Targeted therapies in non-small cell lung cancer: present and future

Lung cancer is the leading cause of malignancy-related death in the United States and the second most common cancer diagnosis worldwide. In the last two decades, lung cancer treatment has evolved to include advances in the development of mutation-based targeting, immunotherapy, radiation therapy, and minimally invasive surgical techniques. The discovery of lung cancer as a molecularly heterogeneous disease has driven investigation into the development of targeted therapies resulting in improved patient outcomes. Despite these advances, there remain opportunities, through further investigation of mechanisms of resistance, to develop novel therapeutics that better direct the personalization of lung cancer therapy. In this review, we highlight developments in the evolution of targeted therapies in non-small cell lung cancer, as well as future directions shaped by emerging patterns of resistance.


Introduction
Lung cancer remains the second-most common cancer diagnosis worldwide, afflicting 2.2 million people and accounting for 18% of cancer deaths 1 .In the United States (U.S.), lung cancer continues to be the leading cause of malignancy-associated death at approximately 22% 2 .In 2023, epidemiologists estimate that there will be 238,340 new cases of lung cancer and 127,070 deaths attributed to lung cancer in the U.S. alone 3 .The histopathologic subtypes of lung cancer follow the 2021 WHO classification schema and are largely based on morphology and immunohistochemical (IHC) staining patterns, which impact treatment decision-making and prognosis 4 .The two largest categories of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which account for 14% and 85% of cases, respectively 5 .Current survival estimates of lung cancer are based on the stage at diagnosis.NSCLC has a 5-year survival rate of 65% in localized disease and 9% in metastatic disease.SCLC has even more dismal odds, with a 5-year survival rate of 30% in localized disease and 3% in metastatic disease 6 .In the last two decades, significant gains have been made in understanding the underlying biomolecular mechanisms that drive cancer initiation and progression, which have led to the discovery of somatic "driver mutations" (oncogenes) which, when present, block the normal regulatory cellular feedback processes that appropriately maintain cell growth and survival.Such driver mutations can transform normal cells into malignant cells characterized by unchecked growth and proliferation.Targeted therapies interrupt these aberrant pathways and have revolutionized the approach to treatment for affected patients with increased advantages of tolerability and effectiveness in advanced disease.In this review, we explore the current standard of care, as well as emerging targeted therapies in clinical trials for those with NSCLC with driver mutations; we do not address advances in chemotherapeutics or immune checkpoint inhibitors (ICIs).Within each section, we provide up-to-date epidemiological data, pathogenic mechanisms, an overview of therapeutic agents, and currently available clinical trials.

EGFR mutations
One of the most well-understood driver oncogenes in NSCLC is the EGFR (epidermal growth factor receptor) gene on chromosome 7, which encodes one of the erbB family of cell surface transmembrane receptor tyrosine kinases known as erbB-1 or HER1 7 .Once the tyrosine kinase becomes activated, multiple downstream signaling pathways are triggered, such as the Ras-Raf-MEK-ERK, and PI3K-AKT-mTOR, promoting DNA synthesis and cell proliferation 8 .Dysregulation in these pathways drives tumor proliferation, differentiation, and migration.The frequency of activating mutations in EGFR in NSCLC (10-15% prevalence in the US) differs based on histology, smoking status, ethnicity, and sex.These mutations are largely observed in adenocarcinomas, those of Asian descent (22-62%), in non-smokers, and females.Multiple generations of oral EGFR tyrosine kinase inhibitors (TKIs) have been approved by the US Food and Drug Administration (FDA) for first-line therapy in those with EGFR-activating mutations in advanced NSCLC.This is a result of improved outcomes when compared to standard-of-care platinum doublet-based chemotherapy.It should be noted; however, that EGFR amplification or overexpression does not have the same predicted responsiveness to targeted therapies.More recently, testing for EGFR mutations is also recommended for those patients with resectable stage IB to IIIA NSCLC to guide consideration of adjuvant or neoadjuvant targeted therapy 9 .
Among those patients with EGFR driver mutations, the majority have either an exon 19 deletion (45%) or the exon 21-point mutation L858R (40%).These mutations are the most well-studied in NSCLC, with several FDA-approved therapies available impacting patient survival.The early generation TKIs (gefitinib, erlotinib, and afatinib) delivered excellent success rates in improving median progression-free survival (mPFS) when compared to standard chemotherapy in patients with EGFR mutations; however, patients develop disease progression while on therapy [10][11][12][13][14][15][16][17][18] .Osimertinib was approved by the FDA in 2018 to combat the most common resistance mechanisms, T790M mutation on exon 20 of EGFR and exon 21 L858R mutations [19][20][21][22] .Validation studies demonstrated superior overall survival rates for patients treated with osimertinib when compared to other EGFR-TKI therapies, particularly in those with brain metastases 23,24 .Unfortunately, in clinical use, we have learned that many patients develop resistance to osimertinib, which limits further definitive treatment options.Based on the current understanding of tumor heterogeneity and complex cellular signaling within the tumor and microenvironment and advances in molecular sequencing, we have identified both EGFR-dependent activating mutations and EGFR-independent mechanisms of resistance [25][26][27] .

EGFR-dependent activating mutations
A tertiary EGFR mutation, C797S, has been identified in the presence or absence of the secondary T790M mutation as playing a role in potential therapeutic options, depending on molecular positioning and availability of the binding subunits 26,[28][29][30][31] .In vivo studies are investigating the use of brigatinib, which is a next-generation ALK-TKI, to target triple mutation (exon 19 deletion, T790M mutation, and C979S activating mutation) EGFR NSCLC 32 .Uncommon EGFR tertiary activating mutations on exons 18-25 include L718/G719, G796, and L792, especially when the T790M mutation is retained 33,34 , and S768I, S720F, E709K, and L861Q, which are typically found in conjunction with more common EGFR mutations 35 .Erlotinib has shown disease stability, albeit short-lived, in a subset of these patients with S786I mutations 36 .Afatinib is the only FDA-approved therapy for rare EGFR mutations, including S768I, L861Q, or G719X [37][38][39] .There are small signals that osimertinib has activity against these uncommon mutations in EGFR-positive NSCLC, even in patients with brain metastases 40,41 .
Exon 20 insertion mutations have also been discovered as potential targets for individualized therapies 42,43 .Due to the location on exon 20, the insertion mutation has similar properties as ERBB2 (HER2), although more heterogeneous in nature, making it difficult to systematically identify targetable features.Due to the ERBB inhibitory activity, poziotinib has been studied in vitro with good activity against exon 20 insertion mutations 44 .However, in early clinical studies, there are mixed results with concern for significant adverse effects of skin and gastrointestinal toxicities, which have required significant dose reduction 45,46 .In July 2022, Elamin et al. published a study of 50 patients with EGFR exon 20 point mutation-positive NSCLC who underwent treatment with poziotinib and achieved the primary-end point of an objective response rate (ORR) of 32% and mPFS of 5.5 months; however, clinical activity varied depending on near or far loop insertion of the point mutation 47 .Mobocertinib received FDA approval for subsequent breakthrough therapy in 2021 for patients with exon 20 insertion mutations after Riely et al. showed a confirmed response rate of 43%, median duration of response (mDOR) of 14 months, and mPFS of 7.3 months in 28 patients with exon 20 insertion mutations 48,49 .Unfortunately, the data was most promising in those without brain metastases.Significant side effects of mobocertinib included gastrointestinal side effects in up to 82% of patients with exon 20 insertion mutations.In December of 2021, in an open-label phase I/II study, Zhou et al. confirmed a durable clinical benefit for patients with previous platinum-based therapy who were treated with mobocertinib achieving an ORR of 28%, durable clinical response (DCR) of 78% and duration of response (DoR) of 17.5 months with mPFS of 7.3 months 50 .Amivantamab (JNJ-6118372) is a new fully human EGFR-MET antibody with an immune cell-directing activity that targets EGFR mutations, as well as MET mutations and amplifications.It inhibits ligand binding and promotes a receptor-antibody complex resulting in antibody-dependent cellular toxicity and death 51 .It received FDA approval for breakthrough therapy in patients with NSCLC and exon 20 insertion mutations who have already received platinum-based chemotherapy based on the CHRYSALIS study after achieving an ORR of 40%, including a complete response in 3 patients, a mDoR of 11.1 months, and mPFS of 8.3 months 52 .Side effects of amivantamab are usually less severe, citing rash as the most common side effect (86%), but only 4% of patients experienced severe effects.There are multiple ongoing studies testing these novel antibody mechanisms for new therapies, including the comparison of targeted therapies to the current standard of care in this rare population with limited available treatment options (NCT04129502, NCT04209465, NCT04538664) [53][54][55] .Due to significant clinical effect in other subpopulations, including those with brain metastases, osimertinib is also under investigation for patients with exon 20 insertion mutated EGFR positive NSCLC.

EGFR-independent acquired resistance mechanisms
Loss of the secondary T790M mutation usually results in EGFR-independent resistance mechanisms, which can occur via multiple pathways.Some of the most recognized to date include MET amplification, KRAS mutations, and BRAF mutations, among others 33,34,56,57 .MET amplification has been identified as the second most common mutation for resistance to the current EGFR-TKI therapies 25,26,33,34 .There are preclinical studies evaluating the use of combination EGFR/MET inhibitors in addition to third-generation EGFR-TKIs to overcome resistance with encouraging results in clinical trials in favor of combination therapy over chemotherapy [58][59][60] .Although BRAF is known as a primary oncogenic driver in NSCLC, it has also been implicated as a mechanism of resistance to EGFR-TKI therapy [61][62][63] .In preclinical studies, Jeong et al. discovered EGFR and BRAF fusion as a mechanism of resistance to the third-generation EGFR-TKI, lazertinib 27 .Combination therapy with lazertinib and a MEK inhibitor showed strong anti-tumor activity, suggesting a promising therapeutic option 27 .Some less common but still identifiable resistance mechanisms include HER2 amplification, TP53 mutation, KRAS mutation, induced epithelial-mesenchymal transformation (EMT), ALK resistance, and histologic transformation, including conversion to small cell carcinoma 26,47,[64][65][66][67] .
Additional ERBB family mutations (HER2 mutations) While HER2 mutations are not the next most common primary mutations in NSCLC, they are part of the ERBB receptor tyrosine kinase family and are studied in EGFR mutant NSCLC.HER2 mutations are present in 2-4% of NSCLC and typically expressed in adenocarcinoma among never smokers and women with a reported incidence of 20.4% [68][69][70] .HER2-positive status in NSCLC appears to confer resistance to a standard regimen of platinum-based chemotherapy 70,71 .There are three categories of inhibitors, including pan-HER TKIs, anti-HER2 monoclonal antibodies, and anti-HER2/HER3 antibody-drug conjugates, that have been used to investigate potential targeted treatment options for those with NSCLC 72,73 .Patritumab (HER3-DXd) is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor.This molecule has been studied in Phase I trials in patients with EGFR-mutated NSCLC who developed resistance to EGFR-TKI therapy, with an ORR of 39% and mPFS of 8.2 months 74 .Poziotinib and afatinib showed mixed results in a study of 7 patients, mostly consisting of women non-smokers with stage IV adenocarcinoma and no coexisting EGFR or ALK mutations 68 .The NICHE study reported mixed results in which afatinib achieved disease control in less than 50% of the study participants at 12 weeks 75 .In 2021, Li et al. reported that trastuzumab deruxtecan achieved ORR of 55%, mDoR of 9.3 months, mPFS of 8.2 months, and median overall survival (mOS) of 17.8 months in patients with HER2-mutated NSCLC (DESTINY-Lung01) 76 .The authors of the DESTINY-Lung 02 trial reported a confirmed ORR of 56% and mDOR of 8.7 months, which gained trastuzumab deruxtecan accelerated approval by the FDA in August 2022 for patients with HER2-mutated NSCLC 77 .While there was an adequate safety profile, a select number of patients developed interstitial lung disease, resulting in 2 deaths 76 .More investigation is required to determine additional therapy options.
Studies are ongoing to investigate the emerging resistance patterns of EGFR-mutant NSCLC and new potential therapies [78][79][80][81] .Although many molecular mechanisms of resistance to EGFR-TKI therapy have been identified, our understanding of how these mechanisms impact therapeutic effects is incomplete.

RAS mutations
The KRAS proto-oncogene drives several hallmarks of cancer, including cellular proliferation, differentiation, and survival.KRAS mutations are commonly found in about 30% of patients with adenocarcinoma 82-84 .However, selective targeting of this mutation remains a significant challenge due to multiple downstream signaling pathways.The most common KRAS mutation is KRAS-G12C which is present in about 13% of lung adenocarcinomas.In August of 2020, Jänne et al. reported the success of adagrasib in the KRYSTAL-1 study, where 45% of 51 patients with NSCLC had an objective response and DCR of 96% with mDoR of 8.5 months, which ultimately led to FDA approval of adagrasib in December 2022 85 .Preclinical animal model data supports the need for ongoing studies for the use of adagrasib in brain metastases 86 .In May of 2021, the FDA-approved sotorasib, a RAS GTPase inhibitor, for treatment in those with KRAS G12C mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy 87 .Approval was based on the results of the Codebreak 100 trial, which showed significant responses (37% ORR and 3.2% of patients achieving complete response) with a favorable safety profile and mPFS of 6-8 months 87-89 .As with other kinase inhibitors, some patients are now developing resistance with evidence of disease progression while on therapy.The mechanisms of resistance remain incompletely understood.Awad et al. described 38 patients with KRAS G12C mutations, 10 of whom had colorectal cancer, 1 with appendiceal cancer, and the remaining 27 with NSCLC, who all progressed on adagrasib after 12 weeks 90 .84% of the patients maintained the original KRAS G12C mutation while on therapy.The remaining 16% had no detectable KRAS G12C mutation in plasma after therapy.Mechanisms of resistance included novel secondary KRAS mutations (Y96C, H95Q, H95R, R68S, H95D) in four patients, in addition to KRAS-activating mutations (G12D, G12V, G13D, G12W) 90 .Pathogenic mutations in other receptor tyrosine kinase (RTK)-RAS MAPK pathways were also detected, including NRAS, BRAF-V600E, MAP2K1/MEK1, EGFR, histological transformation, and high-level focal amplification in the KRAS G12C allele, in addition to acquired MET amplification 90,91 .PI3K-AKT has also been implicated as a likely resistance pattern for KRAS-targeted therapies 92 .Deep mutational scanning was used to identify all possible alleles with a single amino acid substitution within KRAS G12C.Novel drug resistance mutations were identified at codons 8, 9, 12, 64, 68, 95, 96, 99, and 117 with strong resistance to KRAS G12C inhibitors in addition to the known adagrasib-resistant KRAS mutations, which were also resistant to MRTX1257 (sotorasib analog) 90 .There were also novel strong resistance mutations to sotorasib at codons 8, 9, 12, 96, and 117 90 .Most were commonly found to occur at the drug-binding site; however, there were amino acids located outside of the drug-binding pocket that impeded GTP hydrolysis (G13D and Q16R) or facilitated GDP to GTP nucleotide exchange (G13D, A59S, and A146P) 90 .Several highly selective KRAS G12C inhibitors are in development, including those that bind to the active GTP bound conformation, which in theory, increases the inhibitory activity and promotes control (RMC-6261) 91 .Epithelial mesenchymal transition (EMT) has been shown to lead to both acquired and intrinsic resistance to KRAS G12C inhibition with multi-targeted therapy showing tumor regression in mice models 93 .There are studies underway to identify additional targets in these pathways 94,95 .In addition to the approval of sotorasib and adagrasib, there are many more KRAS G12C pathway inhibitors under investigation 83,96-101 .There are also active studies of the precursor signals that activate KRAS and contribute to cell survival and proliferation, like Son of Sevenless (SOS1) and SHP2, which have the potential to overcome acquired resistance to KRAS-targeted therapies [102][103][104][105][106][107][108] .

MET mutations or amplification
MET alterations, most commonly skip mutations, occur in 3-4% of NSCLC, and drive tumor proliferation, invasion, and metastasis 10 .A nonselective MET inhibitor, crizotinib achieved an ORR of 32% and mDoR of 9.1 months with PFS of 7.3 months and has been validated in follow-up phase II studies in patients with MET exon 14 mutations 109,110 .Crizotinib was approved for breakthrough therapy in this subclass of patients by the FDA in 2018.In a phase II study, Wolf et al. proved that capmatinib exhibited an ORR of 41% in 69 patients who had previously received therapy and an ORR of 68% in treatment naïve patients 111 .The mDoR was 9.7 months and 12.6 months, respectively.There was less of a response in patients with MET amplification mutations, with an ORR of 29% and 40% for those who were previously treated and treatment naïve, respectively 111 .There are phase II studies reporting activity and response with tepotinib, savolitinib, and capmatinib in NSCLC patients harboring MET exon 14 skip mutations [111][112][113] .The only FDA-approved MET-targeted therapies include capmatinib, which was approved in May 2020, and tepotinib, approved in February 2021 114,115 .Phase III trials are ongoing comparing capmatinib to chemotherapy in those with MET exon 14 skip mutations in NSCLC 116 .The mechanisms of resistance to early-generation MET-TKIs are not fully understood but found to include many of the same resistance mechanisms described in EGFR-positive NSCLC.Recondo et al. studied 20 patients and identified genetic alterations or bypass signaling in 15 of those patients, which included single and polyclonal MET kinase domain mutations at codons H1094, G1163, L1195, D1228, Y1230, high levels of MET amplifications on exon 14, KRAS mutations and amplifications, EGFR, HER3, and BRAF 117 .There are small case reports of BRAF V600E mutation leading to resistance to crizotinib 118 .

BRAF mutations
BRAF is a RAS-activated intracellular serine/tyrosine kinase protein.BRAF mutations are identified in about 2-5% of NSCLCs, resulting in persistent downstream signaling of mitogen-activated protein kinase (MAPK), driving tumor growth and proliferation 10 .Activating V600E mutations comprise half of the cases of BRAF mutations 119,120 .Resistance to therapy emerges through MEK 1 and 2 signaling pathways [121][122][123] .There are three types of targeting inhibitors under investigation (BRAF inhibitors, MEK 1 and 2 inhibitors, and ERK inhibitors).BRAF inhibitor therapy alone has little effect as monotherapy 121,124 .However, the BRAF inhibitor (dabrafenib) plus MEK1 and 2 inhibitor (trametinib) demonstrate good activity in phase II clinical trials with an ORR of 63% and mDoR of 9 to 15 months [125][126][127] .The BRAF inhibitor vemurafenib demonstrates activity among those with BRAF-V600E mutations exhibiting ORR between 37-44% and mPFS of 6.5 months 128,129 .Currently, the only FDA-approved regimen for patients with BRAF V600E mutations in NSCLC is the combination of two agents, trametinib and dabrafenib 130 .Co-occurring mutations most commonly include TP53 in small sample sizes 131 .Unfortunately, very little is known about the resistance mechanisms to BRAF inhibitor therapy 132 .There are multiple drugs under investigation for the treatment of BRAF-mutant NSCLC [133][134][135][136] .

ALK rearrangements and ROS1 rearrangements
ALK fusion mutations drive tumor cell proliferation and survival and are present in 4-5% of adenocarcinomas [137][138][139] .ROS 1 is a kinase receptor with significant structural similarity to ALK 10 .Rearrangements in ROS 1 can develop into fusions of the ROS tyrosine kinase domain with other genes which occur in about 1-2% of NSCLC 121 .There are two main inhibitors associated with ROS, those that inhibit ROS1 and ALK and those that inhibit ROS1 and tyrosine receptor kinase (TRK).Crizotinib, in addition to MET inhibition, also inhibits ALK/ROS1, which was FDA approved in 2011 after early studies showed promising results for patients with fusion mutations and validated in later phase III studies [140][141][142][143][144] .To date, the ALK inhibitors ceritinib, alectinib, and brigatinib show improved ORR and mPFS when compared to either standard chemotherapy or crizotinib alone in treatment naïve patients [145][146][147] .Lorlatinib is a selective ALK/ROS1 TKI with brain penetration.In 2020, Shaw et al. compared lorlatinib to crizotinib and discovered improved overall survival (OS) at 12 months in the lorlatinib group -78% to 39%, respectively, an ORR of 76% and 58%, respectively, and brain metastasis response rate of 82% in lorlatinib and 23% in crizotinib 144 .Lorlatinib received FDA approval for a breakthrough therapy for a DCR rate of 50% overall, including intracranial response in those with brain metastases.In 2021, Camidge et al. reported the benefits of brigatinib as first-line therapy in patients with ALK inhibitor naïve -ALK-positive NSCLC, with superior 3-year PFS versus crizotinib, and increased survival in those with brain metastases 148 .TP53 mutations are the most common genomic co-alteration in ALK-positive NSCLC, with overall worse prognosis and survival, with preclinical studies testing ixazomib (a proteasome inhibition), which induced apoptosis in previously alectinib resistance cells 149 .Known mechanisms of resistance to ALK-TKI therapy include secondary ALK mutations, BRAF-V600E mutations, and a novel discovery of epithelial-mesenchymal transition (EMT) of newly metastatic cells 150 .Three additional ROS1/TRK inhibitors have been studied in ROS1-rearranged NSCLC.Entrectinib is a highly potent ATP-competitive TKI that penetrates the central nervous system.Multiple studies show an ORR of 67.1%, DoR of 15.7 months, and mPFS of 15.7 months in 161 TKI naïve patients 151 .Repotrectinib and taletrectinib are ROS1/TRK inhibitors that can penetrate the CNS.The first in-human phase I study of taletrectinib achieved an ORR of 33.3% in those with critzotinib resistance ROS1 mutations 152 .Repotrectinib has shown activity against ROS1-resistance mutations and there are ongoing studies to confirm anti-tumor activity 153 .Entrectinib is the only ROS1/TRK inhibitor to be approved by the FDA in 2019 151,154,155 .

RET rearrangements
The RET gene encodes a cell surface tyrosine kinase receptor that impacts cell proliferation and differentiation.In 1-2% of those with NSCLC (most often in adenocarcinomas, never-smokers, and younger patients), rearrangements between RET and CCDC6 (coiled-coil domain containing-6), KIF5B (kinesin family 5B), NCOA4 (nuclear receptor coactivator 4), or other domains ultimately results in dysregulated signaling and RET overexpression.Testing via next-generation sequencing (NGS) (RNA-based preferred over DNA-based testing) is the preferred method.Break-apart FISH (fluorescence in situ hybridization) probes or RT-PCR (reverse transcription polymerase chain reaction) can be used; however, they may not detect less common fusion products.Regardless of performance status, first-line systemic therapy for those patients with advanced NSCLC (even with brain metastases) and a RET fusion is often with either of the oral RET TKIs (selpercatinib or pralsetinib), especially since current evidence is limited and suggests mixed efficacy of immune checkpoint inhibitor monotherapy with an ORR of 6% [156][157][158] .The landmark phase I/II multi-cohort open-label trial that led to FDA approval for selpercatinib was LIBRETTO-00, where patients were either treatment-naïve or previously received platinum-based chemotherapy for their RET fusion NSCLC.In the 69 treatment-naïve patients, an ORR of 84%, mPFS of 22 months, and mDoR of 20 months were reported, whereas the 247 previously treated patients had an ORR of 61%, mPFS of 25 months, and mDoR of 29 months 159,160 .Among those patients with brain metastases, 26 had baseline measurable disease and were without any radiation therapy in the two months preceding trial enrollment, and 22 patients had an intracranial response (ORR of 85%) with mDoR of 9.4 months; this was consistent whether prior local or systemic treatments were received 160,161 .These rearrangements result in ligand-independent signaling, which leads to oncogenic proliferation and has been implicated in the pattern of resistance to osimertinib 121 .Small studies investigating multi-kinase inhibitors like cabozantinib and vandetinib have reported ORR of 28% and 47%, respectively, in NSCLC 162,163 .In 2020, more selective RET inhibitors such as pralsetinib demonstrated promising results achieving ORR of 65%, time to response of 1.8 months, and mDoR not being met 164 .Selpercatinib was tested in 105 patients with RET fusion-positive NSCLC and achieved an ORR of 64% and DoR of 17.5 months 159 .The results were superior for treatment-naïve patients achieving an ORR of 85%, and those with nervous system symptoms with an intracranial response rate of 91% 159 .There are ongoing studies under investigation for new selective RET inhibitors [165][166][167][168] .

NTRK fusions
There are several NTRK genes currently identified.These genes serve to encode proteins TRKA, TRKB, and TRKC, which facilitate growth factor receptor binding to induce tyrosine kinase activity, potentiating a cellular signaling cascade [168][169][170] .NTRK fusion genes in malignancy were identified back in the 1980s; however, their role in NSCLC specifically is more novel.Current meta-analyses and systematic reviews detail the prevalence to be between 0.10-0.25% in NSCLC patients [171][172][173] .NGS is the preferred method for identification of these extremely rare fusion genes 174 .The first generation NTRK-TKI, arotrectinib is a highly selective ATP competitive inhibitor of tropomyosin receptor kinases (TRK), received FDA approval in 2018 for adult and pediatric patients with solid tumors and NTRK fusion genes without any additional therapy options 175,176 .Its efficacy was further solidified in a phase I dose escalation study of 70 patients, 8 of whom had TRK gene fusions, and the ORR was 100% 177 .With overall response rates of 75% in a study including adults and children with 17 unique TRK fusion-positive tumors 178 , overall adverse events have been reported to be mild.Entrectinib is an oral selective inhibitor of NTRK proteins, ROS 1, and ALK tyrosine kinase, which received FDA approval in 2019 after Marcus et al. proved a DoR rate of 57%, including a complete response of 7% amongst 54 patients with 10 different NTRK fusion-positive malignancies 179 .There are multiple phase I and II trials under investigation for entrectinib, which include pediatric and adult patients with solid tumors and NTRK fusion genes.10 patients with NSCLC were included and achieved an ORR of 70% 180 .To date, there are select ongoing trials comparing targeted therapies for patients with NTRK-positive NSCLC (NCT04302025, NCT04996121, NCT05192642) [181][182][183] .

Targets on the horizon
Given the molecularly complex nature of NSCLC and potential targeted therapies, the field is evolving rapidly.There are new targets being identified and studied continuously.There are numerous ongoing studies to combine known targeted therapies as adjunct therapy to other modalities, including chemotherapeutics, ICIs, radiation therapy, and surgical resection.The details of these studies are beyond the scope of this review.For a more complete list of molecular targeted therapies under investigation at the time of this publication, we have included ongoing clinical trials for reference in Table 1.

Table 1 . Targetable Mutation therapy, known resistance mechanisms, and ongoing clinical Trials.
PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Recommended 53.A phase 3,

randomized, open-label phase 3 study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in patients with EGFR exon 20ins mutated locally advanced or metastatic non-small cell lung cancer
. 2022; Accessed Nov 4, 2022.

phase II study of AMG 510 in participants with previously treated stage IV or recurrent KRAS G12C mutated non-squamous non-small cell lung cancer (ECOG-ACRIN LUNG-MAP SUB-STUDY). 2021
; Accessed Nov 2, 2022.

phase IB/II study of lorlatinib combinations in anaplastic lymphoma kinase-rearranged lung cancer. 2021; Accessed Jan 22, 2022. Reference Source 107. An open-label, multi-center, phase I, dose finding study of oral TNO155 in adult patients with advanced solid tumors. 2021
; Accessed Jan 22, 2022.

Publisher Full Text | Free Full Text 113
. Lu S, Fang J, Li X, et al.: Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).J Clin Oncol.2020; 38(15_suppl): 9519.Publisher Full Text 114.Research, Center for Drug Evaluation and: FDA

: Phase 1/2a study of entrectinib, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations
PubMed Abstract | Publisher Full Text | Free Full Text 160.Drilon A, Subbiah V, Gautschi O, et al.: Selpercatinib

phase III randomized, open-label study of pralsetinib versus standard of care for first-line treatment of RET fusion-positive, metastatic non-small cell lung cancer
. 2021.Reference Source 169.Lamballe F, Klein R, Barbacid M: trkC,

The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3.
PubMed Abstract | Publisher Full Text | Free Full Text 171.Forsythe A, Zhang W, Phillip Strauss U, et al.: A

PubMed Abstract | Publisher Full Text | Free Full Text 181. A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer. 2023
; Accessed May 29, 2023.

Study of XZP-5955 Tablets in Patients With NTRK or ROS1 Fusion Positive Locally Advanced or Metastatic Solid Tumors. 2023
; Accessed May 29, 2023.

Study Called VICTORIA to Learn More About How Well Larotrectinib Works in Adults With TRK Fusion-positive Cancer by Comparing Larotrectinib Data From Clinical Studies With Data of Other Treatments From Actual Practice
. 2023; Accessed May 29, 2023.Reference Source