Recent updates in targeted therapy for advanced non-small cell lung cancer with actionable genomic alterations: a narrative review

Introduction

Lung cancer remains the most frequently diagnosed malignancy worldwide, accounting for nearly 2.5 million cases in 2022. It is also the leading cause of cancer death globally, making up nearly 19% of all cancer-associated mortality (1). Non-small cell lung cancer (NSCLC) makes up approximately 85% of all lung cancer cases, within which up to 40% or 50% may harbor actionable genomic alterations (AGAs) (2,3). Since the initial report in 2004 of activating mutations in the EGFR gene predicting sensitivity to gefitinib, there have been a series of subsequent breakthroughs in biomarker discovery and targeted therapeutics in NSCLC leading to the current state of multiple AGAs and corresponding targeted therapies (4,5). The pace of development has been rapid, with seven new U.S. Food and Drug Administration (FDA) approvals or indications of targeted therapy for advanced NSCLC in 2024 alone (6-12).

A general overview of recommended treatment sequencing for each of these AGAs in the advanced or metastatic setting is shown in Figure 1. Many of these subgroups share similar clinicoepidemiologic characteristics, with predilection for adenocarcinoma histology, minimal or no smoking exposure, and limited benefit of checkpoint inhibitor immunotherapy, with subtleties and exceptions shown in Table 1. In the following sections, we discuss each NSCLC subtype in turn, focusing on recent, practice-changing, clinical trial updates in the advanced or metastatic setting. While a number of small molecule targeted therapies, particularly osimertinib (ADAURA, LAURA) and alectinib (ALINA), have moved forward into the curative-intent setting, these are beyond the scope of this review (13-15). We present this article in accordance with the Narrative Review reporting checklist (available at https://actr.amegroups.com/article/view/10.21037/actr-25-37/rc).

Figure 1 Suggested treatment sequencing for advanced NSCLC with actionable genomic alterations. CNS, central nervous system; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Methods

A narrative review was conducted for each molecular target, integrating published literature identified through PubMed and Google Scholar as well as clinical trial updates from major medical meetings and ClinicalTrials.gov (Table 2).

EGFR

The EGFR gene encodes a transmembrane receptor tyrosine kinase (RTK) that is the best characterized member of the ErbB-family of transmembrane growth factor receptors. Activating mutations in EGFR lead to constitutive activation of the EGF receptor, stimulating multiple downstream signaling pathways (16,17). Mutations in EGFR are observed in approximately 20% of NSCLC cases, with significant variation by geography and ethnic origin (18,19). Across multiple studies, EGFR mutations in NSCLC are associated with adenocarcinoma histology, female gender, Asian ethnicity, and minimal or no smoking exposure (20,21). The classic sensitizing EGFR mutations (exon 19 deletion and exon 21 L858R) are most common, collectively making up 85–90% of all EGFR alterations (22). EGFR exon 20 insertions are third in incidence, making up 4–12% of EGFR alterations (23,24). The remaining small subset of activating EGFR mutations include S768I, L861Q, G719X, and others, which are lumped together as atypical mutations (25).

Classic sensitizing EGFR mutations (exon 19 deletion, exon 21 L858R)

Since 2018, osimertinib has been the standard first-line systemic treatment for patients with advanced NSCLC harboring a classic sensitizing EGFR mutation (26-28). The randomized, phase 3 FLAURA study demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to first-generation EGFR tyrosine kinase inhibitors (TKIs), with a standard-setting median PFS of 18.9 months (29). Despite these favorable outcomes and general tolerability, all patients eventually develop resistance and disease progression, as is seen with other targeted therapies.

In this context, there has been increasing interest in intensifying first-line systemic therapy for this population. The phase 3 FLAURA2 study randomized treatment-naïve patients to either osimertinib with platinum-pemetrexed chemotherapy or osimertinib alone, demonstrating superior median PFS for the combination (26 versus 17 months), particularly in patients with L858R mutation or central nervous system (CNS) metastases (30,31). As with any study testing a concurrent versus sequential strategy, the gold-standard outcome should be OS. At present, OS data for FLAURA2 remain immature, however numerically favors the osimertinib plus chemotherapy arm and appears likely to show a significant OS benefit (32). Analogously, the phase 3 MARIPOSA trial demonstrated superior median PFS for the combination of the EGFR-MET bispecific antibody amivantamab with the third-generation EGFR TKI lazertinib, compared to osimertinib or lazertinib alone (24 months for the combination versus 17 months for osimertinib) (33). In the final OS analysis with a median follow-up of 37.8 months, amivantamab plus lazertinib demonstrated a significant OS benefit over osimertinib [not reached versus 36.7 months, hazard ratio (HR) 0.75], though lack of crossover (to receive amivantamab) in the osimertinib control arm remains a methodologic concern (34). Both osimertinib with chemotherapy and amivantamab with lazertinib are now approved first-line regimens in this population (7,9).

In clinical practice, choosing between what are now three reasonable first-line treatment options remains a patient-specific conversation. Both the FLAURA2 and MARIPOSA regimens add inconvenience in frequency of visits and infusions, as well as toxicity, which must be weighed against an individual’s priorities and values. Yet also important to recognize is that 31% of patients in the FLAURA trial of osimertinib did not go on to subsequent systemic therapy (35). While we review all options with newly diagnosed patients, we have slight preference for combination therapy in patients with CNS metastases, and mechanistically might favor amivantamab plus lazertinib for patients with de novo pathogenic MET alterations or pre-existing MET amplification, which is likely a very small proportion of EGFR-mutated NSCLC. Whether circulating tumor DNA (ctDNA) and other clinical and molecular risk factors can help in this decision-making remain outstanding questions.

If osimertinib monotherapy is used in the first-line setting, amivantamab plus chemotherapy is approved for subsequent treatment based on MARIPOSA-2, a phase 3 study demonstrating a modest PFS benefit for the combination when compared to chemotherapy alone (6.3 versus 4.2 months) (10,36). In general, repeat biopsy with molecular profiling is recommended at the time of disease progression, to assess for histologic transformation and to determine if there is a targetable resistance mechanism to guide subsequent-line therapy. Liquid biopsy using ctDNA is a practical alternative when repeat biopsy is not feasible, but cannot reliably assess for histologic transformation and is less sensitive for amplifications and subclonal resistance. Emerging therapies, particularly antibody-drug conjugates (ADCs) such as patritumab deruxtecan, which targets HER3, and datopotamab deruxtecan, which targets trophoblast cell-surface antigen 2 (TROP-2), may have a role in the future, but currently remain investigational (37).

EGFR exon 20 insertion mutation

While there is significant heterogeneity within the class of EGFR exon 20 insertions, all result in conformational change of the ATP-binding pocket of EGFR (38,39). This renders NSCLC with EGFR exon 20 insertions largely insensitive to most EGFR TKIs approved for common sensitizing mutations (40). In addition, as there appears to be minimal benefit of added immunotherapy in this subset, for many years the standard-of-care first line systemic therapy remained platinum-doublet chemotherapy (41).

Since early 2024, the combination of platinum-doublet chemotherapy with amivantamab has become the standard first-line systemic therapy in this population (8). Data supporting this approval came from the phase 3 PAPILLON trial, an international study randomizing patients with untreated NSCLC with EGFR exon 20 insertion to either IV amivantamab plus chemotherapy or chemotherapy alone. Adding amivantamab to chemotherapy improved both overall response rate (ORR) (73% versus 47%) and median PFS (11.4 versus 6.7 months), with OS data immature but numerically favoring the amivantamab plus chemotherapy arm (not reached versus 24.4 months). Adverse events (AEs) were more common in the combination arm, particularly toxicities like paronychia, rash, peripheral edema, and infusion-related reaction (which are mechanistically attributable to amivantamab) (42). However, despite these toxicity concerns and the relatively high frequency of dose interruptions and reductions, the PAPILLON regimen represents a meaningful therapeutic advance for patients with NSCLC with EGFR exon 20 insertion.

If amivantamab is not used in the first-line setting with chemotherapy, it can be considered as monotherapy in the second-line setting and beyond (43). This approval was based on the phase 1 CHRYSALIS study, which enrolled 81 patients with NSCLC with EGFR exon 20 insertion and a median of 2 prior lines of systemic therapy. Among this population, ORR was 40% and median PFS 8.3 months with amivantamab (44). Notably though, this scenario will become less common as amivantamab is moved forward into the first-line setting. Furthermore, targeted options beyond platinum-doublet chemotherapy and amivantamab are not well defined. Mobocertinib was an oral EGFR TKI designed to selectively target exon 20 insertions that was previously approved based on encouraging phase 1/2 data. However, it has since been voluntarily withdrawn from the market based on a negative phase 3 confirmatory trial (45-47). While not approved for this indication, modest efficacy (response rates of 20–30%) has been observed in small subsets of pretreated patients receiving double-dose osimertinib 160 mg daily (48,49). In terms of emerging therapies, there are a number of newer-generation EGFR TKIs with activity against EGFR exon 20 insertion that are being actively investigated (sunvozertinib, zipalertinib, furmonertinib, among others), but none are available in routine clinical practice (50-52).

Other atypical EGFR mutations

While “atypical” has traditionally referred to any EGFR mutation other than exon 19 deletion or L858R, recent work has proposed a structure-function classification that may help predict response to targeted therapies (53). In this system, classical-like mutations have little effect on the overall structure of EGFR, and includes the classic sensitizing mutations as well as L861Q and L861R. P-loop alpha C-helix compression (PACC) mutations change the drug binding pocket, and include mutations such as G719X and S768I. T790M-like and exon 20 loop insertions are the final two subgroups in this system (54). Emerging retrospective data suggests use of osimertinib for classical-like mutations, whereas second-generation TKIs such as afatinib or dacomitinib may be better suited for PACC mutations (54,55). At present, afatinib remains the only approved EGFR TKI for advanced NSCLC with EGFR S768I, L861Q, or G719X mutations, based on data from 75 TKI-naïve NSCLC cases with atypical EGFR mutations treated with afatinib, among which ORR was 72% and median PFS 10.7 months (56,57). While effective in atypical EGFR mutations, the second-generation inhibitors including afatinib typically have higher incidence of ≥ grade 3 toxicities such as rash and diarrhea, which are characteristic of all EGFR TKIs (58).

HER2 (ERBB2)

HER2 (ERBB2) encodes a RTK belonging to the ErbB-family of transmembrane growth factor receptors, involved in promotion of cell growth and proliferation through MAPK, PI3K/AKT, and other downstream signaling pathways (59). In NSCLC, activating alterations of HER2 include gene mutations, gene amplifications, and protein overexpression. Presently, there are approved targeted agents for NSCLC with HER2 mutations as well as a tumor-agnostic approval for trastuzumab deruxtecan (T-DXd) in HER2-positive solid tumors (60,61). As of yet, there are no such approvals for HER2 amplification, the definition of which has been variable across studies (62,63).

HER2 (ERBB2) mutation

Activating HER2 mutations are identified in approximately 2–4% of NSCLC (59,64,65). The most frequent mutations are in-frame insertions within exon 20, which are structurally analogous to EGFR exon 20 insertions (66,67). Response to HER2-targeted therapies can be heterogenous by specific mutation. Importantly, HER2 expression cannot be used as a proxy for HER2 mutations, and sequencing is needed to identify this patient population (68). From an epidemiologic standpoint, patients with NSCLC and activating HER2 mutations share many features with EGFR-mutated disease. Patients are more often female, of younger age at diagnosis, and with minimal or no smoking history (59,64,65). Historically, prognosis has been poor compared to other NSCLC with AGAs like EGFR and ALK, likely due to the lack of effective targeted therapies.

T-DXd is an ADC consisting of a humanized anti-HER2 monoclonal antibody conjugated to a topoisomerase I inhibitor payload via a cleavable peptide linker (69,70). Following a first-in-human basket study, T-DXd was studied in the single-arm, phase 2 DESTINY-Lung-01 trial, enrolling patients with metastatic NSCLC and either HER2 activating mutation or HER2 overexpression (71,72). Among 91 patients with HER2-mutated NSCLC, ORR was 55% and median PFS 8.2 months. While these results were encouraging, safety data at the dose of 6.4 mg/kg every 3 weeks was notable for neutropenia (19% with ≥ grade 3) as well as drug-related interstitial lung disease (ILD) (26% with any grade, 7% with ≥ grade 3, including 2 deaths) (72). With this background, the phase 2, randomized DESTINY-Lung-02 trial studied T-DXd at 2 doses, 5.4 or 6.4 mg/kg every 3 weeks, in patients with HER2-mutated NSCLC. Response rates were comparable between these doses—ORR 49% [median duration of response (DOR) 16.8 months] for the 5.4 mg/kg dose, compared to ORR 56% (median DOR not evaluable) for the 6.4 mg/kg dose. Notably, safety profile favored the 5.4 mg/kg dose, with adjudicated ILD rates of 13% for the 5.4 mg/kg dose compared to 28% for the 6.4 mg/kg dose (73). Based on these data, T-DXd was approved in 2022 at a recommended dose of 5.4 mg/kg every 3 weeks (60).

In clinical practice, we continue to recommend first-line platinum-doublet chemotherapy with or without bevacizumab, with equivocal data for added immunotherapy for patients with HER2-mutated NSCLC. We reserve T-DXd for the second-line setting, the context in which published data and FDA approval support its use. However, we recognize that the favorable response data leads to momentum towards consideration in the first-line setting, a question which is being investigated in the ongoing DESTINY-Lung-04 trial (74).

Ado-trastuzumab emtansine (T-DM1), an ADC composed of trastuzumab, the microtubule inhibitor emtansine, and a non-cleavable linker, has also been studied in HER2-altered NSCLC. Response rates across a number of small studies of pretreated patients have ranged widely from 6–50%, however response duration appears limited (2–5 months), and its role has been curtailed with the approval of T-DXd. While a number of HER2 targeted TKIs (both selective and non-selective) have been studied in patients with HER2-mutated NSCLC, many of the earlier molecules lacked potency or had significant toxicity (75). A number of novel, selective HER2 inhibitors are in active development, including zongertinib. In the Beamion LUNG-1 study of patients with previously treated advanced HER2-altered NSCLC, ORR was 71% and median PFS 12.4 months among tumors harboring a tyrosine kinase domain mutation not previously treated with HER2-directed ADC (76). Zongertinib recently received FDA priority review designation based on promising anti-tumor activity and tolerability (75,77-79).

HER2 (ERBB2) overexpression

HER2 overexpression is assessed by immunohistochemistry (IHC) for the HER2 protein, which until recently was not routinely assessed in advanced NSCLC. T-DXd has a tumor-agnostic approval for unresectable or metastatic solid tumors that are HER2-positive, defined as IHC 3+ (61). The aforementioned phase 2 DESTINY-Lung-01 study included a cohort of patients with HER2 IHC 2+ or 3+ and no known HER2 mutations. ORR was 27% in patients receiving T-DXd at a dose of 6.4 mg/kg every 3 weeks and 34% in patients receiving 5.4 mg/kg every 3 weeks (80). Though sample sizes were small, response rates appeared similar between IHC 2+ (26%) and IHC 3+ (20%) (81). The role of T-DXd, alone or in combination with immunotherapy, is being further studied in the phase 1B DESTINY-Lung-03 trial (82). At present, data support T-DXd for NSCLC with HER2 IHC 3+ overexpression after other standard therapy options have been exhausted, recognizing that this has not been studied against conventional second-line chemotherapy (e.g., docetaxel), and thus either option would be reasonable.

KRAS G12C mutation

Activating mutations in KRAS are the most common AGA in NSCLC, occurring in up to 30% of cases (83-85). KRAS G12C is most frequently observed, followed by G12V, G12D, and less common mutations in codon 13 and 61 (83,85). In general, KRAS mutations result in constitutive activation of downstream signaling pathways via GTP-bound active state KRAS proteins, though different variants may have differential downstream patterns (86). From an epidemiologic standpoint, there are differences between KRAS variants. Most notably, KRAS G12C and G12V are typically found in patients who are current or former smokers, whereas KRAS G12D is associated with minimal or no tobacco exposure (83,87). This is consistent with the genomic signature of NSCLC associated with tobacco exposure, specifically the higher number of C:G → A:T transversions (both G12C and G12V are consequences of C → A mutations) (88,89). Along a similar line of reasoning, patients with KRAS G12C-mutated NSCLC derive more benefit from immunotherapy than those with KRAS G12D (90).

KRAS G12C is presently the only KRAS mutation for which there are approved targeted therapies, namely sotorasib and adagrasib. Both are irreversible, covalent small molecule inhibitors that lock guanine diphosphate (GDP)-bound KRAS G12C in its inactivated “off” state. Sotorasib received accelerated approval based on the CodeBreaK 100 trial, a single-arm, phase 2 study in patients with pretreated KRAS G12C-mutated NSCLC (median of 2 prior lines of therapy) (91,92). With long-term follow-up of 2 years, ORR was 41%, median PFS 6.3 months, and median OS 12.5 months. Intracranial responses were observed in 3 of 16 (19%) evaluable patients (93). In the follow-up phase 3 study (CodeBreaK 200), patients who had progressed on previous chemotherapy and immunotherapy were randomized to either sotorasib or docetaxel. A modest but significant PFS benefit was demonstrated favoring sotorasib (5.6 versus 4.5 months), but there was no OS benefit. Despite this, there remains a role for sotorasib in the second-line setting, as it may be better tolerated than docetaxel for some patients, with lower rates of treatment-related AEs and AEs leading to dose reduction (94). The most frequent toxicities with sotorasib include diarrhea, nausea, anorexia, and liver chemistry abnormalities (92-94).

Adagrasib was approved based on a similar phase 2 trial (KRYSTAL-1) of patients previously treated with chemotherapy and immunotherapy (95,96). With 2-year follow-up, ORR was 43%, median PFS 6.9 months, and median OS 14.1 months (97). Intracranial response rate at the time of initial study publication was 33% (11 of 33 evaluable patients). The most common AEs in this single-arm study were diarrhea, nausea, and fatigue; liver chemistry abnormalities were also observed (96). Preliminary data from the phase 3 randomized controlled trial (RCT) of adagrasib versus docetaxel in the second-line or later (KRYSTAL-12) was recently presented, demonstrating a small improvement in PFS (5.5 versus 3.8 months) and ORR (32% versus 9%) for adagrasib compared to docetaxel. Median follow-up for this study remains short at 9.4 months, and OS outcomes are presently immature (98).

In general, current evidence supports first-line platinum-doublet chemotherapy with immunotherapy in patients with KRAS G12C-mutated NSCLC. Of note, inactivating mutations in the tumor suppressor genes STK11 and KEAP1 are enriched in KRAS-mutated NSCLC and have been associated with an immunosuppressive tumor microenvironment and programmed cell death 1 (PD-1) inhibitor resistance (99-101). Recent evidence supports consideration of chemo-immunotherapy with dual immune checkpoint inhibitor blockade {CTLA4 inhibitors and programmed death-(ligand) 1 [PD-(L)1] inhibitors} in this population (102). We reserve kinase inhibitor therapy for the second-line setting, recognizing that the median PFS for both sotorasib and adagrasib in this context is around 6 months. While neither has demonstrated OS benefit compared to standard second-line chemotherapy with docetaxel, the oral route of administration and overall side effect profile remain preferable for many patients. We have slight preference for adagrasib given more evidence of CNS activity (103,104). Sotorasib, adagrasib, and several other KRAS G12C “off” inhibitors are being further studied as monotherapy and in combination with other systemic agents including checkpoint inhibitor immunotherapy and cetuximab (105-107). In development and with the potential to circumvent resistance due to increased KRAS-GTP loading are newer-generation inhibitors targeting the GTP-bound state of KRAS, so-called KRAS G12C “on” inhibitors, as well as pan-RAS inhibitors (105,108-110).

MET exon 14 skipping mutation

Exon 14 of the MET gene encodes a key regulatory region of the MET receptor. Functional loss of this region, as in exon 14 skipping mutations, leads to impaired receptor degradation, increased signaling through the MET receptor, and augmented downstream cell proliferation (111,112). MET exon 14 skipping mutations are found in approximately 2% of NSCLC and are enriched in cases of sarcomatoid histology (113). Unlike many other NSCLC subtypes with AGAs, patients whose tumors have MET exon 14 skipping mutations are typically older (median age: 73 years), and a history of smoking is observed in approximately half of cases (113).

Capmatinib was the first MET-selective oral TKI approved for NSCLC with MET exon 14 skipping mutation (114). It was studied in the phase 2, single-arm, GEOMETRY mono-1 trial, which included multiple cohorts of patients based on previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification) (115). In cases with MET exon 14 skipping mutation, ORR was 68% among treatment-naïve patients and 44% among previously treated patients. Corresponding PFS was 12.5 months in the treatment-naïve setting and 5.5 months in the second- or third-line setting (116). Intracranial responses were observed in 57% of evaluable patients, consistent with earlier evidence that capmatinib crosses the blood-brain barrier (BBB) (116-118). Another MET-selective oral inhibitor, tepotinib, was studied in the similar phase 2 VISION trial that led to FDA-approval (119,120). With long-term follow-up, among treatment-naïve patients, ORR was 57% and median PFS 12.6 months. In pre-treated patients, ORR was 45% and median PFS 11.0 months. Intracranial responses by RANO-BM were comparable to those with capmatinib, observed in 10 of 15 patients with evaluable target lesions (121). Both capmatinib and tepotinib share similar toxicity profiles, including peripheral edema as a leading cause of dose modification and treatment discontinuation. Other common toxicities include gastrointestinal side effects (nausea, vomiting, diarrhea) and increased creatinine levels (115,120).

In clinical practice, we consider either capmatinib or tepotinib to be relatively equivalent and often use them in the first-line setting, recognizing that patients need to be carefully counseled about anticipated treatment-related AEs. Alternatively, standard chemotherapy with or without immunotherapy can be considered up front, particularly for patients with significant smoking history or high programmed death-ligand 1 (PD-L1) expression on tumors. While crizotinib was historically used off-label to treat NSCLC with MET exon 14 skipping mutation, response rates and DOR are lower than for the MET-selective TKIs and its use has fallen out of favor. Cabozantinib is another multi-kinase TKI with anti-MET activity, though again we favor the MET-selective agents (122). Amivantamab has been studied as monotherapy in advanced NSCLC with MET exon 14 skipping mutation in a cohort of the ongoing phase I CHRYSALIS trial, demonstrating an ORR of 46% in those who were MET inhibitor-naïve and 19% in those who were MET inhibitor-experienced, with median DOR of 11.2 months among responders (123). Combinations of amivantamab and MET-selective TKIs are also being investigated (124).

MET overexpression

Overexpression of the c-Met protein has been reported in approximately 25% of EGFR wild-type non-squamous NSCLC (125). The c-Met-directed ADC telisotuzumab vedotin (Teliso-V) has received accelerated approval in advanced, non-squamous NSCLC with high c-Met protein overexpression (defined as ≥50% of tumor cells with 3+ staining by IHC) based on data from the phase 2 LUMINOSITY trial (126,127). Among 84 patients meeting these criteria whose cancers were EGFR wild-type, ORR was 35% and median PFS 5.5 months when given in the second- or third-line setting. In the overall safety cohort, the most common treatment-related AEs included peripheral sensory neuropathy, peripheral edema, and fatigue. Importantly, pneumonitis occurred in 11% of patients and was the most common AE leading to treatment discontinuation. Of note, this study had additional cohorts for non-squamous EGFR-mutated disease and squamous histology—both were not continued into the dose expansion stage due to futility, and the agent is not approved in these settings (126). TeliMET NSCLC-01 (NCT04928846) is the ongoing randomized phase III trial comparing Teliso-V to docetaxel in the previously treated setting.

In contrast, primary MET amplification has been reported in 2–5% of NSCLC overall (66,128). Though MET inhibitors can be considered for high-level MET amplification, response rates for current MET-selective TKIs in MET amplification are lower than for MET exon 14 skipping mutation and such use remains off-label (115,129). In addition, the reporting of MET amplification varies between fluorescence in situ hybridization (FISH) and DNA next-generation sequencing (NGS)-based methods, with ongoing need for further standardization.

BRAF V600E mutation

The BRAF proto-oncogene encodes a serine/threonine protein kinase upstream of the MAPK signaling pathway (130). Activating BRAF mutations are found in 1–3% of NSCLC (67,131-133). BRAF V600E is the most common mutation, and confers constitutive BRAF kinase activity leading to increased cellular proliferation (134,135). It is among the group of class I BRAF mutations occurring at codon 600, leading to aberrantly activated monomers for which currently approved BRAF inhibitors are effective. In contrast, novel therapeutic strategies are needed for class II BRAF mutations (which form BRAF-active, RAS signaling-independent dimers) and class III BRAF mutations (which form kinase-dead dimers that activate RAS) (136). Clinically, patients with BRAF-mutated tumors have more heterogenous characteristics than for other AGAs, with cases reported among a range of ages, ethnicities, and smoking histories (137).

Clinical trials of BRAF inhibition in BRAF V600-mutated NSCLC were initially of BRAF inhibitor monotherapy with either vemurafenib or dabrafenib. These generally demonstrated response rates around 35–45% with variable PFS ranging from 5–13 months (138-140). As in metastatic melanoma, subsequent studies of combination BRAF and MEK inhibitors demonstrated synergistic activity, and are now the preferred strategy. Dabrafenib plus trametinib was approved for metastatic NSCLC with BRAF V600E mutation in 2017, with later expansion of this approval to all solid tumors with this mutation (141,142). This approval was based on a single-arm, phase 2 trial enrolling both treatment-naïve and previously treated patients. In both cohorts, ORR was 63–64% and median PFS 9–11 months (143,144). A subsequent real-world retrospective study demonstrated lower risk of death in patients receiving first-line dabrafenib plus trametinib compared to chemotherapy, but equivalent prospective data are not available (145). Similarly, encorafenib plus binimetinib is also approved based on data from the single-arm, phase 2 PHAROS trial (146,147). Here, the ORR was 75% and median PFS not evaluable among the treatment-naïve cohort, compared to ORR 46% and median PFS 9.3 months among previously treated patients (147). Gastrointestinal side effects such as nausea, vomiting, and diarrhea are common with both BRAF/MEK inhibitor combinations. Pyrexia is more common with dabrafenib plus trametinib, and led to more dose reduction and treatment discontinuation in the corresponding phase 2 study (143,144,147).

Approvals for current BRAF inhibitors (with or without MEK inhibitors) are specifically for the V600E mutation (141,146). Clinical data are limited for patients with non-V600E mutations, and we generally recommend consideration of clinical trials, where available. A number of next-generation BRAF inhibitors target dimerization, which may open the therapeutic armamentarium for patients with class II and III BRAF mutations (148,149).

ALK gene fusion

The ALK gene encodes a RTK in the insulin receptor superfamily that is highly homologous with ROS1 (150). In NSCLC as well as a few other cancer types, ALK gene fusions lead to ligand-independent dimerization and constitutive activation of downstream signaling pathways promoting tumorigenesis (151). ALK gene fusions are found in 4–6% of lung adenocarcinomas, and occur more frequently in younger patients with minimal or no smoking history (152). EML4 is the most common fusion partner, within which there are multiple variants associated with differential outcomes and sensitivity to various agents, but in clinical practice the specific ALK fusion variant does not affect treatment decision-making (153).

There are currently 6 FDA-approved ALK inhibitors in advanced NSCLC (12,154-158). Crizotinib was the first such agent, initially approved in 2011 based on a single-arm phase 1 study where ORR was 61% and median PFS 9.7 months (159). The subsequent phase 3 RCT of crizotinib versus platinum-pemetrexed chemotherapy in the treatment-naïve setting prospectively established ALK TKIs as the preferred first-line therapy (PFS 10.9 versus 7.0 months, ORR 74 versus 45%, OS difference not significant but crossover to crizotinib allowed in control arm) (160,161). Subsequent clinical trials of second- and third-generation ALK TKIs have used crizotinib as the control arm, with no rigorous head-to-head comparisons among next-generation inhibitors.

For a number of years, alectinib was most often the preferred first-line treatment for advanced ALK fusion-positive NSCLC, as it was the first to demonstrate superiority compared to crizotinib. The phase 3 ALEX study of first-line alectinib versus crizotinib demonstrated notable improvements in median PFS (35 versus 11 months) and time to CNS progression (HR 0.16) (162). Shortly thereafter, the phase 3 ALTA-1L trial demonstrated similarly superior overall and intracranial efficacy for brigatinib, noting that this trial also included a quarter of patients who had received one prior line of systemic therapy (163,164). In this context, the initial interim analysis of the phase 3 CROWN trial of first-line lorlatinib versus crizotinib demonstrated a median PFS that was not reached in the lorlatinib arm after a median 18 months of follow-up. Incidence of grade 3 or higher AEs was high (72%), with notable patient-centered concerns about weight gain and cognitive side effects (165). At that point, weighing the toxicity profile of lorlatinib against the relatively short follow-up period, most providers continued with alectinib or brigatinib in the first-line. However, more recent data on updated outcomes from CROWN demonstrated median PFS and time to intracranial progression that were not reached in the lorlatinib arm with over 5 years of median follow-up. Exploratory analysis of end-of-treatment ctDNA also suggested suppression of on-target ALK resistance mutations with lorlatinib (166). Given these data, we have strong support to consider lorlatinib as preferred therapy in the first-line setting, though a careful discussion of patient preferences and anticipated side effects is needed.

In sum, with the updated data from CROWN, lorlatinib should be discussed in the first-line setting with most patients, and prioritized in those with baseline CNS disease. Alectinib and brigatinib are other preferred first-line treatment options which may be considered. Less preferred is ceritinib, which has only been compared against platinum-doublet chemotherapy rather than crizotinib and has a less favorable gastrointestinal side effect profile (167). Most recently approved is ensartinib, with clinical outcomes that appear generally similar to other second-generation ALK TKIs, but is exceptionally well tolerated for most patients in our experience (168). Investigational fourth-generation ALK TKIs are being developed to address on-target ALK mutations, but will not address ALK-independent resistance mechanisms such as bypass tracks and lineage transition changes (169,170).

ROS1 gene fusion

The oncogenic potential of ROS1 gene fusions in cancer has been known since 1987 (171,172). ROS1 fusions occur in 1–2% of patients with NSCLC, and are associated with younger age at diagnosis and minimal or no smoking history (173,174).

Crizotinib was the first FDA-approved TKI for advanced ROS1 fusion-positive NSCLC (154). This approval was based on an expansion cohort of the phase 1 PROFILE 1001 study, demonstrating an ORR of 72% and median PFS of 19.2 months among 50 patients, most of whom (86%) had received previous systemic therapy for advanced disease (175). Additional observational data have highlighted the limited CNS activity and high frequency of CNS progression with crizotinib (176). In this setting emerged multiple CNS-penetrant TKIs with anti-ROS1 activity, two of which (entrectinib and repotrectinib) are specifically approved in ROS1 fusion-positive NSCLC (177,178). Evidence for entrectinib comes from an integrated analysis of three phase 1–2 trials (ALKA-372-001, STARTRK-1, and STARTRK-2). Among 168 patients naïve to ROS1 TKI (35% of whom had CNS disease at baseline), ORR was 68% and median PFS 15.7 months. Patients with and without baseline CNS disease had similar response rates, and intracranial ORR was 80% (179). Data for the next-generation ROS1 TKI repotrectinib derives from the phase 1/2 TRIDENT-1 study, demonstrating an ORR of 79%, median PFS of 35.7 months, and intracranial ORR of 89% in patients naïve to ROS1 TKI. In patients who’d received one prior TKI (82% of which was crizotinib) but no chemotherapy, ORR was 38%, median PFS 9.0 months, and intracranial ORR 38% (180). While both entrectinib and repotrectinib have improved CNS efficacy compared to crizotinib, both are associated with neurologic toxicities attributable to TRK inhibition (dizziness, paresthesia, and weight gain, among others) (179,180).

Phase 3 trials comparing entrectinib (NCT04603807) or repotrectinib (NCT06140836) to crizotinib for first-line therapy are ongoing, but prospective data in this setting are not yet available. Certainly, for patients with known CNS metastases, entrectinib or repotrectinib would be favored given clear improvement in CNS activity over crizotinib. Among patients with ROS1 fusion-positive NSCLC in general, the nearly three-year PFS for repotrectinib in patients naïve to ROS1 TKI is highly impressive, however cannot be robustly compared across studies to the earlier ROS1 TKIs (175,179,180). Therefore, though our preference is to use first-line repotrectinib, it remains reasonable to choose any of these TKIs in the first-line setting in the absence of CNS disease. If a patient does receive first-line crizotinib, lorlatinib is another option (in addition to entrectinib and repotrectinib) in the subsequent-line setting (181). A number of emerging investigational ROS1 inhibitors are in development, such as taletrectinib, which aims to address ROS1 resistance mechanisms, and zidesamtinib (NVL-520), which may have less toxicity associated with TRK inhibition (182,183).

RET gene fusion

The RET proto-oncogene encodes a transmembrane RTK, with gain-of-function alterations observed in three forms: point mutations, fusions, and amplifications (184,185). In NSCLC, RET fusions are observed in 1–2% of unselected cases, with the most common fusion partners being KIF5B, CCDC6, and NCOA4 (186).

Selpercatinib and pralsetinib are both selective, ATP-competitive, small molecule RET inhibitors approved for patients with advanced or metastatic RET fusion-positive NSCLC (187,188). The phase 3 LIBRETTO-431 trial randomized patients with untreated RET fusion-positive NSCLC to either first-line selpercatinib or platinum-doublet chemotherapy with or without pembrolizumab. This study demonstrated a median PFS of 24.8 months and ORR of 84% for selpercatinib, compared to 11.8 months and 65% for the control arm. OS data are immature, however, time to CNS progression was also improved with selpercatinib (HR 0.28) (189). The equivalent phase 3 trial for pralsetinib (AcceleRET-Lung) has not yet reported results. Hence, evidence for pralsetinib comes from the single-arm, phase 1/2 ARROW study, which enrolled 233 patients in the intent-to-treat population. Among treatment-naïve patients, ORR was 72% and median PFS 13.0 months. Among those with prior platinum-doublet chemotherapy, ORR was 59% and median PFS 16.5 months. In 10 patients with measurable CNS disease, intracranial response rate was 70% (190). While both selpercatinib and pralsetinib are generally well-tolerated, QTc prolongation appears more common with selpercatinib, whereas myelosuppression is more frequent with pralsetinib (189-191).

These potent, RET-selective TKIs are the preferred first-line systemic therapy for this lung cancer subtype. Given phase 3 RCT evidence for selpercatinib compared to standard first-line chemoimmunotherapy, selpercatinib is generally preferred, however pralsetinib is likely an equally effective alternative. Earlier-generation multikinase TKIs with anti-RET activity, particularly cabozantinib (but also vandetanib, lenvatinib, and alectinib), can be considered in subsequent lines of therapy, with attention to toxicity from off-target kinase inhibition (192-196). There is ongoing development of drugs to overcome on-target resistance, such as EP0031 (197). As with other target-selective TKIs, repeat molecular profiling at the time of progressive disease can help guide subsequent therapeutic decisions.

NTRK1/2/3 gene fusion

The NTRK1, NTRK2, and NTRK3 genes encode for the TRKA, TRKB, and TRKC proteins, respectively, which are transmembrane RTKs activated by neurotrophins. NTRK gene fusions, via constitutive tyrosine kinase activity, lead to ligand-independent signaling through the TRK receptors, and subsequent oncogenic potential (198). NTRK gene fusions are rare in NSCLC, with an estimated frequency of 0.1–0.2% (198,199). Clinically, patients with NSCLC and NTRK gene fusions tend to be younger with minimal tobacco exposure, though variability exists (199,200). Our understanding of standard chemotherapy and immunotherapy efficacy in NTRK fusion-positive NSCLC is limited to a handful of small case reports and case series (200-202).

TRK inhibitors have generally been studied in basket trials of patients with a variety of advanced solid tumors. Larotrectinib and entrectinib are both first-generation, ATP-competitive inhibitors of TRKA, TRKB, and TRKC (199). Larotrectinib was the first-in-class compound, receiving accelerated approval in 2018 for solid tumors with NTRK gene fusions (203). Among 30 patients with NSCLC, 40% of whom had baseline CNS metastases, ORR for larotrectinib was 74%, with a median PFS of 33.0 months (204). Similarly, entrectinib received accelerated approval for the same population in the following year (177). Pooled analysis from three single-arm clinical trials including 31 patients treated with entrectinib (48% with baseline CNS metastases) demonstrated an ORR of 65% and median PFS of 20.8 months [95% confidence interval (CI): 13.8–30.4] (205). Both agents share similar side effect profiles, though the frequency of dose reduction and treatment discontinuation was slightly higher for entrectinib in registrational trials, possibly due to a broader spectrum of kinase inhibition (206). Specifically, neurologic side effects including dizziness, weight gain, and withdrawal-associated pain are on-target AEs associated with the role of the TRK pathway in maintenance of the nervous system (207).

Most recently, repotrectinib received accelerated approval for solid tumors with NTRK gene fusions (208). This compound is a next-generation TRK and ROS1 TKI designed to overcome resistance mutations to first-generation TKIs (209). The phase 2 portion of the TRIDENT-1 study included patients with NTRK fusion-positive solid tumors who were both TKI-naïve and -pretreated. Among cases of TKI-naïve NSCLC, ORR was 62% and estimated 12-month PFS 64%. By comparison, in the TKI-pretreated population, ORR was 42% and estimated 12-month PFS 23% (210). Extrapolating from data published of repotrectinib in patients with ROS1 fusion-positive NSCLC, the toxicity profile, including neurologic toxicities related to TRK inhibition, appear similar (180).

In clinical practice, we would consider either larotrectinib or entrectinib as first-line or subsequent systemic therapy in patients with NTRK fusion-positive NSCLC. While repotrectinib can also be used in the frontline setting, it is not known whether doing so confers longer term benefit, as none of these TRK inhibitors have been compared head-to-head. Therefore, repotrectinib can also be used for its specific efficacy in tumors previously exposed to first-generation TRK inhibitors with on-target solvent front mutations.

NRG1 gene fusion

The NRG1 gene encodes for neuregulin-1, a protein ligand that contains an EGF-like domain, activating RTKs in the ErbB family (211). Fusions involving NRG1, best characterized for the most frequent CD74 fusion partner, are proposed to result in a membrane-tethered EGF-like domain, leading to induction of ErbB2-ErbB3 (HER2-HER3) heterodimers and downstream activation of oncogenic signaling pathways (212). NRG1 fusions are rare, with an estimated incidence of 0.2% across a number of solid tumors (213). While the initial report of NRG1 fusions in NSCLC involved five female patients with mucinous adenocarcinoma and no prior smoking history, a subsequent molecular registry better illustrates the heterogeneity of this population (214,215). While data on efficacy of standard therapies is limited, the global eNRGy1 registry of 110 patients with NRG1 fusion-positive lung cancers demonstrated low response rates and poor PFS to platinum-doublet chemotherapy (ORR 13%, median PFS 5.8 months), chemoimmunotherapy (ORR 0%, median PFS 3.3 months), and single-agent immunotherapy (ORR 20%, median PFS 3.6 months) (214). Though a few case reports or small case series have provided anecdotal evidence of clinical benefit with the pan-ERBB inhibitor afatinib, efficacy was disappointing in the eNRGy1 registry (ORR 25%, median PFS 2.8 months) (214,216-218).

Zenocutuzumab is a HER2 x HER3 bispecific antibody which docks to HER2 and blocks NRG1 binding to HER3, preventing HER2-HER3 heterodimerization (219). Zenocutuzumab received accelerated approval in 2024 for adults with pretreated, advanced or metastatic NSCLC harboring NRG1 fusions, based on data from the phase 1/2 eNRGy trial (11). The phase 2 portion of this study included 94 patients with NRG1 fusion-positive NSCLC, demonstrating an ORR of 29% and median DOR of 12.7 months across multiple NRG1 fusion partners (220). Therapy was overall well-tolerated with low incidence of grade 3 or 4 AEs (11,220,221).

Given the reported tolerability, potential for durable response, and limited treatment options in this rare patient population, zenocutuzumab should be considered for patients with previously treated NRG1 fusion-positive NSCLC. In the first-line setting, we continue to favor platinum-doublet chemotherapy with low enthusiasm for immunotherapy.

Strengths and limitations

The strengths of this review include its breadth in providing updates on clinically-relevant advances in the treatment of NSCLC with AGAs, as well as in highlighting anticipated areas of future development. As a narrative review, the intent of this study was not to comprehensively review the literature in this field, which would be practically untenable for such a broad topic. In addition, given the rapid pace of development in this field, new developments may have emerged by the time of this publication which are not fully addressed in this work.

Conclusions

The identification of AGAs and subsequent development of targeted therapeutics in NSCLC has led the way for personalized, molecular-directed therapy in oncology. This paradigm shift further emphasizes the importance of biomarker testing at initial diagnosis, with both prognostic and predictive utility. While progress thus far is encouraging across multiple targets, multiple additional challenges remain. The prognostic impact of co-mutations, particularly in tumor suppressor genes such as TP53, have been described at length particularly in EGFR-mutated disease. Yet whether these molecular risk factors have predictive utility to warrant alternative or escalated targeted therapy remains unproven. Other important areas of ongoing and future study include strategies to overcome acquired resistance, appropriate therapeutic sequencing to improve outcomes, and minimizing treatment-related toxicity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://actr.amegroups.com/article/view/10.21037/actr-25-37/rc

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-37/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-37/coif). F.S. reports receiving honoraria from MJH Life Sciences, and has participated in advisory boards for OncoHost. J.W.N. reports receiving research funding from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, AbbVie, Nuvalent, and Novocure; honoraria from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences, Medical Educator Consortium, and HMP Education; and consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, Anheart Therapeutics, Bristol-Myers Squibb, Daiichi Sankyo/AstraZeneca, and Nuvation Bio. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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