Version May 2024
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 c-ROS oncogene 1 (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. Unfortunately, the proportion of patients with advanced adenocarcinoma receiving tumor genetic testing remains low, and it is therefore important to increase awareness regarding potentially targetable genetic alterations. A general discussion of these alterations, as well as other potential driver mutations, is found in this topic. A treatment approach to advanced NSCLC, as well as more detailed discussion regarding EGFR-mutated and ALK-positive lung cancers, is found elsewhere.
●(See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
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 transforming, 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 downregulation 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 upfront 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 one-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).
Similarly, in the United States, the Lung Cancer Mutation Consortium analyzed tumors from 1007 patients for at least one gene, and from 733 patients for 10 genes (patients with full genotyping), identifying a targetable driver mutation in 64 percent of the cases examined by full genotyping [2]. Among 260 patients with an oncogenic driver who received a targeted agent, the median survival was 3.5 years; among 318 patients with a driver but without targeted therapy, median survival was 2.4 years; and among 360 patients without a driver, median survival was 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 — Patients with advanced NSCLC should have tumor assessed for the presence of driver mutations [3]. Guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association of Molecular Pathologists 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 any component of adenocarcinoma histology, or who have light- or never-smoking history [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 nonsquamous NSCLC patients, we initially recommend testing for EGFR (by a method that takes <1 to 2 weeks, on either tissue or blood) and ALK (by immunohistochemistry [IHC] or fluorescence in-situ testing [FISH]). Next-generation sequencing on tissue or blood 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 or other types of NSCLC, for example those with a light- or never-smoking history. In addition, we recommend programmed cell 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):
●DNA 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. Usually, turnaround is <1 week. 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.
●DNA 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 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 represents a technological leap forward from direct sequencing in that it is a multiplexed test and tends to be faster (a few days) 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.
●DNA and RNA 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. The sensitivity is high enough to identify many molecular rearrangements in blood (circulating tumor DNA [ctDNA]) (see 'Liquid biopsies' below). Moreover, NGS can often detect intronic gene alterations that would historically be identified only by FISH. We routinely use DNA NGS in our clinical practice. RNA-based sequencing tests are becoming more routine and may be more sensitive to detect gene fusions and MET exon-14 alterations than DNA-based methods.
●Fluorescence in-situ testing (FISH) – FISH is typically used to detect gene rearrangements such as translocations and other alternations such as amplifications or deletions, for example, ALK or c-ROS oncogene 1 (ROS1) rearrangements. 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-positive NSCLC and is very reliable and rapid (one day). However, IHC is still evolving for the detection of other targetable genomic alterations. In lung cancer IHC is the only 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 "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy'.)
Liquid biopsies — While molecular diagnostics have traditionally been performed on 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, potentially in cases with insufficient tumor samples for tissue sequencing, and may offer a chance to monitor the molecular features of a cancer through the course of treatment, or predict relapse after adjuvant treatment [6-9]. Some data have also suggested that such assays may be done on pleural and pericardial fluid as well [10,11].
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 [12]. 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) [13]. 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 take one to three 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 or clonal mutations in hematopoietic stem cells [12-14].
The US Food and Drug Administration has approved ctDNA tests to identify EGFR mutation-positive patients [15-17], and one of the tests uses NGS to also identify genetic abnormalities in 55 genes [16]. It is likely that as more data emerge, the use of liquid biopsies to assess other molecular abnormalities will become more widespread. (See 'EGFR mutations' below.)
However, a limitation of ctDNA-based 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. Liquid biopsies may yield results that predict clinical response to targeted agents, but the sensitivity ranges between 60 and 80 percent [18,19]. 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. 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 [20]. Furthermore, tests for PD-L1 expression cannot be conducted on liquid biopsies. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Factors in choosing initial therapy'.)
Finally, we do not use such assays to screen for or diagnose lung cancer. Although blood-based assays to diagnose a variety of cancers have been described [21-23], further investigation is needed prior to routine clinical use. Screening for lung cancer is discussed elsewhere. (See "Screening for lung cancer".)
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. In addition to individual studies, the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) study, LUNG-MAP cooperative group study, and other platform trials often include substudies for many of the genomic alterations mentioned below (NCT02465060, NCT03851445).
EGFR mutations — Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinomas in the United States and occur more frequently in nonsmokers [24]. In Asian populations, the incidence of EGFR mutations is substantially higher, up to 62 percent [25]. The use of EGFR tyrosine kinase inhibitors (TKIs) is based upon the detection of these mutations, which may be detected either in solid tissue biopsies or in liquid biopsies [26]. Any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory EGFR mutation result is generally acceptable for clinical decision-making [27]. In advanced NSCLC, the presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR TKIs, and therefore, targeted therapy should be used ahead of chemotherapy and immunotherapy in EGFR-positive NSCLC. For patients treated progressing on a first- or second-generation EGFR TKI, we offer repeat tumor or liquid biopsy to identify mechanisms of acquired resistance. However, the use of first-line osimertinib may largely prevent the development of T790M resistance [28]. For patients with EGFR-positive NSCLC who previously have been exposed to immunotherapy, there are important toxicity considerations discussed elsewhere, along with a detailed discussion of the general treatment of EGFR-mutant NSCLC. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
ALK rearrangements — Rearrangements involving the anaplastic lymphoma kinase (ALK) tyrosine kinase are present in approximately 4 percent of NSCLC adenocarcinomas 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 gene rearrangement (ALK-positive NSCLC) strongly predicts for sensitivity to ALK TKIs (eg, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib), and treatment with these agents significantly prolongs progression-free survival (PFS). 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 rearrangements — c-ROS oncogene 1 (ROS1) is a receptor tyrosine kinase that acts as a driver oncogene in 1 to 2 percent of NSCLCs via a genetic translocation between ROS1 and other genes, the most common of which is CD74 [29-32]. Histologic and clinical features that are associated with ROS1-positive NSCLC 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.
●Initial treatment options – The ROS1 tyrosine kinase is highly sensitive to the ROS1/MET inhibitor crizotinib as well as the ROS1/tropomyosin receptor kinase (TRK) inhibitors entrectinib and repotrectinib; these agents are US Food and Drug Administration (FDA) approved for patients with the ROS1 translocation, including those who have received chemotherapy and those who are treatment naïve, and we suggest the use of any of these agent in the first-line setting, whenever possible [33-36]. Though the efficacy in systemic disease appears comparable, we favor entrectinib or repotrectinib for patients with central nervous system (CNS) involvement, due to better intracranial penetration [34]. (See "Brain metastases in non-small cell lung cancer", section on 'ROS1 translocations'.)
•Entrectinib – In a pooled analysis of three phase I or II trials including 161 patients with ROS1 fusion-positive NSCLC, with or without CNS metastases, the ORR to entrectinib was 67 percent, the median PFS was 15.7 months, and the 12-month OS was 81 percent. Responses appeared durable, with a median duration of response of 15.7 months [37]. Sixty-three percent of patients had received ≥1 prior line of systemic therapy. These results are similar to earlier analyses of these trials, which led to FDA approval [34,38]. In a pooled safety analysis including 355 patients, the most common adverse effects included fatigue (48 percent), edema (40 percent), constipation (46 percent), dysgeusia (44 percent), dizziness (38 percent), nausea (34 percent), dysesthesia (34 percent), cognitive impairment (27 percent), vomiting (24 percent), and pyrexia (21 percent) [34].
•Repotrectinib – In a phase I/II study, among 71 patients who were naïve to tyrosine kinase inhibitors (TKIs), the objective response rate was 79 percent, the median PFS was 36 months and the 18-month survival rate was 88 percent; among 56 patients with one prior TKI and no chemotherapy, the objective response rate was 35 percent, the median PFS was nine months, and the median OS was 25 months [39]. Among 426 patients included in a safety analysis (irrespective of tumor type), grade ≥3 adverse events occurred in 29 percent, with the most common being anemia (in 4 percent) and increased blood creatine kinase level (in 4 percent). In a separate pooled safety analysis including 351 patients, the most common adverse effects included dizziness (64 percent), dysgeusia (50 percent), peripheral neuropathy (47 percent), constipation (37 percent), dyspnea (30 percent), ataxia (29 percent), and cognitive disorders (23 percent) [36].
•Crizotinib – Observational data support the use of crizotinib for ROS1-positive NSCLCs [40]. In an open-label, international study of crizotinib of 53 patients with ROS1-positive NSCLC, over 80 percent of whom had received one or more prior chemotherapy regimens, the objective response rate (ORR) was 72 percent (6 complete and 32 partial responses). The median duration of response was 25 months, and the median PFS and overall survival (OS) were 19.3 and 51 months, respectively [41,42]. A similar response rate was observed in a phase II trial of crizotinib in 127 East Asian patients with ROS1-positive NSCLC, with median PFS of 15.9 months [43]. These results compare favorably with indirect comparisons with chemotherapy or chemoimmunotherapy, in which the median OS has been reported to be on the order of nine months to two years, respectively, as discussed elsewhere. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)
The side-effect profile associated with treatment was consistent with that seen when crizotinib has been used in ALK-positive NSCLC, and it has resulted in improved quality of life relative to patients on chemotherapy in a randomized trial in that setting [44]. However, the intracranial penetration of crizotinib is limited, and CNS-only relapses are often seen [40]. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer" and "Brain metastases in non-small cell lung cancer", section on 'ROS1 translocations'.)
●After progression on crizotinib – If a patient has experienced progression on crizotinib, we suggest lorlatinib as next-line therapy. Lorlatinib, approved in ALK-positive NSCLC after progression on other ALK inhibitors, appears to also overcome acquired resistance to crizotinib in ROS1-positive NSCLC. In a phase I/II trial including 69 patients with ROS1-positive NSCLC, 48 of whom had received a prior ROS1 TKI treatment, treatment with lorlatinib led to responses in both crizotinib-naïve patients (ORR, 62 percent) as well as in those with prior crizotinib exposure (ORR of 35 percent among those who had received crizotinib as their only prior TKI) [45]. Intracranial activity has also been demonstrated. After progression on lorlatinib, we move to nontargeted approaches (ie, chemotherapy and consideration of immunotherapy, though responses to immunotherapy are very rare [46]). (See "Brain metastases in non-small cell lung cancer" and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)
Other TKIs are also being tested in ROS1-positive NSCLC. Case reports suggest that cabozantinib may be effective in ROS1-translocated cancers that have become resistant to crizotinib [47-49]. Additionally, ceritinib has activity, though it does not otherwise appear to overcome acquired resistance to crizotinib. In a phase II trial of 28 evaluable patients with advanced ROS1-rearranged NSCLC, the ORR with ceritinib was 62 percent, duration of response was 21 months, and disease control rate was 81 percent [50]. The median PFS was 9.3 months overall and 19.3 months for crizotinib-naïve patients. Median OS was 24 months. Five of eight patients with brain metastases experienced disease control. However, with the improved CNS penetration of entrectinib, the role for this off-label strategy is unclear. Alectinib and brigatinib, while effective in ALK-positive NSCLC, have little to no established ROS1 inhibitory activity. Additionally, the investigational agent DS-6051b has emerging results in early-phase clinical trials in ROS1 NSCLC [51,52].
MET abnormalities — MET is a tyrosine kinase receptor for hepatocyte growth factor. MET abnormalities include MET exon-14-skipping mutations (in 3 percent of lung adenocarcinomas and up to 20 percent of the relatively rare sarcomatoid-histology NSCLC) and MET gene amplification (in 2 to 4 percent of treatment-naïve NSCLC, and 5 to 20 percent of EGFR-mutated tumors that have acquired resistance to EGFR inhibitors) [53-66]. Exon-14-skipping mutations are most commonly found by DNA or RNA NGS, while MET amplification may be detected by FISH or some NGS panels [67,68]. Our approach is as follows.
●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. The MET inhibitors capmatinib and tepotinib are approved by the FDA for adult patients with a MET exon-14-skipping mutation, and we suggest the use of either in the front-line setting for such patients, rather than immunotherapy and/or chemotherapy [69]. However, alternatively, it is also acceptable to use these agents in the subsequent-line setting, after progression on chemotherapy and/or immunotherapy [70].
In the GEOMETRY-mono-1 trial including 97 patients with advanced NSCLC associated with a MET exon-14-skipping mutation, among 28 patients with treatment-naïve disease, the overall response rate with capmatinib was 68 percent and median PFS was 12.4 months; among 69 previously treated patients, the overall response rate was 41 percent and median PFS was 5.4 months [71]. The most common treatment-related adverse events included peripheral edema (43 percent), nausea (34 percent), increased creatinine (18 percent), and vomiting (19 percent). A separate phase I trial, as well as a retrospective series also reported responses to capmatinib in patients with NSCLC and these mutations [64,72]. Capmatinib also showed activity among the subset with brain metastases, as discussed elsewhere. (See "Brain metastases in non-small cell lung cancer", section on 'MET exon-14-skipping mutations'.)
Tepotinib has also demonstrated activity in a single-arm phase II trial of 152 patients with NSCLC and a MET exon-14-skipping mutation, in which the overall response rate with tepotinib was 46 percent, with a median duration of response of 11 months [73]. Peripheral edema was the main toxic effect of grade 3 or higher, occurring in 7 percent.
Crizotinib is another potent MET inhibitor, in addition to inhibiting ALK and ROS1. It was historically used off label in the treatment of MET NSCLC, but we no longer recommend it following the FDA approval of capmatinib for this indication. In a series of 65 patients with MET exon-14-altered NSCLCs treated with crizotinib, the ORR was 32 percent, with a median PFS of 7.3 months and duration of response of 9.1 months [74]. Smaller studies have also suggested activity in NSCLC with MET exon-14-skipping mutations [66,75]. Cabozantinib, a multitargeted TKI that has activity against MET, was given to a patient and resulted in five months of stable disease [64,66].
The MET inhibitors glesatinib and savolitinib are also being tested in clinical trials, as well as the EGFR/MET bispecific antibody amivantamab.
●MET amplification – For those with high-level MET amplification (>5-fold increase in gene copy number [GCN] or MET/CEP7 ratio >5) who have progressed on chemotherapy and/or immunotherapy, or those who have MET amplification as determined by a CLIA-approved DNA NGS test, we suggest treatment with a MET inhibitor (eg, capmatinib or crizotinib) as next-line therapy. However, these agents are not yet approved for this indication by the FDA, and the ideal methodology for determining level of amplification and appropriate cutoffs for treatment are still an active area of research.
•Capmatinib – In a phase I trial of 55 patients with advanced MET-dysregulated NSCLC, roughly three-quarters of whom had received two or more prior systemic therapies, the overall response rate to capmatinib among 15 patients with MET GCN ≥6 was 47 percent, with a median PFS of 9.3 months [72]. The response rates were 25 percent for those with MET GCN between 4 and 6, and 6 percent for those with GCN <4. When MET overexpression was analyzed using other methods, the response rate among patients with a tumor MET/CEP7 ratio of ≥2 was 44 percent, versus 22 percent for those with ratio <2; and 27 percent for those with MET IHC 3+, 14 percent for IHC 2+, and 0 percent for those with IHC 0 to 1+.
•Crizotinib – In a single-arm study including 38 patients with MET amplification by FISH testing (MET-to-CEP7 ratio ≥1.8), those with high MET amplification (≥4 MET-to-CEP7 ratio) had an ORR of 38 percent with crizotinib and median PFS of 6.7 months [76]. Those with medium MET amplification (>2.2 to <4 MET-to-CEP7 ratio) had a response rate of 14 percent and PFS of 1.9 months. Those with low MET amplification (1.8 to ≤2.2 MET-to-CEP7 ratio) had a response rate of 33 percent and PFS of 1.8 months.
Increased MET expression may predict response to MET-targeted drugs, but also appears to be associated with an overall worse prognosis [77,78]. There are several clinical trials available of MET inhibitors for MET-amplified NSCLC.
RET rearrangements — The rearranged during transfection gene (RET) encodes a cell surface tyrosine kinase receptor that is frequently altered in medullary thyroid cancer. Recurrent rearrangements between RET and various fusion partners (coiled-coil domain containing 6 [CCDC6], kinesin family member 5B [KIF5B], nuclear receptor coactivator 4 [NCOA4]) have been identified in 1 to 2 percent of adenocarcinomas, and occur more frequently in younger patients and in never-smokers [79-82]. Rearrangements can be detected with break-apart FISH or NGS.
We suggest use of the RET inhibitor selpercatinib in the front-line setting rather than immunotherapy and/or chemotherapy, but we consider pralsetinib to be an acceptable alternative (though with less supporting data than selpercatinib) [83,84]. However, it is also acceptable to use these agents in the subsequent-line setting. Selpercatinib is also approved for patients with locally advanced RET-positive NSCLC [84].
●In a randomized phase III trial, among 212 patients with advanced RET fusion–positive NSCLC, selpercatinib improved median PFS relative to control treatment, which consisted of platinum-based chemotherapy, with or without pembrolizumab, per investigator's choice (25 versus 11 months; HR 0.46, 95% CI 0.31-0.70) [85]. Improvements were observed with selpercatinib when compared with chemotherapy, irrespective of whether pembrolizumab was administered. Objective response rates were 84 versus 65 percent, respectively. The time to progression affecting the central nervous system was also better with selpercatinib (HR 0.28). Overall, the incidence of grade ≥3 events was higher with selpercatinib than with control treatment (70 versus 57 percent). The most frequent grade ≥3 events with selpercatinib were hypertension (20 percent), alanine aminotransferase increase (22 percent), and aspartate aminotransferase increase (13 percent).
These results are consistent with the previous multicohort, open-label, phase I/II LIBRETTO-001 study [86], in which the overall response rate among 69 treatment-naïve patients with RET fusion-positive NSCLC was 84 percent, with a median PFS of 22 months and median duration of response of 20 months [87]. Among 247 patients previously treated with platinum chemotherapy, the overall response rate was 61 percent, with a median PFS of 25 months, and with a median duration of response of 29 months. (See "Brain metastases in non-small cell lung cancer", section on 'RET fusions'.)
●Separately, in a multicohort, open-label study of 114 patients with metastatic RET fusion-positive NSCLC, among 27 patients with treatment-naïve disease, the overall response rate with pralsetinib was 70 percent, with 58 percent of responses lasting at least six months and median duration of response of 9 months [83,88,89]. Among 87 patients previously treated with platinum chemotherapy, the overall response rate was 61 percent, the median duration of response had not been achieved, and approximately 80 percent of responses lasted at least six months. Serious adverse reactions occurred in 45 percent of patients. Grade 3 to 4 events occurring in at least 2 percent included hypertension (14 percent), pneumonia (8 percent), diarrhea (3 percent), and fatigue (2 percent). Fatal adverse events occurred in 5 percent of patients, and occurred due to pneumonia and sepsis. Pralsetinib also showed activity among patients with brain metastases. (See "Brain metastases in non-small cell lung cancer", section on 'RET fusions'.)
Cabozantinib, vandetanib, alectinib, and sunitinib are multitargeted RET inhibitors that may be useful in certain circumstances as alternatives to selpercatinib and pralsetinib. They are approved by the FDA for other indications but are significantly less potent than the RET inhibitors discussed above. For example, in a phase II trial of cabozantinib including 25 evaluable patients, all of whom had RET-positive tumors, treatment with cabozantinib 60 mg/day led to partial responses in seven (28 percent) and stable disease in nine (36 percent) patients [90,91]. With a median follow-up of 8.9 months, the median PFS was 5.5 months and the median OS was 9.9 months. Reports have also described responses to vandetanib, sunitinib, and alectinib in patients whose tumors were RET positive [92-95]. In a retrospective registry study of 165 patients with RET-positive NSCLC, the response rates to cabozantinib, vandetanib, and sunitinib were 37, 18, and 22 percent, respectively [96].
BRAF mutations — BRAF is a downstream signaling mediator of Kirsten rat sarcoma viral oncogene homolog (KRAS) that activates the mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations have been observed in 1 to 3 percent of NSCLCs and are usually associated with a history of smoking [97-101]. 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.
Clinical characteristics and prognosis, according to mutation — Patients with V600 BRAF mutations appear to have a better prognosis than those with non-V600 BRAF mutations [100]. In general, BRAF-mutant NSCLC (both V600 and non-V600) appears to respond better to immunotherapy than most driver oncogene NSCLC [46].
While sensitivity to TKIs has traditionally led investigators to distinguish BRAF mutations as either V600 or non-V600, a classification scheme (class I to III) that further categorizes BRAF mutations according to their functional impact on the MAPK pathway has also been proposed [102,103]. In this setting, V600 mutations that produce a constitutively active RAF kinase are categorized as class I. Non-V600 mutations are classified as either class II or III depending on whether they produce active or dead forms of the RAF kinase, respectively.
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 [100]. 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 mutations (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. In this experience, no patients were treated with BRAF/MEK combination therapy.
A separate study of 236 patients with BRAF-mutated NSCLC reported similar differences between patients with V600 versus non-V600 mutations. In this cohort, OS was significantly longer among patients with class I V600 mutations (40.1 months) compared with patients with class II (13.9 months) or class III (15.6 months) non-V600 mutations [104]. Compared with patients with non-V600 mutations, those with V600 mutations also had lower rates of CNS metastases, a factor that may contribute to differences in outcomes.
BRAF V600E mutation — For patients with NSCLC with BRAF V600E mutations, combinations of BRAF and MEK inhibitors are effective; two combinations, dabrafenib plus trametinib and encorafenib plus binimetinib, are approved by the FDA [105,106]. We suggest the use of either of these agents in the front-line setting for such patients, rather than immunotherapy and/or chemotherapy, given the response rates and PFS observed in small phase II studies.
As in melanoma, combination therapy may be more durable than single-agent treatment. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib'.)
Although BRAF inhibition with single oral small-molecule TKIs (eg, vemurafenib, dabrafenib) initially appeared to be an effective strategy in the treatment of progressive BRAF V600-mutant NSCLC [107,108], subsequent trials demonstrated that combination therapy consisting of BRAF and MEK inhibitors is the preferred treatment strategy:
●In a phase II study of 57 patients with previously treated, advanced NSCLC with the BRAF V600E mutation, the combination of dabrafenib plus trametinib was associated with an ORR of 68 percent in 52 evaluable patients, and the disease control rate was 81 percent [109]. The median PFS was 10.2 months. The side effect profile was consistent with that observed in dabrafenib plus trametinib clinical trials in patients with melanoma. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'BRAF V600 mutant disease'.)
●In another cohort of the same phase II study, 36 previously untreated patients with advanced NSCLC and a BRAF V600E mutation were treated with dabrafenib plus trametinib [109]. The radiographic overall response rate was 64 percent and included two patients with a complete response and 21 with a partial response. The median PFS was 10.8 months as assessed by investigators.
●The combination of encorafenib plus binimetinib has also demonstrated promising results in patients with BRAF V600E mutant metastatic NSCLC. In a single-arm study, among 98 patients with BRAF V600E mutant metastatic NSCLC (59 treatment-naïve and 39 previously treated, none with prior BRAF/MEK inhibitors), ORR was 75 percent in treatment-naïve and 46 percent in previously treated patients [110]. The median PFS was not estimable at a median follow up of 18 months in treatment-naïve patients; median PFS was 9.3 months in those with previous treatment. Treatment-related serious adverse events occurred in 14 percent, with the most common being colitis (3 percent).
BRAF non-V600E mutations — We do not generally recommend the use of BRAF or MEK inhibitors for non-V600E BRAF-mutant NSCLC.
Other strategies for patients whose cancers harbor BRAF mutations include the use of downstream MEK TKIs as monotherapy (figure 2). While this is of particular interest for some BRAF class II non-V600E tumors that generally appear insensitive to BRAF inhibitors, class III non-V600E BRAF mutations are kinase dead and would not be expected to respond to BRAF or MEK inhibition. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
NTRK fusions — Fusions involving one of three tropomyosin receptor kinases (TRK) occur across many tumor types and are very rare (<1 percent prevalent) in NSCLC. The oral TRK inhibitor larotrectinib is FDA approved for advanced tumors that have all of the following characteristics: harbor a neurotrophic receptor tyrosine kinase (NTRK) gene fusion, lack a known acquired resistance mutation, and have no satisfactory alternative treatments available (or have progressed following treatment) [111]. Entrectinib is another TRK inhibitor that is FDA approved in this setting [112]. Thus, for patients with advanced, NTRK-positive NSCLC, we suggest either larotrectinib or entrectinib, either in the first-line or subsequent treatment setting.
The efficacy of larotrectinib has been shown in early-phase clinical trials [113-115]. For example, in an analysis of three phase I/II trials including 159 patients with various TRK fusion-positive malignancies, the overall response rate by independent review was 79 percent [115]. Responses appeared durable, with 80 percent of responders still on treatment at a follow-up of 12 months. Of the 12 patients with lung tumors, nine experienced a response to treatment (response rate of 75 percent).
The FDA approval for entrectinib is based on combined results of several early-phase trials [112,116,117]. In a pooled analysis including 51 patients with NTRK-positive, unresectable or advanced tumors progressive NSCLC, the overall response rate was 63 percent, with a complete response rate of 11.8 percent [117]. Further details of entrectinib in TRK-positive cancers are found elsewhere. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Efficacy of first-generation TRK inhibitors'.)
Entrectinib and larotrectinib have not been compared head-to-head. As shown above, response rates in small, nonrandomized trials are similar. In the absence of direct comparisons, either option is appropriate for those with NTRK-positive NSCLC.
NRG1 fusions — Fusions involving the neuregulin 1 (NRG1) gene are rare (<1 percent prevalent) in NSCLC and are most reliably detected with tissue RNA NGS. Retrospective data have suggested poor activity of chemotherapy and immunotherapy in NRG1-fusion cancers. In an analysis of NRG1 fusion-positive lung cancers from 22 centers, objective response rate and median PFS to platinum-doublet chemotherapy were 13 percent and 5.8 months, respectively; the activity of chemoimmunotherapy and single-agent immunotherapy was also poor (ORR 0 percent/PFS 3.3 months and ORR 20 percent/PFS 3.6 months, respectively) [118].
A case series of five patients who received afatinib therapy for NRG1-positive lung cancer demonstrated four partial radiographic responses in five patients, with three of these lasting over 18 months [119]. Other targeted therapeutics against NRG1 fusions are in clinical trial development, such as seribantumab.
RAS mutations — The RAS family of oncogenes was originally identified through the study of rat sarcoma(ras)-inducing retrovirus, and includes Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), and Harvey rat sarcoma viral oncogene homologs (HRAS) [120]. Activating KRAS mutations, which activate a number of downstream signaling pathways (figure 2), are observed in approximately 20 to 25 percent of lung adenocarcinomas in the United States, and are generally associated with smoking [121,122]. The presence of a KRAS mutation appears to have at most a limited effect on OS in patients with early-stage NSCLC [123], although some older data had suggested that it was associated with a worse prognosis [124]. NRAS is homologous to KRAS, associated with smoking, and mutations have been observed in approximately 1 percent of NSCLCs [97]. The clinical significance of NRAS mutations is unclear, and no effective targeted therapies have been identified.
The 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 [125], as well as irreversible inhibitors of KRAS G12C.
Multiple agents specifically targeting the KRAS G12C mutation, which comprises almost 50 percent of KRAS mutations in NSCLC, have emerged.
Sotorasib — Sotorasib was the first targeted agent with regulatory approval for KRAS G12C-mutated NSCLC. It is approved by the FDA for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy [126]. Sotorasib has several drug interactions and should typically not be coadministered with proton pump inhibitors, H2-receptor antagonists, and strong cytochrome P450 3A4 (CYP3A4) inducers, and certain CYP3A4 substrates and P-gp substrates.
In an open-label, randomized controlled trial among 345 patients with KRAS G12C-mutated advanced NSCLC who experienced progression on platinum-based chemotherapy and a programmed cell death 1 or programmed cell death ligand 1 inhibitor, those assigned to sotorasib had a better PFS compared with the docetaxel group by blinded independent review (5.6 versus 4.5 months, HR 0.66, 95% CI 0.51-0.86), with fewer grade ≥3 toxicities (33 versus 40 percent) and serious treatment-related adverse events (11 versus 23 percent) [127]. OS was similar between the treatment groups (10.6 months with sotorasib and 11.3 months with docetaxel, HR 1.0). The most common treatment-related grade ≥3 adverse events were diarrhea (12 percent), and elevation in transaminases (5 to 8 percent).
In the previous phase I study, sotorasib was associated with an ORR of 41 percent, median PFS of 6.3 months, OS of 12.5 months, and two-year OS rate of 33 percent [128].
Adagrasib — Adagrasib is a related molecule that also has FDA approval for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy [129].
In a single arm study in 116 patients with KRAS G12C-mutated NSCLC, almost all of whom had received prior chemotherapy and immunotherapy, adagrasib 600 mg twice daily was associated with a median progression-free survival of 6.5 months, duration of response of 8.5 months, response rate of 43 percent, and overall survival of 12.6 months [130]. Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33 percent. Grade ≥3 treatment related adverse events occurred in 45 percent, the most common of which were fatigue, nausea, and increased liver function tests. There were two grade 5 events, one cardiac failure in a patient with a medical history of pericardial effusion and one pulmonary hemorrhage.
Others — Other agents are under investigation for G12C KRAS-mutant NSCLC. As an example, in a phase I study of 137 patients with advanced KRAS-mutant cancers, the objective response rate to the covalent KRAS G12C inhibitor divarasib (GDC-6036) was 53 percent among the 60 patients with NSCLC, with a median PFS of 13.1 months [131]. In the entire cohort, grade 3 events occurred in 15 patients (11 percent), and one patient experienced a grade 4 event (1 percent). Further data and/or regulatory approval are needed.
Based on available data, there are few promising treatments for non-G12C KRAS-mutant NSCLC. Results of a phase III trial with the oral MEK inhibitor selumetinib in combination with docetaxel did not demonstrate benefit of the MEK inhibitor strategy [132]. In this trial, 510 patients were randomized, but there were no differences observed in the selumetinib plus docetaxel arm compared with docetaxel alone with regard to PFS (3.9 versus 2.8 months), OS (8.7 versus 7.9 months), or response rate (20 versus 14 percent).
Mechanisms of resistance to KRAS inhibition have been described [133], and strategies to delay and overcome resistance are being investigated.
HER2 mutations and amplifications — Human epidermal growth factor receptor 2 (HER2 [ERBB2]) is an EGFR family receptor tyrosine kinase. Mutations in HER2 have been detected using PCR or NGS in approximately 1 to 3 percent of NSCLC tumors [134-136]. 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, a trastuzumab-based antibody-drug conjugate (ADC) could be considered after progression on prior therapy. Fam-trastuzumab deruxtecan is approved by the FDA for patients with unresectable or metastatic NSCLC whose tumors have activating HER2-mutations, and who have received a prior systemic therapy [137]. Ado-trastuzumab emtansine is approved for other indications and is an appropriate alternative. Supporting data are as follows:
●Fam-trastuzumab deruxtecan – In the DESTINY-Lung01 study, fam-trastuzumab deruxtecan (T-DXd) was administered at 6.4 mg/kg to 91 patients with HER2 mutation-positive NSCLC that had progressed on standard treatment, with a median PFS of 8.2 months, overall survival of 17.8 months, and response rate of 55 percent [138]. In a separate study in 152 patients with HER2-mutant NSCLC, T-DXd 5.4 and 6.4 mg/kg were associated with objective response rates of 49 and 56 percent, respectively, and grade ≥3 treatment-related adverse events of 39 and 58 percent, respectively [139].
●Ado-trastuzumab emtansine – In a 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 ORR was 44 percent, median PFS was five months, and the median duration of response was four months [140].
●Trastuzumab-based approaches and investigative options – Case and early-phase clinical trials suggest that patients with tumors harboring HER2 mutations may also respond to trastuzumab-based regimens [135,141-144]. 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 PFS was 5.1 and 3.9 months, respectively [145].
Many other HER2-targeted small molecules are under study. For example, the small-molecule TKIs poziotinib, pyrotinib, and TAK-788 (mobocertinib) each have reported efficacy in HER2 exon-20-insertion NSCLC [146-151].
There is no clear association between HER2 amplification and HER2 mutations. While early clinical trials demonstrated no benefit of targeted therapy in HER2-amplified NSCLC [152,153], a separate interim analysis of the DESTINY-Lung01 study discussed above showed a 24.5 percent response rate with fam-trastuzumab deruxtecan in HER2-overexpressed, IHC 2+ or 3+, HER2 mutation-negative NSCLC, which may correlate with HER2 amplification [154].
Other genotypes — Other alterations in oncogenes such as phosphatidylinositol 3-kinase (PI3K) and catenin beta-1 (CTNNB1), and tumor suppressors such as serine/threonine kinase 11 (STK11 [LKB1]), kelch-like ECH-associated protein 1 (KEAP1), and nuclear factor erythroid 2-related factor 2 (NFE2L2) have not been demonstrated to be confer sensitivity to targeted therapy. However, STK11 alterations may confer relative resistance to immunotherapy, and KEAP1 mutations may increase resistance to radiotherapy. Therapeutics targeting these pathways are in clinical development.
SPECIAL CONSIDERATIONS
Obese patients — If targeted therapy is indicated, we suggest that standard drug doses be administered to all patients regardless of body mass index. This is consistent with clinical practice guidelines from the American Society of Clinical Oncology [155]. (See "Dosing of anticancer agents in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)
SUMMARY AND RECOMMENDATIONS
●Driver mutations as biomarkers – It is critical to identify biomarkers of the molecular pathways that drive malignancy in patients with non-small cell lung cancer (NSCLC), particularly in those patients with adenocarcinoma histology and a light- or never-smoking history regardless of histology, because of the availability of effective targeted agents for many of these cancers. Driver mutations often impart an oncogene-addicted biology to the transformed cell, meaning that the mutated protein confers cell growth and survival advantages for the cancer cell.
●Molecular testing – The gold standard for molecular testing in NSCLC is tissue-based testing. At minimum, we recommend determination of epidermal growth factor receptor (EGFR) mutation status and anaplastic lymphoma kinase (ALK) rearrangement status prior to initiating therapy because rapid and sensitive tests are available, and initiation of immunotherapy could increase toxicity of tyrosine kinase inhibitors later in the patient's course. However, more comprehensive testing can also identify candidates for first-line treatment with US Food and Drug Administration-approved therapies for c-ROS oncogene 1 (ROS1), BRAF, MET, rearranged during transfection gene (RET), and neurotrophic receptor tyrosine kinase (NTRK). If EGFR and ALK are negative, more comprehensive testing (for example, next-generation sequencing) should be pursued, either prior to or concurrent with initiation of first line treatment. (See 'Driver mutations as biomarkers' above and 'Molecular testing' above.)
•Blood-based tests or so-called "liquid" biopsies, based on circulating tumor DNA, can provide a convenient and rapid method to comprehensively identify these biomarkers, though sensitivity is less than that in tissue, and programmed cell death ligand 1 testing cannot be performed with liquid biopsy. (See 'Liquid biopsies' above.)
●EGFR or ALK – For patients with advanced EGFR-mutant NSCLC, or ALK-positive NSCLC, initial treatment is with targeted therapy, as discussed elsewhere. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
●ROS1 – For patients with advanced ROS1-positive NSCLC, we suggest a ROS1 inhibitor (ie, crizotinib, entrectinib, or repotrectinib) in the first-line setting rather than chemotherapy or chemoimmunotherapy (Grade 2C). However, if treatment was initiated prior to knowledge of the genetic alteration, it may be used upon progression on initial therapy. Although any of these agents may be chosen for those without brain metastases, entrectinib or repotrectinib is favored for those with central nervous system involvement. (See 'ROS1 rearrangements' above and "Brain metastases in non-small cell lung cancer", section on 'ROS1 translocations'.)
●MET – For patients with advanced NSCLC that harbors a MET exon-14-skipping mutation, we suggest capmatinib or tepotinib in the first-line setting (Grade 2C), although it is also reasonable to use these agents in the subsequent line, after progression on chemotherapy and/or immunotherapy. For patients with MET-amplified advanced NSCLC a MET inhibitor is an appropriate later-line option, after progression on immunotherapy and chemotherapy options. (See 'MET abnormalities' above.)
●RET – For patients with advanced NSCLC that is RET rearrangement-positive, we suggest selpercatinib in the first-line setting rather than chemotherapy or chemoimmunotherapy (Grade 2B), but consider pralsetinib to be a reasonable alternative. Cabozantinib, vandetanib, and alectinib are other RET inhibitors but appear less effective. (See 'RET rearrangements' above.)
●BRAF – For patients with advanced NSCLC whose tumors harbor a BRAF V600 mutation, we suggest either dabrafenib plus trametinib or encorafenib plus binimetinib in the first-line setting (Grade 2C), although it is also reasonable to use it in the subsequent line after progression on chemotherapy and/or immunotherapy. For non-BRAF-V600E tumors, MEK inhibitors may be considered after standard treatment options have been exhausted. (See 'BRAF mutations' above.)
●NTRK – For patients with advanced NSCLC that is neurotrophic receptor tyrosine kinase (NTRK) fusion-positive, either targeted therapy (ie, larotrectinib or entrectinib) or immunotherapy, with or without chemotherapy are appropriate front-line options, with a choice between these strategies driven by patient preference regarding toxicity profiles. (See 'NTRK fusions' above.)
●KRAS – For patients with advanced NSCLC with a Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation that has progressed on a prior line of therapy, we suggest sotorasib or adagrasib rather than subsequent chemotherapy and/or immunotherapy (Grade 2C). For KRAS alterations other than G12C, there are no targeted therapy options, so only standard chemotherapy and/or immunotherapy is indicated. (See 'Sotorasib' above.)
●HER2 – For patients with NSCLC with mutations in human epidermal growth factor receptor 2 (HER2), who have experienced progression on prior therapy, we suggest fam-trastuzumab-deruxtecan (Grade 2C), although ado-trastuzumab emtansine or participation in clinical trials are also reasonable approaches. (See 'HER2 mutations and amplifications' above.)
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