Growing evidence suggests the value of targeted therapy when used as first-line therapy in patients with certain rare actionable driver alterations. It is therefore essential that patients receive the optimal, indicated first-line treatment; early identification of molecular alterations can help achieve this goal.

In adult patients with advanced non–small cell lung cancer (NSCLC), nine actionable oncogenic driver genomic alterations have been identified. While some of these actionable alterations are relatively common (eg, EGFR and KRAS alterations occur in ~30% of patients), rarer oncogenic alterations can also occur such as those affecting ALK (4.4%), NTRK (0.1%–1%), RET (2%), and ROS1 (~2%).1 Other alterations, such as those affecting ERBB2 (HER2), BRAF, and MET exon 14 skipping alteration, can also occur.2 Such changes can result in the production of abnormal proteins and dysregulated cell signaling pathways that contribute to NSCLC carcinogenesis, tumor progression, and metastasis.

Clinical trials of tyrosine kinase inhibitors (TKIs) targeting these rare alterations have supported their approvals in patients whose tumors bear such changes (eg, alectinib for ALK-positive NSCLC, entrectinib for ROS1- and NTRK-positive tumors, selpercatinib and pralsetinib for RET-driven cancers).3-5 For all these alterations, at least one targeted agent has been approved by the U.S. Food and Drug Administration for the treatment of advanced NSCLC, in some cases as first-line therapy.6-10 Current guidelines from ASCO recommend the use of first-line targeted therapy for advanced NSCLC based on the specific oncogenic driver alteration present.11 Emerging results suggest the value of targeted therapy when used as first-line therapy in patients with ALK, EGFR, or RET alterations (data from first-line trials for other actionable genomic alterations are not yet available).12,13 It is therefore essential that patients receive the optimal, indicated first-line treatment; early identification of molecular alterations can help achieve this goal.

The use of first-line targeted therapy depends on accurate and timely detection of actionable genomic alterations, including those that are less common. The increased availability of agents targeting uncommon alterations in advanced NSCLC has led to greater molecular profiling of patients. Comprehensive upfront molecular analysis is therefore recommended for all patients with advanced NSCLC prior to making first-line treatment decisions, to aid in prognostic assessment and selection of appropriate targeted therapy.14 Failure to perform accurate molecular testing, or delayed test results, may result in use of less effective therapy (with or without immunotherapy), which may lead to poorer outcomes.15,16 Rapid, guideline-concordant genomic testing is the standard of care for advanced NSCLC, and testing rates have been increasing over the past several years. However, rates of comprehensive testing for all five frequently occurring NSCLC alterations (EGFR, ALK, ROS1, BRAF, and PD-L1) are still low compared with rates for single genes (Figure 1).17 The continual increase in the number of biomarkers and frequent revisions in testing guidelines, along with emerging technologies such as liquid biopsies and RNA-based next-generation sequencing (NGS; see below), can present challenges to clinicians who need to remain current on NSCLC testing. Additionally, many patients do not have access to high-quality molecular testing and concomitant biomarker-informed treatment decisions prior to first-line therapy.18,19

Figure 1. NGS Biomarker Testing Rates Over Time (Stage IV NSCLC)

Data from the MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) ConsortiumTM study of comprehensive biomarker testing in patients with metastatic NSCLC initiating first-line systemic therapy between April 1, 2018 and March 31, 2020.17
NSCLC = non–small cell lung cancer.

Variability in Testing

Despite improvements in availability, speed, and cost, variability in NSCLC molecular testing still exists, and clinical adoption has been slower than expected, highlighting the need for improvement. Reasons for suboptimal uptake are varied and include but are not limited to cost, reimbursement, awareness, inadequate tumor samples, slow turnaround time, and other logistical considerations.20 Tejas Patil, MD, Assistant Professor, Medicine, at the University of Colorado Cancer Center, noted that access to testing can also be a factor. “Patients who are not getting molecular profiling tend to be from more socioeconomically disadvantaged areas and/or rural areas where testing is very difficult and there is a lack of resources for access of care,” he said.

Patients who are not getting molecular profiling tend to be from more socioeconomically disadvantaged areas and/or rural areas where testing is very difficult and there is a lack of resources for access of care. Tejas Patil, MD

Various clinical practice gaps have been identified that can negatively impact NSCLC biomarker testing and receipt of results, thus affecting treatment decisions regarding use of targeted therapy. A recent survey found that 37% of ASCO members waited 3 weeks or longer to receive NSCLC biomarker test results; in many cases this resulted in initiating nontargeted therapy rather than biomarker-targeted treatment.21 In a claims database analysis of over 500,000 patients with newly diagnosed advanced NSCLC who were eligible for personalized treatment, nearly half never received biomarker test results due to preanalytic and analytic practice gaps (eg, ordering of testing, sample processing, performance, reporting of test results). Of those who did undergo testing, 29.2% did not receive appropriate targeted therapy on the basis of their test results. In total, an estimated 64% of potentially eligible patients were not able to access precision oncology therapy.22 Addressing these gaps can therefore improve biomarker testing and the delivery of precision oncology care.

According to Eric Konnick, MD, MS, Assistant Professor of Laboratory Medicine and Associate Director of the Genetics and Solid Tumor Lab at UW Medicine, many factors can contribute to testing delays apart from the time needed to actually perform the test. These include preauthorization; time required to obtain a tissue sample; and communication between oncologists, pathologists, and other members of the multidisciplinary team—which is becoming increasingly important. Dr. Konnick indicated that “about 20% to 40% of my day is devoted to communication with my colleagues, working to make sure the oncologists and patients are getting the information they need to make the right treatment decisions.” This point was reinforced by Dr. Patil, who stressed the importance of having system processes in place to ensure efficient coordination of molecular testing and early treatment decisions.

About 20% to 40% of my day is devoted to communication with my [multidisciplinary team], working to make sure the oncologists and patients are getting the information they need to make the right treatment decisions. Eric Konnick, MD, MS

Testing Methodologies

Comprehensive testing for NSCLC using NGS, where available, is generally preferred over sequential single-analyte testing since NGS can simultaneously screen for multiple therapeutically relevant alterations and may be more cost effective.23,24 Compared with non-NGS methods, NGS may help avoid potentially missed therapeutic targets.25 Improved identification of genomic alterations might also facilitate patient enrollment in appropriate clinical trials. Moreover, because of the ability to assess for multiple targets at the same time, NGS testing may be more efficient than single-gene methods, resulting in less tissue wastage, and may obviate the need for additional biopsies. Multiple lung cancer guidelines recommend NGS for the detection of NSCLC genomic alterations.26,27 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC “strongly [advise] broader molecular profiling with the goal of identifying rare driver alterations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials.”14 Although median time from diagnosis to receipt of test results is longer with NGS, this is expected to decrease as NGS uptake and sequencing technology continue to improve.

Longstanding fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) assays to detect certain NSCLC alterations, such as selected rearrangements and gene amplifications, are relatively fast and inexpensive, and can rapidly provide oncologists with important information they can use to make treatment decisions. In general, though, non-NGS techniques are not suitable for detecting all classes of genomic alterations, may be unable to detect selected rare NSCLC alterations, and require use of more tissue compared with NGS. Also, IHC and FISH are susceptible to false-negatives and false-positives. (IHC is not recommended for detection of RET fusions.28,29) Newer techniques such as RNA-based NGS can also be useful for detecting clinically actionable NSCLC alterations such as certain gene fusions and small insertions or deletions, and thus could serve to complement DNA-based NGS.30,31

Although NGS can detect a variety of genomic alterations, it is still underutilized. A chart review of patients with metastatic NSCLC who were initiating first-line systemic therapy found that while 90% had at least one biomarker test, less than half had received tests for all five actionable alterations evaluated at that time (ALK, BRAF, EGFR, ROS1, and PD-L1), indicating room for improvement.17 According to Dr. Konnick, keeping abreast of evolving testing guidelines can be a challenge for general oncologists in the community setting, particularly with regard to rare NSCLC biomarkers. With appropriate procedures and organization, community oncology practices can improve their NGS testing rates and turnaround times.18

Interest is growing in the use of noninvasive liquid biopsies for analysis of cell-free DNA or circulating tumor DNA to allow for faster detection of targetable NSCLC alterations and monitoring of response. While this approach affords reasonable sensitivity and faster turnaround compared with tissue-based analyses, it has a high false-negative rate.14,33 Dr. Patil emphasized that patients with a low tumor burden might have negative results with a circulating tumor DNA test, but this must be confirmed with a tissue diagnosis. Liquid biopsies can be considered as complementary to tissue-based testing but should not replace it if tissue is available. Liquid biopsies may serve as a surrogate in special cases, such as when tumor tissue cannot be obtained or the sample size is insufficient.33 This approach might also have a role in repeat molecular testing after a patient progresses, to determine what new alterations may have occurred that could inform selection of subsequent therapy.

Guideline-Concordant Biomarker Testing and Treatment

Use of first-line therapy concordant with biomarker testing guidelines and treatment guidelines may improve outcomes for patients with advanced NSCLC. NGS in particular may result in greater use of personalized first-line NSCLC therapy compared with other biomarker testing methodologies. Analysis of a large U.S. electronic health records database confirmed that patients with advanced NSCLC who underwent NGS were more likely to receive first-line targeted therapy directed against their specific alteration or to enroll in a clinical trial.34 In another study of patients with advanced NSCLC who initiated systemic therapy, detection of actionable genetic alterations by NGS allowed for administration of at least one targeted first-line treatment to 36.4% of patients, with another 22.9% receiving targeted therapy upon progression. This resulted in significantly longer progression-free survival and overall survival compared with chemotherapy.35

Early genomic testing in NSCLC is recommended to identify alterations that may be present and inform selection of personalized first-line therapy.36,37 The benefits of upfront testing can be seen in the recent PAPILLON study of first-line amivantamab plus chemotherapy in patients with advanced NSCLC bearing EGFR exon 20 insertions. The amivantamab regimen significantly improved progression-free survival compared to chemotherapy alone.38 Similarly, in the LIBRETTO-431 trial, the RET inhibitor selpercatinib significantly increased progression-free survival in the first-line setting compared with pemetrexed plus platinum-based chemotherapy (with or without pembrolizumab) in patients confirmed to have RET fusion–positive advanced NSCLC. (The most common grade ≥ 3 adverse events seen with selpercatinib were ALT increase, AST increase, and hypertension.)13

Figure 2. Impact of Biomarker Testing on Survival in Patients With Advanced NSCLC

Overall survival of patients tested or never tested for at least one actionable biomarker (EGFR, BRAF, ROS1, or ALK) prior to or upon initiation of first-line therapy for advanced NSCLC, based on an analysis of real-world electronic healthcare records.15
CI = confidence interval; mo = months; NSCLC = non–small cell lung cancer; OS = overall survival.

For patients with advanced NSCLC bearing actionable alterations, use of guideline-concordant first-line targeted therapy is often associated with significantly longer progression-free survival and overall survival compared with chemotherapy. Several trials of targeted therapy for advanced NSCLC bearing actionable mutations have demonstrated clinically significant improvement in progression-free survival compared with control arms.13,35,37,38 In a database analysis, of the 88% of advanced NSCLC patients who had at least one biomarker test, more than 30% did not receive testing before or at the start of first-line therapy. In this study, the adjusted hazard ratio (HR) for death was 25% higher in patients who never underwent biomarker testing (vs those who did) and 12% higher in those who did not receive testing before or at start of first-line therapy (Figure 2).15 These results support the need for early biomarker testing to inform and expedite clinical decision-making regarding first-line therapy for patients with advanced NSCLC. Another real-world database analysis of patients who underwent biomarker testing also found that those who were NCCN testing guideline–concordant had a significantly lower risk of mortality compared with nonadherent patients (HR = 0.89; P < .01). For the nearly 70% of patients who went on to receive appropriate biomarker-based guideline-concordant first-line therapy, median time to treatment discontinuation was significantly longer for adherent vs nonadherent patients.39 Similarly, in another study patients who received guideline-concordant therapy had improved relative survival compared with those who did not, at both 1 year (51% vs 28.2%) and 2 years (34.1% vs 17.5%).40 Biomarker testing and first-line therapy that are both concordant with guidelines can therefore result in improved survival. These results illustrate the benefits of adhering to biomarker testing guidelines and the impact of selecting appropriate first-line NSCLC therapy based on genomic test results. Conversely, use of inappropriate targeted therapy or chemotherapy may provide less benefit than treatments based on a patient’s specific molecular alterations. Waiting for molecular test results may thus facilitate use of appropriate guideline-concordant target-directed therapy, potentially improving outcomes.

As Dr. Patil noted, “there are toxicities associated with giving immune checkpoint inhibitors first, especially for patients who eventually do have these rare alterations that are going to be treated with targeted therapies.” In general, biomarker-indicated targeted therapy may be more effective than immune-based monotherapy in patients with NSCLC driver alterations, and can obviate the risk of immune-related adverse events.14,41,42 In cases where test results are significantly delayed or immediate therapy is required, withholding immunotherapy and initiating chemotherapy, prior to switching to a targeted agent once molecular profiling results are known, may therefore be an option.

There are toxicities associated with giving immune checkpoint inhibitors first, especially for patients who eventually do have these [alterations] that are going to be treated with targeted therapies. Tejas Patil, MD


Given the rapid evolution in targeted therapy for oncogenic alterations in advanced NSCLC, adherence to guidelines for biomarker testing is recommended to increase detection of rare alterations and inform selection of biomarker-driven first-line therapy. Continued education of health-care professionals can increase use of NGS-based testing and application of results to clinical decision-making, particularly for those who do not order such testing often. Patient education regarding the benefits of genomic testing is also recommended, as well as the rationale for a “test-wait-treat” approach (ie, delaying treatment initiation until all molecular results are available). Alternatively, a “test-treat-switch” approach may be an option when waiting for test results is not practical. These steps can help clinicians optimize classification and precision treatment for patients with advanced NSCLC who have uncommon actionable alterations, thus improving outcomes.


Dr. Patil has received honoraria from AstraZeneca, Bristol Myers Squibb, Elevation Oncology, Janssen, Lilly, Mirati Therapeutics, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; and has received research funding from EMD Serono and Janssen.

Dr. Konnick has received honoraria from Bristol Myers Squibb, Caris Life Sciences, Lilly, Merck, MJH Healthcare Holdings, LLC, and WebMD; has served as a consultant or advisor to Roche; and reported travel, accommodations, and expenses from Bristol Myers Squibb.


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