Abstract
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Lung cancer is the second most commonly diagnosed cancer worldwide, after breast cancer, with over 2.2 million new cases recorded in 2020 by the World Health Organization's International Agency for Research on Cancer. It also accounted for nearly 1.8 million deaths in that year, making it the leading cause of cancer mortality.
The disease is broadly divided into two types based on histology: Around 85% are non-small cell lung cancers (NSCLC) and about 15% are small cell lung cancers. Tumors can then be further characterized by histology but also according to the presence of certain genetic mutations that are known to predict disease biology, treatment, and outcomes.
The U.S. National Comprehensive Cancer Network (NCCN) NSCLC guidelines recommend molecular testing for 11 driver mutations for which targeted therapies may be available to ensure that patients receive the most appropriate treatment.1 These include mutations in BRAF, EGFR, HER2, and KRAS; ALK, RET, ROS1 and NTRK1/2/3 gene fusions; and METex14 skipping mutations. The guidelines also “strongly advise broader molecular profiling,” particularly as patients may be eligible for clinical trials for either established targeted agents or newly developed drugs.
Historically, testing for these mutations has been done on a one gene per test basis using techniques such as fluorescent in situ hybridization (FISH) and PCR. The advent of next-generation sequencing (NGS) technologies has opened up the possibility of sequencing multiple genes within a single tumor sample, providing the clinician with more information and the patients with potentially more treatment options than if they had only been tested for a single gene. NGS has “really allowed us to unlock the promise of precision oncology,” says Sandip Patel, professor of medical oncology at the University of California, San Diego.
Sandip Patel, professor of medical oncology, University of California, San Diego
Kathy Davy, vice president and general manager clinical sequencing solutions at Thermo Fisher Scientific, explains that “NGS targeted panels are increasingly becoming the testing option of choice to maximize the utility of what is often limited tissue available for genomic profiling.” Targeted panels are defined by the Centers for Medicare & Medicaid Services in the U.S. as “tests that identify somatic alterations known to occur in certain ‘hotspot' regions within specific genes of interest for cancer management.”2 The panels look for specific, predefined variants within the hotspot regions that typically represent response or lack thereof to corresponding targeted cancer therapies.
Kathy Davy, vice president and general manager, clinical sequencing solutions, Thermo Fisher Scientific
“Comprehensive genomic profiling (CGP) offers an additional level of detail, delivering a more complete picture of a patient's tumor,” says Davy. CGP tests also use NGS technology but aim to more comprehensively describe the genomic makeup of a tumor, by screening hundreds of genes, which may help identify underlying mechanisms of disease and guide clinical decision making. The method not only looks at mutations in relevant individual genes but can also analyze patterns of mutations across related genes in established cancer pathways and assess more complex biomarkers such as tumor mutational burden (TMB). Depending on its design, CGP testing may also include RNA sequencing to detect structural variations, such as translocations or large deletions, and to detect functional splicing mutations.
Other than reporting more biomarkers, CGP offers a number of advantages over targeted panel testing. For example, multi-bio-marker signatures such as microsatellite instability, TMB, and homologous recombination deficiency are only possible with large panels, and the tests offer somewhat future proofed designs because clinicians will already have the results when new targeted therapies are introduced.
Many advanced cancer patients have access to CGP or targeted panel testing as a covered benefit through their health insurance. Some U.S. commercial payers provide coverage specifically for FDA-approved companion diagnostic (CDx) assays, such as Thermo Fisher Scientific's Oncomine Dx Target Test, Foundation Medicine's FoundationOne®CDx and FoundationOne® Liquid CDx assays, and/or Guardant Health's Guardant 360 CDx test. Most payers allow for a broader array of tests, regardless of their approval status. Coverage may include restrictions around regulatory status of the assay, tumor type, line of treatment, or other factors limiting access.
Once a clinician has the molecular profile of the tumor they can select an appropriate targeted therapy. According to mycancergenome.org, there are currently 25 FDA-approved, biomarker-directed therapies for NSCLC in at least one setting and 29 that have NCCN guidelines.
However, Patel stresses that while CGP can help select appropriate therapy, it should also be used “to avoid inappropriate therapies such as immunotherapy.”
Immunotherapy is prescribed to patients with NSCLC who have high levels of the protein PD-L1 expressed on their tumors. Yet, high PD-L1 expression and the presence of tumor driver mutations are not mutually exclusive and prescribing immunotherapy without knowing the mutation status is problematic on three counts, said Patel. Firstly, it won't work, secondly it is expensive, and thirdly it can be dangerous. For example, EGFR-mutated patients who are given immunotherapy then switched to an EGFR-targeted agent are at increased risk for toxicity, including pneumonitis lung inflammation, which can be life-threatening. “So, you want to measure twice and cut once because if you're wrong, you're not only not helping the patient but actually hurting them in terms of their subsequent treatment,” Patel remarks.
Improving access to CGP by working together
Despite NSCLC being one of the most obvious candidates for CGP, with its high number of targetable mutations relative to other cancers, there is still “a really large need” to advocate for increased coverage by insurers, says Suzanne Belinson, vice president of commercial markets at Tempusand vice chair for the Access to Comprehensive Genomic Profiling (ACGP) coalition.
Suzanne Belinson, vice president of commercial markets, Tempus, Inc.
The idea for the ACGP coalition came about 2–3 years ago following a conversation at a conference among employees from three different commercial companies who had a shared goal to improve coverage for CGP by commercial insurers.
“We had been trying to move CGP commercial coverage forward, we all had distinct activities, but it still wasn't going at the pace that we thought it would go, it still hadn't seen the up-take from commercial payers that we thought we would see,” says Maude Champagne, director of market access and strategy at Illumina and ACGP treasurer. They therefore decided to create a space where they could work together in an “above brand” fashion to understand the reasons for coverage disparities and educate payers on the need for CGP.
Maude Champagne, director of market access and strategy, Illumina
ACGP was officially created 2 years ago and now has 14 members, including laboratory providers, CGP test manufacturers, and pharmaceutical companies that are making the therapies that are prescribed based on biomarker status as determined by CGP.
One of the biggest disparities that members had noticed several years ago was the fact that Medicare, which is typically used by people over 65 years of age, widely covered CGP, but commercial insurance, typically used by younger people, did not. The two groups have the same evidence to review yet “they come up with different coverage decisions regarding the clinical usefulness of a test like CGP,” says Champagne. “So, a lot of our efforts have been around educating commercial payers on the value of CGP.”
At the start, the coalition spent time understanding what the payers thought the issues were with CGP. “This led us into an approach in our first year and a half, which really focused on getting medical policies to acknowledge and have medical policy statements that related to the measurement of tumor mutational burden,” says Belinson. “And as you now look at payer policies across the United States, both in terms of individual payers and benefit management companies that manage the medical policies for a number of payers, we're now seeing those tumor mutational burden policies appear.”
However, there is still much more work to be done. “Unfortunately, half of Americans diagnosed with advanced NSCLC still receive biomarker testing that's limited to a few single gene results,” says Rob Dumanois, director of reimbursement, strategy with Thermo Fisher Scientific and ACGP vice chair. Reasons for this might include physician education and comfort to an extent, but also the slow adoption of broader coverage of CGP with commercial payers.
Robert Dumanois, director of reimbursement, strategy, Thermo Fisher Scientific
ACGP clearly still has work to do, but Dumanois is looking forward to the time when they are no longer needed. “When we get to the point where comprehensive genomic profiling is recognized by the majority of payers in the United States, I'd love to say our work is done. It's really difficult to say what's next on the horizon but I hope this is something where this group has one or two years left.”
Outside of the U.S., EUCOPE—the European trade association for small to mid-sized innovative health technology companies—is working on launching a similar initiative, noted Champagne. The European Coalition for Access to Comprehensive Genomic Profiling, or ECGP, will consist of EUCOPE member companies, including Illumina, that either develop advanced diagnostics or targeted therapeutics that rely on those tests for therapy selection and clinical trial enrolment. ECGP's aim will be to convene decision-makers and stakeholders in EU countries where the coverage decisions are made, exchanging best practices and clinical, economic, and operational evidence, in order to address the lack of access to CGP in Europe for cancer patients. The ambitious coalition is likely to launch sometime in Q2 of 2023.
Along with the need to advocate for broader coverage of CGP, it is also clear that there is a need to make it more accessible, with many centers still taking a single gene testing approach. “There may be centers globally that say, I think for first line I can do fine with EGFR, ALK, and KRAS and I'll save the NGS for back up,” says thoracic oncologist Geoff Oxnard, vice president of clinical development at Foundation Medicine. “The risk is that then the patient in front of you has to make it through first-line therapy before accessing CGP. You risk giving immunotherapy to a patient with an undetected ROS1 fusion—who could end up with a bad outcome instead of the potential for durable benefit from a ROS inhibitor that can last for years.”
Geoff Oxnard, vice president, clinical development, Foundation Medicine
Oxnard believes that increased access to CGP can come through using liquid biopsies—tests that offer CGP with the convenience of a simple blood sample. Liquid biopsies may lack sensitivity relative to tumor-based testing because they are searching for a much smaller amount of DNA. However, when testing for driver alterations in advanced NSCLC, Oxnard and team have recently shown that liquid biopsy CGP adds meaningful information in patients tested with more limited tissue testing panels.3
“I'm not convinced that if you're using an FDA-approved send out NGS test you need to add liquid biopsy because I don't think liquid [CGP] always adds to tissue. But if you're using a limited more local test, liquid biopsy does make CGP more accessible,” Oxnard remarked. He added the caveat, however, that although liquid biopsy is now very accessible in the U.S., where it's an FDA-approved CDx, in other parts of the world it is not yet widely reimbursed.
A number of commercial companies and charities are also working together to increase accessibility to CGP. In April last year, ACGP member Loxo@Lilly launched their Lung Cancer Sponsored Testing Program, which is a pay-for-testing program that provides no-cost access to CGP testing for eligible patients with lung cancer in areas where testing is currently underutilized.
“Patient out-of-pocket cost is often a significant barrier to broad utilization of comprehensive biomarker testing,” says Anthony Sireci, MD, senior vice president, clinical biomarkers and diagnostics development, Loxo@Lilly. “As a result, certain patient populations are not consistently receiving guideline-concordant biomarker testing and are left without access to precision therapies and the benefits they may provide.” These include patients of color, those who are under- or uninsured, and those who are treated in rural community settings.
Anthony Sireci, senior vice president, clinical biomarkers and diagnostics development
Loxo@Lilly has partnered with three large, national reference laboratories (Tempus, LabCorp, and NeoGenomics) to provide the service to institutions that are low or late adopters of high-quality, comprehensive biomarker testing, with a particular focus on Minority/Underserved Community Sites as designated by the National Cancer Institute, as well as institutions that still routinely utilize sequential single-gene testing rather than CGP. The patients pay no out-of-pocket cost and their insurance companies are not billed. So far, the initiative has “provided comprehensive biomarker testing to over 1,000 patients at over 170 cancer sites who may otherwise have gone without it,” says Sireci.
Beyond Thermo Fisher Scientific's involvement with ACGP, Davy notes the company supports emerging research through its Oncomine Clinical Research Grant program and collaboration with LUNGevity. The program funds studies addressing unmet diagnostic needs using NGS for both solid and hematologic cancers. The LUNGevity Foundation aims to improve outcomes for patients with lung cancer through research, education, and patient support. Their “No One Missed” campaign focuses on informing patients of the importance of knowing their biomarkers.
High mutational yield among younger patients
CGP is broadly indicated for all patients with lung cancer, but some groups, such as younger patients, never smokers, and women, are more likely to have a specific known genomic driver mutation than others.
Younger patients, often described as below 50 years of age in lung cancer research, are an interesting group because they typically present late with advanced disease. While the incidence in this group could be considered low compared with older patients, the fact that lung cancer is common means that the absolute numbers are quite high. “We see about two new cases a month,” says Alex Georgiou, consultant medical oncologist at Guy's and St Thomas's NHS Foundation Trust in London. “There are entire solid tumor entities that we wouldn't expect to see two new cases per month, and that's the key message: yes, lung cancer in young patients is far less common than in older patients but in terms of absolute numbers this amounts to a considerable number of patients.”
Alexandros Georgiou, consultant medical oncologist, Guy's and St Thomas's NHS Foundation Trust
Georgiou and colleagues recently published research in Cancers showing that 67% of 248 patients aged 18–50 years diagnosed at a single cancer center in London between 2011 and 2020 presented with stage IV NSCLC.4 By comparison, the proportion of all U.K. patients presenting at stage IV in 2020 was 46%.5 Possible reasons for late presentation in this age group include a lower index of suspicion, particularly as more-than-expected are also female and non-smokers, with a good level of fitness.
The study timeline meant that the type of mutation screening evolved as the years progressed, and none of the tumor samples were tested by CGP. Despite this, individuals with a targeted therapy option as determined by targeted PCR during the early years, targeted NGS in the later years of the study, or fluorescence in situ hybridization for EGFR, BRAF, and KRAS mutations, plus ALK or ROS1 rearrangements, survived for substantially longer than those without a targeted therapy option (median survival 28.7 vs 6.6 months). In all, 19% had an EGFR mutation, 10% and ALK translocation, 4% a ROS1 translocation, 12% a KRAS mutation, and 1% a BRAF mutation.
“I think you have to be aware that these younger patients who often do not have smoking-related NSCLC are less likely to benefit from the newer advances such as immunotherapy […] and we've shown that they are very much more likely to benefit by finding a genomic driver,” says Georgiou. Indeed, patients diagnosed in the latter years of the study had better outcomes largely due to a wider genomic testing and more targeted therapy options available. The research paper therefore concludes that the findings “highlight the particular importance of rapid-turnaround comprehensive genomic profiling in this age group and the need to identify strategies to facilitate earlier diagnosis in young NSCLC patients.”
Having said that, a take home message highlighted by both Georgiou and Patel is that “if you have lungs, you can get lung cancer,” meaning it should no longer be considered just a disease of smokers and anything that can be done to improve patient outcomes, including CGP, is vitally important.
The future beyond CGP
Looking to the future, Davy believes that in the next 10 years, “we will continue to see data validating the use of CGP through rapid next-generation sequencing as a critical first step in determining the best course of treatment for cancer patients.” She also thinks that “as the technology becomes more accessible, we will start to see the democratization of this testing not just for patients with NSCLC but for many cancer types because this will be in more labs, enabling more access to this type of testing.”
Patel says that RNA will play a greater part. “Right now, there are 11 targets, but more targets are being discovered. Some of these are RNA, in fact, so DNA is insufficient.” He says that NRG1 fusions, for example, may be actionable very soon. A drawback of RNA is that it can currently only be detected in tissue-based biopsies, but “if we want to be thorough and we're using tissue, my bias is towards DNA plus RNA sequencing,” says Patel.
Other fields including proteomics and spatial transcriptomics may also eventually be important for guiding therapy not just in NSCLC but in oncology overall. But they're for another day.