than a third of providers in the survey said they had trouble understanding test results. Some NGS panels gauge hundreds of genes, and physicians have previously complained about receiving reports for some patients that are more than a hundred pages long. 

Meanwhile, lengthy test turnaround times and the quality of requisitioned samples are difficulties that have long plagued clinical trials using NGS testing to investigate the efficacy of precision oncology therapeutic strategies. These difficulties are also captured in this survey. For example, among those surveyed, 47 percent indicated that in their country there was no policy or strategy to improve the quality of the tissue samples. 

However, cost, by far, was the most commonly cited barrier to molecular testing in the survey. 

In an interview Smeltzer acknowledged that there is definitely country-to-country variability in terms of which genes are being tested and in the use of single-gene tests and multi-gene panels, and these differences may be due in large part to variations in coverage. An expert advisory committee that's helping researchers interpret the latest survey results has suggested that this variability may be reduced if the field can standardize which genes are included in NGS panels.  

IASLC's survey comes as some of the biggest precision oncology successes are happening in lung cancer. There are now third-generation EGFR inhibitors that can shut down resistance mutations, and new ALK inhibitors that can benefit patients who develop brain metastasis. 

Molecularly defined subsets of NSCLC that previously didn't have targeted treatment options soon will. The US Food and Drug Administration has granted breakthrough therapy designation to several drugs to treat NSCLC characterized by MET exon 14 skipping mutations, including crizotinib (Pfizer's Xalkori), Novartis' capmatinib, Merck KGaA's tepotinib. 

In addition, at this same lung cancer conference, researchers presented data from the Phase I/II LIBRETTO-001 study, in which 68 percent of 105 heavily pretreated NSCLC patients with RET fusions saw their tumors shrink after treatment with Eli Lilly's selpercatinib, and among patients with brain metastasis, the objective response rate was 91 percent.

These are all rare biomarkers that in order to be identified in lung cancer patients would require a broad testing policy using an NGS panel. "Lung cancer is biomarker driven, and [NGS] testing is so important," said Jordan Clark, chief technical officer at diagnostics data analytics firm Diaceutics. However, the data collected by Diaceutics shows that even in the US, which has some of the best access to molecular testing in the world, NGS testing rates are only at around 50 percent. 

In European countries, such as Italy and Spain, NGS testing rates are below 25 percent. "This is due to reimbursement barriers," Clark said. "The costs are just not covered within those healthcare systems and that's been a real problem." 

He estimated that while some countries are doing single-gene testing of genes that have been known for several years, such as EGFR and ALK, the lack of NGS reimbursement will hinder access to newer drugs for even rarer molecularly defined indications, such as NTRK inhibitors larotrectinib (Bayer's Vitrakvi) and entrectinib (Roche's Rozlytrek) 

Although the IASLC survey similarly indicates testing rates are suboptimal globally, with some of the lowest molecular testing rates in Latin America, the genetic tests respondents said they most frequently ordered is EGFR, followed by ALK, KRAS, BRAF, ROS1, and HER2. 

When asked how providers choose patients for genetic testing, the survey revealed that female patients with adenocarcinomas who are young and never smokers may be prioritized for testing. Although this is the clinical profile of individuals most likely to harbor mutations in the genes recommended for testing, studies also show that using clinical factors to decide who to genetically test will miss a proportion of patients with mutations who can benefit from therapy. 

The CAP/IASLC/AMP guidelines recommend molecular testing for all lung adenocarcinoma patients, regardless of their age, sex, or smoking status. "That's an indication that even though the guidelines are broader, people are still deciding who to test based on these other characteristics," Smeltzer said. 

He also expressed concern that the survey revealed that 33 percent of all respondents indicated they were unaware of the most recent CAP/IASLC/AMP guidelines –- with some of the lowest awareness among respondents from Asia. Smeltzer hypothesized that the survey may not be fully capturing the scope of the problem. 

"The respondents were individuals interested [in molecular testing] enough to click on a link to take a survey about it," he noted. "If they were unaware, then they were probably less likely to answer the survey, so this could be an issue of selection bias." 

The fact that 33 percent were interested enough in molecular testing to take the survey but still weren't aware of the guidelines was still worrying to Smeltzer. "That's an area we can try to address with improved interventions," he said. 

Other surveys have also identified hindrances to molecular testing among cancer patients. For example, in 2017 Diaceutics estimated that 78,000 cancer patients in the US each year weren't getting personalized treatments because of incorrect, inconclusive, and delayed test results for 13 oncology biomarkers. Diaceutics looked into the impact of inadequate testing not only on patients but also on drugmakers' revenues and estimated that pharma was losing $8.3 billion annually by not investing in efficiencies such as better sample quality, faster turnaround times, and lower false-positive rates.  

Clark noted that Diaceutics will soon release updated data, which generally shows around a 10 percent increase in NGS testing rates in the US from 2018 to the first quarter of 2019. At the same time, over those two years, more complex lung cancer biomarkers, such as NTRK fusions, have emerged, which require different types of NGS detection methods. 

"Not all NGS testing is equal," he said, noting that not all panels on the market are able to detect novel RNA fusion transcripts, for example. As such, the next Diaceutics analysis will get even more detailed and try to evaluate whether the testing being done can detect all the latest biomarkers. 

While Smeltzer and his colleagues are digging further into the IASLC survey findings, the top take-home message is that many in the lung cancer community are dissatisfied with the state of molecular testing. The next phase of this project, Smeltzer said, is for IASLC to intensify education around molecular testing on a national and international scale to ensure more patients are getting access to precision medicine. 

"We have to look at how we're teaching medical school students about precision medicine," Clark said. "And, we have to look at how we're educating physicians treating patients around the guidelines, since they are updated so often." 

However, in Clark's view, drugmakers also have an important role to play in easing test access. "Pharmaceutical companies are still not paying enough attention and [spending enough] resources to commercialize [predictive] tests," Clark said. "They're not putting in the same effort commercializing the test as they put behind commercializing the drug."