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Personalized, genotype-directed therapy for advanced non-small cell lung cancer
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Personalized, genotype-directed therapy for advanced non-small cell lung cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jun 30, 2016.

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, has led to the development of agents that target specific molecular pathways in malignant cells. 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, 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. Research in this area and its potential applications to the clinical treatment of patients with NSCLC will be covered in this topic.

(See "Overview of the treatment of advanced non-small cell lung cancer".)

(See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

(See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

RATIONALE — 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 (non-cancer) 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 non-cancerous 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 non-existent).

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 targeted agent as first-line therapy in half of these cases [1]. 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). In the United States, the Lung Cancer Mutation Consortium analyzed samples using multiplex genotyping from 733 patients with adenocarcinoma at 14 centers in the United States, identifying a targetable driver mutation in 466 cases (64 percent) [2]. 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 [3]. 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 one standard platform for testing. In general, several techniques have been used:

Sequencing of the gene is the most comprehensive method for mutation testing. Direct sequencing can be used for discovery when the target abnormality is not known, but this process can be expensive and time-consuming. Furthermore, the mutation must be fairly prevalent among all the cells in the tissue sample in order to be detected by direct sequencing.

Next-generation sequencing overcomes many of the shortcomings of direct sequencing. 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, but is not yet used routinely in clinical practice.

Allele-specific testing analyzes the DNA for a predefined abnormality. The raw DNA is typically amplified using polymerase chain reactions (PCR) before the search for the mutated allele is undertaken, allowing for rare signals to be detected with greater sensitivity. This method tends to be faster and cheaper, but only pre-specified targets can be identified. Thus allele-specific testing cannot be used to identify new abnormalities.

Mass spectrometry, a method that analyzes short bits of DNA by mass and can detect when a segment is a different molecular weight than expected, equating to a mutation. This method also can only identify predefined abnormalities.

Fluorescence in-situ testing (FISH) is typically used to detect gene translocations, amplifications, and other rearrangements. With FISH, DNA probes are used to interrogate the chromosomes for the presence or absence of a specific DNA sequence. Following denaturation, a fluorescent labeled DNA probe is directly hybridized with the chromosomes on the slide (hence, the term "in situ" hybridization); immediate detection of the fluorescent signal is possible via fluorescence microscopy. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

The role of immunohistochemistry (IHC) is evolving [4,5]. IHC is considered an alternative to FISH in evaluating for ALK translocations. However, IHC is not currently recommended for testing for EGFR driver mutations since positive or negative results by IHC do not necessarily correlate with the presence or absence of an EGFR mutation.

Features of the various testing platforms that are most useful for clinical genotyping are those that:

Utilize clinically-available samples (most commonly formalin-fixed, paraffin-embedded tissue)

Are relatively inexpensive

Have clinically relevant turn-around times

Are semi-automated so that they are not reliant upon a single operator

Multiplexed genotyping — Multiplexed genotype testing allows an entire panel of genotypes of interest to be queried at a single time from a single tissue sample instead of doing the tests sequentially one by one [6,7]. This is the most tissue-efficient approach, particularly when dealing with small tumor samples. In addition, multiplexed genotyping is the most time-efficient process for screening patients and thus to facilitate prompt treatment or protocol inclusion.

Abnormalities seen in 5 percent or more of cases included KRAS mutations, EGFR sensitizing mutations, and ALK rearrangements (25, 17, and 8 percent of cases). Less common driver mutations included EGFR (other uncommon sites), ERBB2 (HER2), BRAF, PIK3CA, NRAS, MEK1, and AKT1 (4, 3, 2, <1, <1, <1, and 0 percent, respectively). In addition, 24 patients (3 percent) had two or more mutations, and MET amplification was observed <1 percent of the time.

The results of multiplex testing were used to guide therapy. For the 275 patients with a driver mutation who received targeted therapy, median survival was 3.5 years. In contrast, median survival for the 318 patients with a driver mutation who did not receive targeted therapy was 2.4 years, and the median survival for the 360 patients without a driver mutation was 2.1 years.

NSCLC GENOTYPES — This section reviews the most common driver mutations that have been identified in NSCLC for which targeted therapies specifically aimed at the driver mutation have been developed or are under investigation, as well as some frequently identified passenger alterations that may or may not be targetable.

Targeted agents should be considered for patients with a tumor harboring one of these driver mutations. When there is no established therapy for a given driver mutation or when inclusion in a clinical trial is not feasible, patients should be managed with chemotherapy like those without a driver mutation. (See "Overview of the treatment of advanced non-small cell lung cancer".)

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 [8]. In Asian populations, the incidence of EGFR mutations is substantially higher, up to 62 percent [9].

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, and afatinib. The use of EGFR TKIs is based upon the detection of these mutations. A discussion of the diagnosis and 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".)

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.

In advanced stage NSCLC, the presence of an ALK translocation strongly predicts for sensitivity to ALK TKIs (eg, crizotinib, ceritinib), 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".)

RAS mutations — 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 [10]. As a membrane-bound intracellular GTPase, the RAS family of proteins is a central mediator of the mitogen-activated protein kinase (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.

Frequency of mutations — Activating KRAS mutations are observed in approximately 20 to 25 percent of lung adenocarcinomas in the United States and are generally associated with a history of smoking:

In a study of 106 patients with adenocarcinoma of the lung, KRAS mutations were noted in exclusively in smokers (43 percent versus zero) [11].

In another series of 482 lung adenocarcinomas sequenced for KRAS mutations, transversion mutations (G->T or G->C) were more common in patients with a smoking history (22 percent) while transition mutations (G->A) were found in 15 percent of patients with lung adenocarcinoma who have never smoked cigarettes [12].

NRAS is homologous to KRAS, associated with smoking, and mutations have been observed in approximately 1 percent of NSCLC [6]. The clinical significance of NRAS mutations is unclear, and no effective targeted therapies have been identified.

Impact on prognosis — The presence of a KRAS mutation appears to have at most a limited effect on overall survival in patients with early stage NSCLC [13], although some of older data had suggested that it was associated with a worse prognosis [14].

The most extensive data on patients with resected NSCLC come from a combined analysis of four trials of adjuvant chemotherapy following resection [13]. In aggregate, these trials included 1543 patients, of whom 300 had mutations in KRAS. The difference in overall survival was not statistically significant when those with a mutation were compared with those with wild-type KRAS (hazard ratio [HR] for death 1.17, 95% CI 0.96-1.42).

In patients with stage IV NSCLC, the presence of a KRAS mutation appears to be associated with a worse prognosis. However, the interpretation of these results is complicated by the heterogeneity of the comparison group, which includes patients with EGFR mutations, who are known to have a better prognosis, as well as treatment arms that include EGFR TKIs to which KRAS patients generally do not respond.

In the phase III SATURN trial of maintenance erlotinib, KRAS mutation conferred a shorter time to progression than wild-type patients (HR 1.50, 95% CI 1.06-2.12) among the 239 patients on the placebo arm. However, the difference in overall survival was not statistically significant (HR 1.30, 95% CI 0.90-1.90) [15].

Retrospective series suggest that the presence of a KRAS mutation may be associated with shorter survival [16,17]. In one study of 1036 patients, multivariate analysis demonstrated that the presence of KRAS mutation was associated with shorter survival (HR 1.21, p = 0.048), while EGFR mutation was associated with longer survival (HR 0.6, p <0.001) [16].

Effect on response to therapies — KRAS mutations have been associated with response or resistance to particular therapies:

EGFR TKIs – There are conflicting data regarding sensitivity of KRAS mutant tumors to erlotinib. In the phase III TRIBUTE trial, among 55 patients with KRAS mutations, those treated with carboplatin and paclitaxel chemotherapy had a response rate of 23 percent while those treated with chemotherapy plus erlotinib had a response rate of 8 percent and a worse overall survival (HR 2.1) [18]. In the phase III SATURN trial, subgroup analysis of 90 patients with KRAS mutations showed a marginal trend toward benefit from maintenance erlotinib, with wide confidence intervals (HR 0.77, 95% CI 0.50-1.19) [15]. In the second line BR.21 trial of erlotinib versus placebo, those who were KRAS wild-type had a survival benefit from erlotinib (HR 0.69, p = 0.03) but those with KRAS mutations did not (HR = 1.67, p = 0.31) [19].

KRAS mutations confer resistance to cetuximab in patients with colorectal cancer. However, in subgroup analyses of the phase III FLEX and BMS099 clinical trials in NSCLC, the response to cetuximab was preserved among 75 and 202 patients with KRAS mutations [20,21].

KRAS mutations may sensitize tumors to antifolates [22,23] such as pemetrexed, possibly by upregulation of mir-181c, a micro RNA that can downregulate KRAS.

In a combined analysis of four adjuvant chemotherapy trials, patients with a KRAS codon 12 mutation derived benefit from chemotherapy similar to patients with wild-type KRAS. However, the presence of a codon 13 mutation appeared predictive of worse survival from adjuvant chemotherapy, though the total number of patients with codon 13 mutations was small [13].

Targeted therapy for KRAS-mutated lung cancer — Multiple early 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.

The current focus of targeted therapeutics for patients with KRAS-mutated lung cancer is against downstream effectors of activated KRAS. This approach is promising in KRAS mutant lung cancer, as demonstrated by an experiment in mice harboring KRAS mutant tumors whose tumors were markedly reduced following treatment with the combination of MEK and PI3K small molecule inhibitors [24].

Evidence supporting targeted therapy against downstream targets comes from several studies:

MEK inhibition with selumetinib – In a phase II trial, 87 previously treated patients with KRAS mutant NSCLC were randomly assigned to docetaxel with or without selumetinib, an oral MEK inhibitor (figure 2) [25]. The addition of selumetinib significantly improved progression-free survival (median 5.3 mo versus 2.1 mo, HR 0.58 80% CI 0.42-0.79), and there was a trend toward increased overall survival (median 9.4 mo versus 5.2 mo, HR 0.80, 80% CI 0.56-1.14). Objective partial responses were observed in 16 of 43 patients (37 percent) treated with docetaxel plus selumetinib compared with none of 40 receiving docetaxel plus placebo. However, toxicity was also greater with more febrile neutropenia, diarrhea, nausea, vomiting, and rash.

A parallel preclinical study using genetically engineered mice found that KRAS-only mutant tumors were very sensitive to the combination of selumetinib and docetaxel, while tumors with KRAS and p53 alteration were of intermediate sensitivity, and KRAS plus LKB1 mutations were resistant to treatment. These results suggest that KRAS mutant tumors may be heterogenous with the efficacy of targeted treatment dependent upon the "passenger" mutation context.

However, in another phase II trial, patients with advanced NSCLC were randomly assigned to selumetinib or selumetinib plus erlotinib [26]. No evidence of increased activity with the combination regimen was observed in patients with either wild-type or mutant KRAS.

MEK inhibition with trametinib – Indirect evidence supporting the inhibition of this pathway comes from patients with metastatic melanoma and BRAF mutations, which also activates MEK signaling via the MAPK pathway. In that setting, the oral downstream MEK TKI trametinib was US Food and Drug Administration (FDA)-approved in 2013 for significantly prolonging progression-free and overall survival [27].

Trametinib may also have activity in NSCLC, although it is not clear that KRAS mutational status is a predictor of efficacy [28-30]. 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 [30]. The objective response rate of 12 percent in both treatment groups; there were no statistically significant differences between KRAS mutant and KRAS wild-type 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 [29]. A parallel study treated 42 patients with pemetrexed plus trametinib showed response rates of 17 percent regardless of KRAS status as well [28].

mTOR inhibition – KRAS mutant NSCLC may also be dependent on downstream mTOR signaling pathways. A randomized discontinuation clinical trial evaluating the mTOR inhibitor ridaforolimus in 79 patients with NSCLC demonstrated a response rate of 1 percent, but demonstrated doubling of progression-free survival for patients with stable disease at eight weeks randomized to continue drug versus those randomized to discontinue (4 versus 2 month, HR 0.36, p = 0.013), and also showed a trend toward overall survival improvement (18 versus 5 month, HR 0.46, p = 0.09) [31].

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 mutation status. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation".)

ROS1 translocation — ROS1 is a receptor tyrosine kinase of the insulin receptor family 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 [32-34]. 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.

The ROS1 tyrosine kinase is highly sensitive to crizotinib in preclinical models due to a high degree of homology between the ALK and ROS tyrosine kinase domains, and this information led to its clinical evaluation [32]. An open label, international study of crizotinib was conducted in 50 patients, all of whose tumors contained the ROS1 translocation (NCT00585195) [35]. Over 80 percent of patients had received one or more prior chemotherapy treatment regimens. 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 [36].

The side effects 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".)

Based upon these results, treatment with crizotinib is recommended for patients with the ROS1 translocation whenever possible, including those who have received chemotherapy and those who are treatment naive. Other second generation inhibitors are also under development, but there are currently no data regarding the use of ceritinib in patients with ROS1 acquired resistance to crizotinib.

HER2 mutation — HER2 (ERBB2) is an EGFR family receptor tyrosine kinase. Mutations in HER2 have been detected in approximately 1 to 2 percent of NSCLC tumors [37,38]. 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. There is no obvious association between HER2 amplification and HER2 mutations, and previous trials demonstrated no benefit for trastuzumab in HER2 amplified NSCLC [39,40].

However, newer case series suggest that patients with tumors harboring HER2 insertions often respond to trastuzumab and chemotherapy [38,41] or to afatinib, an EGFR/HER2 TKI [38,42], with time to progression generally around four months.

A phase I study conducted with the irreversible pan-HER inhibitor neratinib and the 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 [43].

Larger clinical trials are ongoing to further define efficacy of these classes of agents in this lung cancer subtype.

BRAF mutation — BRAF is a downstream signaling mediator of KRAS which activates the MAP kinase pathway. BRAF mutations have been observed in 1 to 3 percent of NSCLC and are usually associated with a history of smoking [6,44-47]. In NSCLC, BRAF mutations have been identified predominantly in patients with adenocarcinoma. Activating BRAF mutations can occur either at the V600 position of exon 15, like in melanoma, or outside this domain. BRAF mutations have also been described as a resistance mechanism in EGFR mutation positive NSCLC [48].

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 [46]. 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 is over six months.

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.

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) [49]. All but two of these patients had progressed on a prior line of platinum-based chemotherapy [50,51]. 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 [49].  

In a phase II trial of dabrafenib in 78 patients with BRAF V600 mutation-positive NSCLC who had received one or more prior systemic therapies alone [52], the objective response rate was 32 percent, and the disease control rate (objective responses plus stable disease) was 56 percent. The median duration of response was 11.8 months [53].

Combination therapies with BRAF inhibitors are also an area of active investigation. In a phase II study of 59 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 57 evaluable patients, and the disease control rate was 79 percent [54]. The side effect profile was consistent with that observed in dabrafenib and dabrafenib plus trametinib clinical trials in patients with melanoma. (See "Molecularly targeted therapy for metastatic 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 'Targeted therapy for KRAS-mutated lung cancer' above.)

MET abnormalities — MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF). Abnormalities associated with MET include overexpression due to gene amplification and exon 14 skipping mutations.

Increased MET expression may predict response to MET targeted drugs [55]. Standard testing methods for MET expression testing include immunohistochemistry (IHC), which is positive in 25 to 50 percent of NSCLC specimens, and FISH for MET gene amplification, which occurs at an intermediate or high level in approximately 6 percent of patients with NSCLC and appears to be smoking related [56,57]. MET expression also appears to be associated with a worse prognosis [58,59].

The MET exon 14 skipping mutation reduces degradation of the MET protein, causing it to behave as an oncogenic driver. This mutation has been identified in approximately 3 to 4 percent of nonsquamous NSCLC patients [60,61]. Pulmonary sarcomatoid carcinoma appears to have a particularly high incidence of these mutations, which were observed in 8 of 36 tumors with this diagnosis [61-63].

A number of inhibitors with activity against MET are being tested in NSCLC for the following genetic lesions:

MET amplification – In addition to blocking ALK and ROS1, crizotinib is also a potent MET inhibitor. Initial studies of crizotinib in a highly selected group of 12 patients with intermediate or high MET gene amplification demonstrated responses in 5 patients and stable disease in 5 additional, which were unusually prolonged in MET-high patients [56]. Several centers in the United States have a clinical trial of crizotinib open for MET-amplified patients (NCT00585195).

MET exon 14 skipping mutations – In a small series of four patients treated with crizotinib, three had a partial tumor response and one had progressive disease [63]. Cabozantinib, which has activity against MET, was given to a patient and resulted in five months of stable disease [63]. Another series reported responses to capmatinib, an investigational MET inhibitor, in patients with NSCLC and these mutations [61].

MET and EGFR co-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 the various fusion partners (CCDC6, KIF5B, NCOA4) have been identified in 1 to 2 percent of patients with adenocarcinoma or adenosquamous carcinoma of the lung [64-67]. In a series of 13 cases, those with a RET translocation tended to be younger and never smokers [66].

Vandetanib, sorafenib, and sunitinib all inhibit the RET tyrosine kinase, as well as other targets. Large clinical trials in unselected NSCLC patient populations have been conducted with these agents and did not demonstrate a survival benefit. However, case reports have described responses to both vandetanib and cabozantinib in patients whose tumors contained a RET translocation [68-70].

More extensive data come from a phase II trial of cabozantinib [71]. Interim results of this trial were presented at the 2015 American Society of Clinical Oncology (ASCO) meeting. All patients had a RET translocation, and were treated with cabozantinib at a dose of 60 mg/day. In 16 evaluable patients, 7 had partial responses (38 percent) and 9 had stable disease. With a median follow-up of two years, the median progression-free survival was seven months and the median overall survival was 10 months.

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. PTEN inhibits AKT by dephosphorylation. Oncogenic alterations in this pathway include gain-of-function mutations in PIK3CA and AKT1, and loss of PTEN function. Alterations in the PI3K signaling pathway appear more frequently in tumors of squamous histology and smokers [72,73].

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 [6]. No AKT mutations were observed in this series, but AKT1 activating mutations have been previously described in 3/50 specimens of squamous histology [74,75].

In recent analyses of squamous NSCLC tumors, alterations in the PI3K signaling pathway were relatively frequent:

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 [76].

In another series of 95 surgically resected squamous lung cancers, PIK3CA mutations were observed in 4 percent of tumors, and AKT1 mutation in 1 tumor [77].

In advanced stage patients, a series of 27 tumors demonstrated PTEN loss by immunohistochemistry in 3 (11 percent) [78].

PIK3CA mutations also may promote resistance to EGFR TKIs in EGFR-mutant NSCLC [79].

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, therefore clinical efficacy of these agents against specific molecular alterations is unknown.

FGFR1 amplification — Fibroblast growth factor receptor-1 (FGFR1) is a cell surface tyrosine kinase receptor that mediates cell survival and proliferation. Gene amplification of FGFR1 has been detected in 13 to 25 percent of squamous tumors [76,78,80-82]. For patients with squamous cell carcinomas, FGFR1 amplification is associated with smoking and with worse overall survival [82].

Small molecule inhibitors of FGFR1 are in clinical development. A phase I study of the FGFR small molecule TKI BGJ398 included 26 patients with FGFR1-amplified squamous cell carcinoma of the lung treated at a dose of 100 mg/day or higher [83]. Four partial responses (15 percent) were observed.

β-catenin mutation — The CTNNB1 gene encodes β-catenin, which in conjunction with the APC protein is important for the regulation of epithelial cell growth. Mutations in this gene have been observed in approximately 2 percent of NSCLC [6], particularly in tumors with EGFR mutations following acquired resistance to EGFR inhibitors [79]. As these alterations are most often observed in conjunction with another driver mutation, a therapeutic strategy targeting β-catenin is of uncertain benefit.

DDR2 mutation — The DDR2 gene encodes a cell surface receptor tyrosine kinase that is mutated to an active form in about 4 percent of squamous cell carcinomas of the lung [76,84]. Dasatinib inhibits DDR2, and one patient treated with the combination of dasatinib and erlotinib had a tumor response [84]. Clinical trials to confirm efficacy are underway.

MEK1 mutation — The MAP2K1 gene encodes the MEK1 protein, which is downstream of RAF in the MAP kinase pathway, a central mediator of cell proliferation signals. MAP2K1 mutations may be found in approximately 1 percent of adenocarcinomas [85]. The clinical response of MAP2K1 mutant NSCLC to MEK or ERK inhibitors is an area of investigation.

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.

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 the genome of cancer cells within genes that encode for proteins critical to cell growth and survival. 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 'Rationale' above and 'Molecular testing' above.)

The best characterized of these biomarkers are epidermal growth factor receptor (EGFR) mutations and (anaplastic lymphoma kinase) ALK translocation. 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 improved results using targeted therapy in patients with these specific molecular abnormalities has led to an effort to identify other driver mutations and specific therapies appropriate for each driver mutation (see 'NSCLC genotypes' above). For patients without access to a targeted clinical trial, some approved therapies may be used "off label" with anticipated benefit for some patients (algorithm 1 and algorithm 2 and algorithm 3):

ROS1 rearrangements: For patients with a ROS1 rearrangement we recommend first-line management with crizotinib rather than platinum-based chemotherapy (Grade 1B). For patients who have received prior chemotherapy, we recommend treatment with crizotinib rather than second-line chemotherapy (Grade 1A). (See 'ROS1 translocation' above.)

HER2 exon 20 insertion mutations: For patients with a HER2 exon 20 insertion mutation we suggest second-line targeted therapy with either afatinib monotherapy or trastuzumab in combination with single agent chemotherapy (vinorelbine or docetaxel) rather than single agent chemotherapy alone (Grade 2C). (See 'HER2 mutation' above.)

BRAF V600 mutations: For patients with a BRAF V600 mutations, we suggest a BRAF inhibitor (dabrafenib or vemurafenib) and consideration of combined mitogen-activated protein kinase (MAPK) pathway inhibition (dabrafenib plus trametinib) rather than single-agent chemotherapy as second-line therapy (Grade 2C). As in melanoma, combination therapy may be more durable and may be more tolerable. (See 'BRAF mutation' above.)

MET exon 14 skipping mutations: 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 second 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 or vandetanib rather than single agent chemotherapy as second line therapy (Grade 2C). (See 'RET translocation' above.)

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.

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