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INTRODUCTION — Treatment for patients with metastatic non-small cell lung cancer (NSCLC) has historically consisted of systemic cytotoxic chemotherapy. Chemotherapy has a general goal of killing cells that are growing or dividing; chemotherapy reduces symptoms, improves quality of life, and prolongs survival in some patients with NSCLC.
An improved understanding of the molecular pathways that drive malignancy in NSCLC, as well as other neoplasms, led to the development of agents that target specific molecular pathways in malignant cells beginning in the early 2000s. The hope is that these agents will be able to preferentially kill malignant cells, but will be relatively innocuous to normal cells. Many established targeted therapies are administered as orally available small molecule kinase inhibitors, but targeted therapy can also be administered intravenously in the form of monoclonal antibodies or small molecules.
The identification of oncogenic activation of particular tyrosine kinases in some advanced NSCLC tumors, most notably mutations in the epidermal growth factor receptor (EGFR) or rearrangements of the anaplastic lymphoma kinase (ALK) gene or ROS1 gene, has led to a paradigm shift and the development of specific molecular treatments for patients. Furthermore, the identification of these patient subsets has led to an ongoing effort to identify biomarkers and treatments that can be used for other subsets of patients with advanced NSCLC. A general discussion of these alterations, as well as other potential driver mutations, is found in this topic. A treatment approach to advanced non-small cell lung cancer, as well as more detailed discussion regarding EGFR-mutated and ALK-translocated lung cancers, is found elsewhere.
DRIVER MUTATIONS AS BIOMARKERS — The most useful biomarkers for predicting the efficacy of targeted therapy in advanced NSCLC are somatic genome alterations known as "driver mutations." These mutations occur in cancer cells within genes encoding for proteins critical to cell growth and survival. Many other recurrent molecular alterations have been identified in NSCLC that are much less essential to maintain the oncogenic phenotype, and are often referred to as "passenger mutations." Driver mutations are typically not found in the germline (noncancer) genome of the host and are usually mutually exclusive (ie, a cancer is unlikely to have more than one driver mutation) (figure 1).
Driver mutations are typically transformative, which means that they initiate the evolution of a noncancerous cell to malignancy. In addition, driver mutations often impart an oncogene-addicted biology to the transformed cell, meaning that the mutated protein engenders reliance within the cancer cell to receive a signal from the driver in order to survive.
An often used analogy is that a normally functioning cell may have a particular switch in its circuitry that is sometimes turned on and sometimes turned off, but in general is regulated with feedback inhibition loops and specific stimulators. However, in an oncogene-addicted cancer cell, the switch is stuck in the on position all the time and is no longer subject to regulation.
Oncogene addiction tends to make driver mutations good biomarkers for selecting patients for targeted therapies. The extreme reliance of crucial downstream growth and survival pathways in the cell upon a single upstream signal that is "stuck in the on position" serves as an Achilles’ heel, making the cancer uniquely susceptible to down-regulation of signal originating from the driver (ie, unable to survive if a targeted drug essentially turns the switch to the off position because other mechanisms to keep downstream signals flowing are nonexistent).
In NSCLC, as well as with other malignancies, matching a specific targeted drug to the identified driver mutation for an individual patient has resulted in significantly improved therapeutic efficacy, often in conjunction with decreased toxicity. Screening for driver mutations thus has become an increasingly standard part of the diagnostic work-up for NSCLC, and the resultant information is useful in choosing between standard chemotherapy in the absence of a targetable driver mutation versus up-front targeted therapies. As examples, in a nationwide French study in which all lung cancers were subjected to molecular profiling, approximately 50 percent of tumors exhibited a genetic alteration, which led to use of a targeted agent as first-line therapy in half of these cases . The presence of a genetic alteration was associated with improved first-line progression-free survival (10 versus 7.1 months) and overall survival (16.5 versus 11.8 months). Similarly, in the United States, the Lung Cancer Mutation Consortium analyzed samples using multiplex genotyping from 733 patients with adenocarcinoma at 14 centers, identifying a targetable driver mutation in 466 cases (64 percent) . The 260 patients with an oncogenic driver who received a targeted agent had a median survival of 3.5 years; the 318 patients with a driver but without targeted therapy, 2.4 years; and the 360 patients without a driver, 2.1 years. These studies underscore the potential clinical benefit and prognostic utility provided by large-scale utilization of molecular profiling in lung cancer.
MOLECULAR TESTING — Whenever feasible, patients with advanced NSCLC should have tumor assessed for the presence of a driver mutation . Guidelines from the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association of Molecular Pathologists (AMP) recommend analysis of either the primary tumor or of a metastasis for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) for all patients whose tumor contains an element of adenocarcinoma, regardless of the clinical characteristics of the patient [4,5].
Techniques — Methods for screening NSCLC patients for driver mutations and other abnormalities are continually evolving, and there is no single standard platform for testing. Features that make a platform clinically useful are fast turnaround time (two weeks or less); cost efficiency; ability to be performed on clinically available samples; and semi-automation, eliminating reliance upon a single operator. For newly diagnosed non-squamous NSCLC patients, we initially recommend testing for EGFR (by a polymerase chain reaction [PCR] method that takes <2 weeks, on either tissue or blood); ALK (by immunohistochemistry [IHC] or fluorescence in-situ testing [FISH]); and ROS1 (by FISH). Next generation sequencing can be performed in lieu of these tests, in parallel with these tests, or reflexed if these tests are all negative. Molecular testing can be performed on selected patients with squamous NSCLC, for example those with a light- or never-smoking history. We recommend programmed death-ligand 1 (PD-L1) IHC testing on all patients, regardless of histology.
Techniques used commonly in the clinical setting are described below, with recommended testing for specific alterations summarized in the table (table 1):
●Sequencing – Clinical testing of mutations in lung cancer started historically with sequencing (or direct sequencing) of the gene, which examines the entire length of a single gene for the presence of a mutation. However, the sensitivity is lower than other methods that have since been more widely adopted. This is because the tumor cellularity with the mutation must be high (ideally higher than 10 percent) in the tissue sample in order to be detected by direct sequencing, otherwise the test may be falsely negative.
●Allele-specific testing – Allele-specific testing analyzes the DNA for a predefined abnormality, and largely replaced direct sequencing. Some centers use this as the default test to evaluate EGFR and other abnormalities. The raw DNA is typically amplified using PCR before the search for the mutated allele is undertaken, allowing for rare signals to be detected with greater sensitivity. This method represents a technological leap forward from direct sequencing in that it is a multiplexed test, and tends to be faster and cheaper than sequencing of each gene individually. However, only prespecified targets can be identified. Thus, allele-specific testing cannot be used to identify new abnormalities.
●Next-generation sequencing (NGS) – NGS overcomes many of the shortcomings of direct sequencing and allele-specific testing, and is rapidly becoming adopted by more centers. This massively parallel approach, relying heavily on automation, data storage, and computational processing, allows quantitative analysis of infrequent alleles and simultaneous evaluation of multiple genes or even whole genomes. It retains sensitivity even in specimens with low tumor cellularity, which is an improvement over direct sequencing, and can identify new abnormalities, which would not be detected by allele-specific testing. Moreover, NGS can often detect abnormalities that would historically be tested by FISH. We routinely use it in our clinical practice; however, it is costly and may not be covered by insurance for some patients.
●Fluorescence in-situ testing (FISH) – FISH is typically used to detect gene translocations, amplifications, and other rearrangements, for example, ALK or ROS1 translocations. Identifying rearrangements uses two hybridizing DNA probes of different colors that separate when two parts of a gene have broken apart. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)
●Immunohistochemistry (IHC) – The role of IHC is evolving [4,5]. IHC is considered a sensitive and specific alternative to FISH in evaluating for ALK translocations. However, IHC is not currently recommended for the detection of other genomic alterations. In lung cancer IHC is also the definitive method to assess for PD-L1 protein staining, since PD-L1 protein expression does not appear to be related to known genomic alterations in the PD-L1 gene. Tumor PD-L1 protein expression should be ordered in addition to tumor genotyping to determine first-line treatment options in NSCLC beyond chemotherapy. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Antibodies to PD-1 and PD-L1'.)
Liquid biopsies — While molecular diagnostics have traditionally been performed on biopsies of solid tumor tissue, blood-based tests or so-called "liquid" biopsies are gaining popularity as they provide the opportunity to genotype in a less invasive and less expensive manner, and may offer a chance to monitor the molecular features of a cancer through the course of treatment, or predict relapse after adjuvant treatment [6,7]. There are currently two US Food and Drug Administration (FDA)-approved circulating tumor DNA (ctDNA) tests for lung cancer patients, both in the EGFR mutation-positive setting. It is likely that as more data emerge, the use of liquid biopsies to assess other molecular abnormalities will become more widespread. (See 'EGFR mutation' below.)
The principle behind liquid biopsies is that cell-free ctDNA and/or circulating tumor cells (CTCs) are often present in the blood of patients with lung cancer . Platforms available for clinical use focus almost exclusively on isolating and detecting ctDNA, rather than CTCs. PCR-based platforms include allele-specific PCR, which preferentially amplifies a mutant DNA molecule over wildtype DNA, and emulsion PCR assays, which perform PCR reactions in thousands of droplets of a sample to quantify mutant and wildtype DNA (eg, droplet digital PCR and BEAMing) . While such assays may have a theoretical turnaround time of as little as one day, they generally cover a limited number of common mutations, such as EGFR, KRAS, BRAF, and ALK. NGS-based plasma genotyping platforms are much broader in scope but currently take several weeks for results. In general, all of these methods are highly specific, although some platforms may detect allelic alterations that are present at such a low frequency that they may be clinically insignificant or represent low-level sequencing background noise [8,9].
Liquid biopsies yield results that predict clinical response to targeted agents, although a limitation is that sensitivity ranges between 60 and 80 percent [10,11]. For example, in one study of 58 patients with EGFR-mutated NSCLC that acquired resistance to an EGFR tyrosine kinase inhibitor, T790M was assessed in plasma using BEAMing technology as well as in tissue . Sensitivity of liquid biopsy for T790M was determined to be 70 percent, and patients were found to have similar response rates to the third-generation tyrosine kinase inhibitor osimertinib, regardless of whether the T790M mutation was found in plasma or solid tissue. The limited sensitivity of liquid biopsies is thought to reflect the biology that some cancers do not shed DNA into the bloodstream rather than a feature of any given assay. However, mutation detection in blood has been associated with more advanced disease characteristics, including worsened performance status and prognosis and the presence of more metastatic sites .
A second limitation of liquid biopsies is that the types of studies have a higher chance of being falsely negative compared with traditional biopsies, given the minuscule and variable amounts of DNA that tumors may shed into circulation. Moreover, tests for programmed death-ligand 1 (PD-L1) expression cannot be conducted on liquid biopsies. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Antibodies to PD-1 and PD-L1'.)
NSCLC GENOTYPES — This section reviews the most common targetable driver mutations, as well as some frequently identified passenger alterations that may or may not be targetable. Appropriate therapies are also discussed.
Whenever possible, patients should be enrolled in formal clinical studies. The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) study includes substudies for many of the genomic alterations mentioned below (NCT02465060).
When there is no established therapy or suggested off-label therapy for a given driver mutation or when inclusion in a clinical trial is not feasible, patients should be managed with chemotherapy or immune therapy like those without a driver mutation. (See "Overview of the treatment of advanced non-small cell lung cancer".)
Genotypes with approved targeted therapies — Genotypes with approved targeted therapies are discussed below.
EGFR mutation — Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinoma in the United States and occur more frequently in nonsmokers . In Asian populations, the incidence of EGFR mutations is substantially higher, up to 62 percent . In advanced NSCLC, the presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, afatinib, and osimertinib. A detailed discussion of the treatment of EGFR-mutant NSCLC is presented separately. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
The use of EGFR TKIs is based upon the detection of these mutations, which may be detected either in solid tissue biopsies or in liquid biopsies. The US Food and Drug Administration (FDA)-approved tests are the Cobas EGFR mutation test for common activating mutations or Cobas EGFR mutation test v2 for the T790M mutation; however, any Clinical Laboratory Improvement Amendments (CLIA) certified-laboratory EGFR mutation result is generally acceptable for clinical decision-making . Clinical standards are rapidly evolving, but based on available evidence, we offer liquid biopsy to EGFR mutation-positive patients who progress on their first EGFR TKI to look for the T790M mutation. If positive, such patients can be treated with osimertinib. For those who are T790M-negative on a plasma assay, we proceed with tumor biopsy given an observed false-negative rate of 30 percent associated with plasma genotyping . (See 'Liquid biopsies' above and "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
ALK translocation — Translocations involving the anaplastic lymphoma kinase (ALK) tyrosine kinase are present in approximately 4 percent of NSCLC adenocarcinoma in the United States and occur more frequently in nonsmokers and younger patients. ALK translocations can be identified by fluorescence in-situ testing (FISH), immunohistochemistry (IHC), or most next-generation sequencing (NGS) panels.
In advanced-stage NSCLC, the presence of an ALK translocation strongly predicts for sensitivity to ALK TKIs (eg, crizotinib, ceritinib, alectinib), and treatment with these agents significantly prolongs progression-free survival. The diagnosis and treatment of ALK-positive NSCLC is presented separately. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
ROS1 translocation — ROS1 is a receptor tyrosine kinase that acts as a driver oncogene in 1 to 2 percent of NSCLC via a genetic translocation between ROS1 and other genes, the most common of which is CD74 [16-19]. Histologic and clinical features that are associated with ROS1 translocations include adenocarcinoma histology, younger patients, and never-smokers. ROS1 translocations are identified by a FISH break-apart assay, similar to that used for ALK translocations, or by some NGS panels. The ROS1 tyrosine kinase is highly sensitive to crizotinib due to a high degree of homology between the ALK and ROS tyrosine kinase domains . Treatment with crizotinib is FDA-approved and recommended for patients with the ROS1 translocation, including those who have received chemotherapy and those who are treatment-naïve .
In an open-label, international study of crizotinib of 50 patients with ROS1-translocated NSCLC, over 80 percent of whom had received one or more prior chemotherapy regiments, the objective response rate was 72 percent (3 complete and 33 partial responses). The median duration of response was 17.6 months, and the median progression-free survival was 19.2 months . A similar response rate was observed in another retrospective series of 32 patients treated with crizotinib after detection of a ROS1 rearrangement, although the median progression-free survival was lower at 9.1 months . The side effect profile associated with treatment was consistent with that seen when crizotinib has been used in ALK-positive NSCLC. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
Second-generation inhibitors are also being studied. For example, in a phase II trial of 28 evaluable patients with advanced ROS1-rearranged NSCLC, the objective response rate with ceritinib was 62 percent, duration of response was 21 months, and disease control rate was 81 percent . The median progression-free survival was 9.3 months overall and 19.3 months for crizotinib-naïve patients. Median overall survival was 24 months. Five of eight patients with brain metastases experienced disease control. However, given that ceritinib has not been compared with crizotinib in the frontline setting for those with ROS1 translocations, and there is little evidence that ceritinib can overcome acquired resistance to crizotinib, further study is required prior to routine clinical use of ceritinib for ROS1-driven NSCLCs.
Regarding other second-generation inhibitors, alectinib has no ROS1 inhibitory activity. Preclinical evidence and case reports suggest that cabozantinib may be effective in ROS1-translocated cancers that have become resistant to crizotinib, though more data are required [24-26].
BRAF mutation — BRAF is a downstream signaling mediator of KRAS that activates the mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations have been observed in 1 to 3 percent of NSCLC and are usually associated with a history of smoking [27-31]. They can occur either at the V600 position of exon 15, like in melanoma, or outside this domain, and are detected typically using polymerase chain reactions (PCR) sequencing or NGS methods. For patients with BRAF V600 mutations who have progressed on chemotherapy, we suggest a BRAF inhibitor (dabrafenib or vemurafenib) or combined MAPK pathway inhibition (dabrafenib plus trametinib) rather than single-agent chemotherapy or immunotherapy as second-line therapy. The combination of dabrafenib plus trametinib is approved by the FDA for patients with metastatic NSCLC with a BRAF V600E mutation, as detected by an FDA-approved test. As in melanoma, combination therapy may be more durable than single-agent treatment. (See "Molecularly targeted therapy for metastatic melanoma", section on 'Dabrafenib plus trametinib'.)
BRAF inhibition with oral small-molecule TKIs (eg, vemurafenib and dabrafenib) appears to be an effective strategy in the treatment of progressive BRAF V600-mutant NSCLC [32,33]. For example, in a phase II trial of vemurafenib, responses were seen in 8 of the 19 patients with BRAF V600 mutation-positive NSCLC (42 percent, CI 20-67) . All but two of these patients had progressed on a prior line of platinum-based chemotherapy [34,35]. The median progression-free survival was 7.3 months (CI 3.5-10.8), and median overall survival had not been reached at the time of publication .
Combination therapies with BRAF inhibitors are also an area of active investigation. In a phase II study of 78 patients with previously treated, advanced NSCLC with the V600E mutation, the combination of dabrafenib plus trametinib was associated with an objective response rate of 63 percent in 52 evaluable patients, and the disease control rate was 79 percent [36,37]. The median progression-free survival was 9.7 months. The side effect profile was consistent with that observed in dabrafenib plus trametinib clinical trials in patients with melanoma. Other strategies for patients whose cancers harbor BRAF mutations include the use of downstream MEK TKIs as monotherapy (figure 2), which is of particular interest for some BRAF-mutant non-V600E tumors that generally appear insensitive to BRAF inhibitors. (See "Molecularly targeted therapy for metastatic melanoma" and 'Targeted therapy under investigation' below.)
The clinical characteristics and prognosis of BRAF-mutated adenocarcinoma of the lung are illustrated by a single-center series of 63 patients diagnosed between 2009 and 2013 . The majority (57 percent) had a V600E mutation, and 92 percent were smokers, although those with V600 mutations were more likely to be light or never-smokers compared with those with non-V600 mutations (42 versus 11 percent). Among the 32 patients with early-stage disease, six (19 percent) developed synchronous or metachronous second primary lung cancers, all of which contained mutations in KRAS. For those with advanced NSCLC, the prognosis was significantly better in those with a V600 mutation compared with non-V600 mutation (three-year survival rate, 24 versus 0 percent). Six of the 10 patients with advanced disease and a V600E mutation had a partial response to treatment with a BRAF inhibitor, three had stable disease, and the median duration of response was over six months.
Genotypes with suggested off-label targeted therapies
Sequencing of therapies — Patients with EGFR mutations or ALK or ROS1 translocations are treated with the appropriate frontline targeted therapy. (See 'Genotypes with approved targeted therapies' above.)
However, those with other driver mutations are generally treated with frontline chemotherapy, or, if their tumors express high levels of programmed death-ligand 1 (PD-L1), with immunotherapy. Upon progression, for those who have not yet received chemotherapy, we proceed with platinum-based chemotherapy. However, if chemotherapy has already been administered, available next-line options include off-label targeted therapies or immunotherapy. For patients with one of the genetic alterations below (in HER2, BRAF, MET, or RET), we typically prefer to move next to off-label use of the appropriate targeted agent rather than immunotherapy. For patients with these driver mutations, available targeted agents appear to have activity, with acceptable levels of toxicity. By contrast, trials of immunotherapy in patients with nonsmoking-related, driver mutation-positive NSCLCs have shown lesser efficacy compared with the general population of NSCLC patients [38-40]. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'PD-1 blocking antibodies'.)
HER2 mutation — HER2 (ERBB2) is an EGFR family receptor tyrosine kinase. Mutations in HER2 have been detected using PCR or next-generation sequencing in approximately 1 to 2 percent of NSCLC tumors [41,42]. They usually involve small in-frame insertions in exon 20, but point mutations in exon 20 have also been observed. These tumors are predominantly adenocarcinomas, are more prevalent among never-smokers, and a majority of these patients are women. For patients with a HER2 exon 20 insertion mutation who have progressed on chemotherapy, we suggest incorporation of HER2-targeted agents with next-line therapy, specifically afatinib monotherapy; trastuzumab in combination with single-agent chemotherapy (vinorelbine or docetaxel); or ado-trastuzumab emtansine .
Case series or early-phase clinical trials suggest that patients with tumors harboring HER2 mutations often respond to trastuzumab and chemotherapy [42,44]; or to afatinib, an EGFR/HER2 TKI [42,45]; or to ado-trastuzumab . In a series of 65 patients receiving ERBB2-targeted therapies, the overall response rate was 51 percent. For those receiving trastuzumab in combination with chemotherapy and those receiving afatinib, response rates were 50 and 18 percent; disease control rates were 75 and 64 percent; and progression-free survival was 5.1 and 3.9 months, respectively . Additionally, a pulse dosing strategy of afatinib at 280 mg weekly dose was reported to be tolerable, and of the three patients treated, one had partial response for five months and another had stable disease for 11 months . In preliminary results of a separate phase II trial of ado-trastuzumab emtansine in 18 patients with HER2-mutant advanced lung cancer, with a median of two prior lines of systemic therapy, the objective response rate was 33 percent, median progression-free survival was four months, and the median duration of response was not reached .
Other HER2-targeted agents are under study. A phase I study conducted with the irreversible pan-HER inhibitor neratinib and the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus included five patients with NSCLC and HER2 mutations evaluable for response. Two had partial response for approximately four and eight months, and the other three had stable disease lasting three to five months . Larger clinical trials are ongoing to further define efficacy of these classes of agents in this lung cancer subtype.
There is no obvious association between HER2 amplification and HER2 mutations, and previous trials demonstrated no benefit for trastuzumab in HER2-amplified NSCLC, so we do not recommend this testing in NSCLC [49,50].
MET abnormalities — MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF). MET abnormalities include MET exon 14 skipping mutations (in 3 percent of lung adenocarcinomas and up to 20 percent of pulmonary sarcomatoid carcinomas), MET gene amplification (in 2 to 4 percent of treatment naïve NSCLC), and MET and EGFR comutations (in 5 to 20 percent of EGFR-mutated tumors that have acquired resistance to EGFR inhibitors) [51-64]. Exon 14 skipping mutations are most commonly found by NGS, while MET amplification may be detected by FISH or some NGS panels [65,66]. For patients with a MET exon 14 skipping mutation or MET amplification who have progressed on chemotherapy, we suggest treatment with a MET inhibitor (crizotinib or cabozantinib) as next-line therapy, rather than single-agent chemotherapy or immunotherapy.
A number of inhibitors with activity against MET are being tested in NSCLC for the following genetic lesions:
●MET exon 14 skipping mutations – The MET exon 14 skipping mutation reduces degradation of the MET protein, causing it to behave as an oncogenic driver. Crizotinib is a potent MET inhibitor, in addition to inhibiting ALK and ROS1. In a series of 17 patients with MET exon 14 skipping mutations treated with crizotinib, five had confirmed responses and five had unconfirmed partial responses [64,67]. Cabozantinib, which has activity against MET, was given to a patient and resulted in five months of stable disease . Another series reported responses to capmatinib, an investigational MET inhibitor, in patients with NSCLC and these mutations . Preliminary results from a retrospective study of 61 patients with metastatic MET-mutant NSCLC suggested improved overall survival among those who were treated with at least one MET inhibitor versus those who were not (24.6 months versus 8.1 months, respectively; hazard ratio [HR] 0.11, 95% CI 0.01-0.92) .
●MET amplification – Increased MET expression may predict response to MET-targeted drugs, but also appears to be associated with an overall worse prognosis [69,70]. Initial studies of crizotinib in a highly selected group of 12 patients with intermediate or high MET gene amplification demonstrated responses in five patients and stable disease in five additional patients, which were unusually prolonged for MET-high patients . There are several clinical trials available of MET inhibitors for MET-amplified NSCLC.
●MET and in the setting of EGFR mutations – Since MET amplification can also contribute to acquired resistance to EGFR TKI therapy, combinations of MET inhibitors are being investigated in this patient population as well. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
RET translocation — The RET gene encodes a cell surface tyrosine kinase receptor that is frequently altered in medullary thyroid cancer. Recurrent translocations between RET and various fusion partners (CCDC6, KIF5B, NCOA4) have been identified in 1 to 2 percent of adenocarcinomas, and occur more frequently in younger patients and in never-smokers [71-74]. Translocations can be detected with break-apart FISH or NGS. For patients with RET rearrangements who have progressed on chemotherapy, we suggest next-line treatment with a RET inhibitor such as cabozantinib, vandetanib, or alectinib rather than single-agent chemotherapy or immunotherapy.
In a phase II trial of cabozantinib including 25 evaluable patients, all of whom had a RET translocation, treatment with cabozantinib 60 mg/day led to partial responses in seven (28 percent) and stable disease in nine (36 percent) patients [75,76]. With a median follow-up of 8.9 months, the median progression-free survival was 5.5 months and the median overall survival was 9.9 months.
Reports have also described responses to vandetanib, sunitinib, and alectinib in patients whose tumors contained a RET translocation [77-80]. In a retrospective registry study of 165 patients with RET-rearranged NSCLC, the response rates to cabozantinib, vandetanib, and sunitinib were 37, 18, and 22 percent, respectively .
Genotypes with targeted therapies offered on trial only — Inhibitors that target the following alterations are in development but are not recommended clinically for NSCLC outside of a trial.
RAS mutations — For patients with RAS mutations, a number of agents are being evaluated. For patients unable to participate in a clinical trial, the current treatment recommendations for KRAS-mutant NSCLC are identical to those of NSCLC adenocarcinoma of unknown or untargetable mutation status. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation".)
Activating KRAS mutations are observed in approximately 20 to 25 percent of lung adenocarcinomas in the United States, and are generally associated with smoking [82,83]. The presence of a KRAS mutation appears to have at most a limited effect on overall survival in patients with early-stage NSCLC , although some older data had suggested that it was associated with a worse prognosis . NRAS is homologous to KRAS, associated with smoking, and mutations have been observed in approximately 1 percent of NSCLC . The clinical significance of NRAS mutations is unclear, and no effective targeted therapies have been identified.
The RAS family of oncogenes was originally identified through the study of rat sarcoma(ras)-inducing retrovirus, with KRAS, NRAS, and HRAS each representing different human gene homologs . As a membrane-bound intracellular GTPase, the RAS family of proteins is a central mediator of the MAPK (figure 2), signal transducer and activator of transcription (STAT), and phosphoinositide 3-kinase (PI3K) signaling pathways, which together control cell proliferation and apoptosis. Oncogenic RAS mutations, most commonly those corresponding to missense substitutions in codons 12, 13, or 61, cause constitutive activity of RAS independent of upstream signals by impairing the function of the RAS GTPase.
Targeted therapy under investigation — Numerous agents are under investigation for KRAS-mutant lung cancers, but we do not do not recommend their use outside of a clinical trial. The current focus of targeted therapeutics for patients with KRAS-mutated lung cancer is against downstream effectors of activated KRAS (figure 2), based on previous supporting preclinical evidence .
Studies examining targeted therapy against downstream targets are summarized:
●MEK inhibition with trametinib – Indirect evidence supporting the inhibition of this pathway comes from patients with metastatic melanoma and BRAF mutations, which also activate MEK signaling via the MAPK pathway. While trametinib may also have activity in NSCLC, it is not clear that KRAS mutational status is a predictor of efficacy [88-90].
In a phase II trial, 129 patients with documented KRAS-mutant NSCLC were randomly assigned to either trametinib (86 patients) or docetaxel (43 patients) as second-line therapy . The objective response rate was 12 percent in both treatment groups; there were no statistically significant differences between KRAS-mutant and KRAS wildtype in terms of progression-free survival or overall survival. In a second phase II trial, 47 patients with advanced NSCLC were treated with docetaxel plus trametinib and patients were analyzed by KRAS status with response rates of approximately 30 percent regardless of genotype . A parallel study treated 42 patients with pemetrexed plus trametinib and showed response rates of 17 percent regardless of KRAS status as well [88-90].
●MEK inhibition with selumetinib – Although in a phase II study of 87 patients with pretreated KRAS-mutant NSCLC the addition of the oral MEK inhibitor selumetinib to docetaxel improved response rate and progression-free survival , results of a subsequent phase III study have not confirmed these findings . In this trial, 510 patients were randomized to docetaxel or docetaxel plus selumetinib, but there were no differences observed in the selumetinib plus docetaxel arm with regard to progression-free survival (3.9 versus 2.8 months), overall survival (8.7 versus 7.9 months), or response rate (20 versus 14 percent).
Multiple previous efforts to identify specific RAS inhibitors that are clinically useful against KRAS-mutated lung cancer were unsuccessful. Approaches tested include farnesyl protein transferase and RNA inhibition.
PIK3CA, AKT1, PTEN alterations — PIK3CA encodes the catalytic subunit of phosphatidyl 3-kinase (PI3K), which is an intracellular central mediator of cell survival signals. AKT1 acts immediately downstream of PI3K. Phosphatase and tensin homolog (PTEN) inhibits AKT by dephosphorylation. Oncogenic alterations in this pathway, which occur more frequently in tumors of squamous histology and smokers, include gain-of-function mutations in PIK3CA and AKT1, and loss of PTEN function [93,94]. PIK3CA mutations may also promote resistance to EGFR TKIs in EGFR-mutant NSCLC . Small-molecule inhibitors of PI3Kinase and AKT are in clinical development and hold particular hope for the treatment of squamous cell lung cancer. However, since these alterations often overlap with other molecular changes, they may represent a "passenger" mutation rather than a "driver" alteration, and therefore clinical efficacy of these agents against specific molecular alterations is unknown.
In a series of 552 samples tested for a spectrum of point mutations, gain-of-function mutations in PIK3CA were found in 4 percent of NSCLC, including both adenocarcinoma and squamous cell histologies . No AKT mutations were observed in this series, but AKT1 activating mutations have been previously described in 3/50 specimens of squamous histology [95,96].
In analyses of squamous NSCLC tumors, alterations in the PI3K signaling pathway were relatively frequent [97-99]. For example, in a series of 178 squamous tumor samples analyzed by The Cancer Genome Atlas (TCGA) using a variety of complementary methods, PIK3CA mutations were observed in 16 percent of the samples, PTEN mutations or deletions in 15 percent, and AKT alterations in 20 percent .
SUMMARY AND RECOMMENDATIONS
●An improved understanding of the molecular pathways that drive malignancy in non-small cell lung cancer (NSCLC) has led to the development of agents that specifically target differences between normal and malignant cells. (See 'Introduction' above.)
●The most useful biomarkers for predicting the efficacy of targeted therapy in advanced NSCLC are somatic genome alterations known as "driver mutations." Driver mutations often impart an oncogene-addicted biology to the transformed cell, meaning that the mutated protein engenders reliance within the cancer cell to receive a signal from the driver in order to survive. (See 'Driver mutations as biomarkers' above and 'Molecular testing' above.)
●While molecular diagnostics have traditionally been performed on biopsies of tumor tissue, blood-based tests or so-called "liquid" biopsies are gaining popularity as they provide the opportunity to genotype in a less invasive and less expensive manner, and may offer a chance to monitor the molecular features of a cancer through the course of treatment. (See 'Liquid biopsies' above.)
●The best characterized of the driver mutations are epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, ROS1 rearrangement, and mutation in BRAF V600E. Identification of these biomarkers has led to highly specific treatments that have resulted in a major advance in therapy for tumors harboring these abnormalities. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
●The identification of other specific driver mutations is leading to the development of targeted therapies, which may become the preferred therapy for these NSCLC patient subsets. Whenever possible, patients should be enrolled in formal clinical studies. The NCI-MATCH study includes substudies for many of the genomic alterations mentioned above (NCT02465060). (See 'NSCLC genotypes' above.)
●For patients without access to a targeted clinical trial, some approved therapies may be used "off-label" in the next-line setting after progression on a frontline chemotherapy regimen. For the following subsets of patients, we prefer off-label targeted therapy to immunotherapy or single-agent chemotherapy as the next-line option:
•Human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutations: For patients with a HER2 exon 20 insertion mutation, we suggest next-line targeted therapy with either afatinib monotherapy; or a combination of trastuzumab and single-agent chemotherapy (vinorelbine or docetaxel); or ado-trastuzumab emtansine rather than single-agent chemotherapy alone (Grade 2C). (See 'HER2 mutation' above.)
•MET exon 14 skipping mutations or amplification: For patients with a MET exon 14 skipping mutations, we suggest treatment with a MET inhibitor (crizotinib or cabozantinib) rather than single-agent chemotherapy as next-line therapy (Grade 2C). (See 'MET abnormalities' above.)
•RET rearrangements: For patients with RET rearrangements, we suggest treatment with a RET inhibitor such as cabozantinib, vandetanib, or alectinib rather than single-agent chemotherapy as next-line therapy (Grade 2C). (See 'RET translocation' above.)
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