Targeting rare oncogenic mutations in resectable non-small cell lung cancer: emerging perioperative strategies

Introduction

Lung cancer continues to be the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases (1). Surgical resection is the cornerstone of curative treatment for patients with stage I–IIIA NSCLC. Nevertheless, the risk of recurrence remains substantial, especially in stage II–IIIA disease, leading to 5-year overall survival (OS) rates of only 30% to 60%, depending on nodal involvement. These outcomes highlight the urgent need for more effective perioperative therapeutic strategies (2). In recent years, the management of NSCLC has evolved from a histology-based to a genotype-directed therapeutic approach. For patients with driver-negative or unknown genetic status, perioperative chemo-immunotherapy has demonstrated considerable clinical benefits. Landmark trials including KEYNOTE-671, AEGEAN, and CheckMate 77T have established that incorporating immune checkpoint inhibitors (ICIs) alongside platinum-based chemotherapy in the neoadjuvant setting, followed by adjuvant ICI monotherapy, significantly enhances pathological response and event-free survival (EFS) (3-5).

However, these landmark trials frequently excluded patients harboring driver oncogenes, particularly epidermal growth factor receptor (EGFR) and ALK alterations. For patients with resectable NSCLC harboring EGFR or ALK mutations, adjuvant targeted therapy has become the standard of care, significantly improving recurrence-free survival (RFS). The ADAURA trial established a new standard with adjuvant osimertinib, demonstrating significant improvements in both RFS and OS in resectable NSCLC with EGFR exon 19 deletions or EGFR exon 21 L858R substitution mutations (6). Similarly, the landmark ALINA trial showed that adjuvant alectinib markedly prolonged disease-free survival (DFS) in patients with IB–IIIA stage ALK-positive NSCLC (7). These pivotal findings have fundamentally reshaped perioperative treatment strategies for early-stage, oncogene-defined NSCLC subsets.

Although well-recognized adjuvant treatment strategies exist for resectable NSCLC with classical driver mutations such as EGFR exon 19 deletions, exon 21 L858R substitutions, and ALK rearrangements, the optimal perioperative management for NSCLC harboring rare genetic alterations, including EGFR exon 20 insertions (ex20ins), HER2 mutations, MET exon 14 skipping (METex14), as well as RET rearrangement and NTRK fusions, along with BRAF V600E and KRAS G12C mutations, remains undefined. Although each of these mutations is individually uncommon, they collectively occur in up to 20% of lung adenocarcinomas (8). In the advanced disease setting, several targeted agents such as amivantamab for EGFRex20ins, trastuzumab deruxtecan for HER2 mutations, selpercatinib for RET rearrangement, and sotorasib for KRAS G12C mutations, have demonstrated clinically meaningful efficacy and gained regulatory approval (9-12). However, translating these targeted therapies into the perioperative setting presents distinct challenges. On the one hand, the low prevalence and significant molecular heterogeneity of rare mutations pose major obstacles to conducting adequately powered randomized clinical trials. On the other hand, while most perioperative chemoimmunotherapy trials have excluded patients with classic driver mutations such as EGFR or ALK, the potential benefits or risks of chemoimmunotherapy in other rare-mutant NSCLC subtypes remain poorly characterized.

Nevertheless, initial clinical investigations are already underway. For example, the phase III LIBRETTO-432 trial is assessing perioperative selpercatinib in patients with RET-rearranged NSCLC (NCT04819100) (13). These studies mark an important advancement toward personalized, biomarker-driven perioperative care. As comprehensive genomic profiling is increasingly integrated into the diagnostic workup of early-stage NSCLC, it has become feasible to identify rare oncogenic drivers prior to surgical intervention. A key unresolved question is how to optimally incorporate targeted agents into perioperative treatment—whether as neoadjuvant induction to enhance resectability and pathologic response, or as adjuvant treatment to eradicate micrometastatic residues. Critical aspects such as optimal treatment sequencing, therapy duration, selection of endpoints, and potential synergies with chemotherapy or immunotherapy urgently require clarification. In addition to exploring novel agents, personalized approaches incorporating minimal residual disease (MRD) assessment via circulating tumor DNA (ctDNA) are gaining traction. MRD positivity post-surgery has been strongly correlated with disease recurrence and may serve as a tool to guide adjuvant therapy intensification or de-escalation (14,15).

In this review, we aim to systematically evaluate the current evidence and ongoing clinical investigations for the perioperative management of NSCLC harboring rare oncogenic alterations (Figure 1). By emphasizing molecular subtype-specific approaches, we provide a critical framework to guide clinical decision-making and inform future research in this rapidly evolving area of oncology.

Figure 1 The illustration of receptor binding sites and intracellular signaling pathways representing potential therapeutic targets in the perioperative management of NSCLC with rare oncogenic alterations. The figure was created with BioRender. AKT, AKT serine/threonine kinase; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK, mitogen-activated protein kinase kinase; MET, MET proto-oncogene; mTOR, mechanistic target of rapamycin; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAS, RAS proto-oncogene; RET, RET proto-oncogene; ROS1, ROS proto-oncogene 1.

Perioperative treatment for NSCLC with rare mutations

NSCLC patients harboring rare oncogenic alterations such as EGFRex20ins, METex14, RET, ROS1, and NTRK fusions, BRAF V600E, KRAS G12C, and HER2 mutations have shown significant clinical benefit from targeted agents in advanced settings (9,11,16-24). Among these rare alterations, mutations such as METex14, BRAF V600E and KRAS G12C are associated with an immunologically active tumor microenvironment characterized by elevated tumor mutational burden (TMB), increased neoantigen load, and heightened sensitivity to ICIs. In contrast, NSCLCs harboring EGFRex20ins, HER2 mutations, or rearrangements in ROS1, RET, and NTRK typically exhibit an immune-excluded or “cold” tumor microenvironment and often demonstrate limited response to immunotherapy (25,26). Although existing trials of neoadjuvant/adjuvant chemoimmunotherapy have not excluded patients with these rare alterations, subgroup data specific to these populations remain either unclear or underpowered to definitively establish the benefit of perioperative chemoimmunotherapy in NSCLC harboring rare driver mutations (3-5,27,28). In this context, perioperative treatment strategies including neoadjuvant, adjuvant, or perioperative approaches should be tailored according to the specific molecular alteration (Figure 2).

Figure 2 Proposed perioperative treatment strategies for resectable NSCLC with rare oncogenic alterations. For tumors exhibiting an immunologically active tumor microenvironment, neoadjuvant options may include immunotherapy combined with targeted therapy (TKI), immunotherapy with chemotherapy, or TKI with chemotherapy. Adjuvant strategies may involve chemotherapy followed by TKI, immunotherapy maintenance, TKI monotherapy, or immunotherapy alone in cases with PD-L1 expression ≥50%. In tumors characterized by an immune‑cold microenvironment, neoadjuvant approaches can consist of TKI monotherapy, TKI combined with chemotherapy, or chemotherapy plus an ADC. Postoperative options may include chemotherapy followed by TKI, TKI monotherapy, or ADC-based regimens. The figure was created with BioRender. ADC, antibody-drug conjugate; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, MET proto-oncogene; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed death-ligand 1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; TKI, tyrosine kinase inhibitor.

EGFRex20ins

EGFRex20ins constitute a structurally and therapeutically distinct subclass of EGFR mutations. These alterations are characterized by in-frame insertions within the exon 20 loop region, which induce conformational changes that retain high affinity for adenosine triphosphate (ATP) while conferring intrinsic resistance to conventional first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) (29). In the CHRYSALIS trial, amivantamab, a bispecific antibody targeting EGFR and MET, demonstrated an objective response rate (ORR) of 40% and a median progression-free survival (PFS) of 8.3 months among previously treated patients with EGFRex20ins (30). The subsequent PAPILLON trial evaluated amivantamab in combination with chemotherapy for untreated EGFRex20ins-mutated NSCLC, reporting a median PFS of 11.4 months and an ORR of 73% (9). Besides, sunvozertinib has been reported to induce rapid tumor regression in platinum-pretreated advanced NSCLC patients, with a median time to response of 43 days and an ORR of 61% (31). Similarly, in the FAVOUR study, furmonertinib achieved an ORR of 78.6% and a median duration of response (DOR) of 15.2 months in treatment-naïve EGFRex20ins-positive NSCLC patients (32).

Despite these advances, the perioperative application of EGFR 20ins-targeted therapies remains unexplored. Patients with these mutations were not included in landmark trials such as ADAURA, and there are currently no approved indications or completed trials evaluating the use of amivantamab or sunvozertinib in resectable NSCLC. Given the limited efficacy of ICIs and the modest benefits of chemotherapy alone in NSCLC with EGFRex20ins mutation, targeted therapies either as single agents or in combination with chemotherapy may represent a promising perioperative strategy. Several clinical trials are currently underway to evaluate the role of EGFRex20ins-specific agents in the perioperative setting, including neoadjuvant amivantamab, adjuvant furmonertinib, and perioperative sunvozertinib (Table 1). Considering that neoadjuvant therapy should balance tumor shrinkage with safety, whereas adjuvant therapy places greater emphasis on drug tolerability and long-term safety, different strategies should be employed for perioperative management of NSCLC with EGFRex20ins mutation. Specifically, combinations such as amivantamab plus platinum-based doublet chemotherapy or sunvozertinib may be more appropriate in the neoadjuvant setting, while single-agent TKIs such as sunvozertinib or furmonertinib are more suitable for use in the adjuvant context.

METex14

METex14 alterations can lead to impaired MET protein degradation, resulting in sustained oncogenic signaling (33). In advanced-stage disease, the therapeutic relevance of METex14 alterations has been firmly established. Selective MET TKIs including capmatinib, tepotinib and savolitinib have demonstrated ORRs of 40–50% in treatment-naïve METex14-positive NSCLC, leading to regulatory approvals across multiple jurisdictions (21,34,35). Despite this progress, the role of MET inhibitors in early-stage, resectable NSCLC remains almost entirely undefined, representing a major gap in perioperative precision oncology. Previous studies have indicated that approximately 40% to 60% of METex14 patients exhibit high PD-L1 expression [tumor proportion score (TPS) ≥50%]; however, reported ORR to ICIs in this population vary widely, ranging from 17% to 44% (36-38).

A few early-phase studies are beginning to address this evidence gap. The GEOMETRY-N trial (NCT04926831), a multicenter phase II study, is evaluating neoadjuvant capmatinib in patients with resectable METex14 NSCLC. Primary endpoints include major pathologic response (MPR) and surgical feasibility. This trial is one of the first to directly investigate a MET TKI in the perioperative setting, however, the study was terminated early due to recruitment challenges. A clinical trial led by Chunxia Su is currently investigating the use of perioperative bozitinib in combination with chemotherapy for stage IIA–IIIC NSCLC with MET alterations, including METex14, MET amplification, and MET protein overexpression (NCT07153770). The study also aims to evaluate the role of MRD monitoring in guiding adjuvant therapy. In addition, several umbrella trials are underway evaluating neoadjuvant strategies such as dabrafenib plus trametinib (NCT06054191) or toripalimab combined with chemotherapy (NCT05800340) in NSCLC harboring other rare genomic alterations (Table 1).

Given the high ORR observed with MET TKIs in METex14 NSCLC, these agents are anticipated to form the cornerstone of neoadjuvant therapy in this population. For patients with high PD-L1 expression, perioperative immunotherapy should be considered, particularly in the adjuvant setting given that MET-TKIs are generally associated with a higher incidence of adverse events compared to ICIs, with potentially greater impact on patients’ quality of life (39).

RET fusions

RET fusions represent a distinct molecular subset characterized by chromosomal rearrangements that lead to constitutive activation of the RET tyrosine kinase (40). These fusions typically involve KIF5B, CCDC6, or NCOA4 as 5' fusion partners and are generally mutually exclusive with other oncogenic drivers such as EGFR, ALK, or ROS1 (41). In the advanced disease setting, the advent of highly selective RET inhibitors has transformed the treatment landscape. Both selpercatinib and pralsetinib have shown substantial efficacy in phase I/II trials, with reported ORRs of up to 84% and 61% in treatment-naïve patients, accompanied by durable responses and robust central nervous system (CNS) activity (23,42). These outcomes have led to regulatory approvals by the Food and Drug Administration (FDA) and inclusion in first-line therapeutic regimens. Given the favorable therapeutic index and potent activity of these agents, there is growing interest in extending RET-targeted strategies to the perioperative setting, where disease remains potentially curable.

LIBRETTO-432 trial (NCT04819100) is the active phase III study specifically evaluating a selective RET inhibitor in early-stage NSCLC (13). This randomized, double-blind, placebo-controlled trial is enrolling patients with completely resected stage IB–IIIA RET fusion-positive NSCLC. Participants are randomized to receive either adjuvant selpercatinib or placebo for up to 3 years, with EFS as the primary endpoint and OS as the secondary endpoint. Importantly, the trial allows prior adjuvant chemotherapy, aligning with real-world practices where cytotoxic therapy may be delivered prior to molecular test results. Results will likely define the future standard of care in this population. In the neoadjuvant setting, a case report described a patient with stage IB KIF5B-RET fusion-positive NSCLC who was treated with neoadjuvant selpercatinib for 8 weeks followed by curative resection, achieving a pathologic complete response (pCR) (43). The cohort 7 of LIBRETTO-001 trial (NCT03157128) employs a Simon’s two-stage design to evaluate the efficacy of neoadjuvant selpercatinib in patients with resectable stage IB–IIIA RET fusion-positive NSCLC, with MPR as the primary endpoint. Furthermore, an umbrella trial assessing the efficacy of neoadjuvant toripalimab combined with chemotherapy in rare-mutant NSCLC also includes RET fusion-positive cases (NCT05800340). The role of immunotherapy in RET fusion-positive tumors appears limited. Although PD-L1 expression may be variable, retrospective analyses reveal that RET fusions appear to be associated with poor response to immunotherapy in NSCLC patients with ORR and disease control rate (DCR) being 24.0% and 61.0% (44). Thus, targeted therapy with RET inhibitors is more likely to benefit NSCLC patients harboring RET fusions in the perioperative setting.

ROS1 and NTRK fusions

ROS1 and NTRK gene fusions represent rare, yet therapeutically actionable, oncogenic drivers in NSCLC. ROS1 rearrangements are characterized by chromosomal translocations that result in constitutive activation of the ROS1 tyrosine kinase (45). These fusions most commonly involve CD74, SDC4, or EZR as 5' fusion partners (46). NTRK fusions result from chromosomal rearrangements that lead to constitutive activation of TRK kinase signaling which typically involve NTRK1, NTRK2, or NTRK3 genes (47). In advanced disease, both ROS1 and NTRK fusions have demonstrated high sensitivity to targeted therapies. For ROS1-positive NSCLC, crizotinib, entrectinib, and lorlatinib have all shown ORRs of 62–82% in treatment-naïve settings, with entrectinib also offering meaningful CNS penetration (48-50). Similarly, for NTRK fusions, larotrectinib and entrectinib have demonstrated ORRs >60% in lung cancer, with durable responses and favorable safety profiles (51-53). To date, a lack of robust data from randomized clinical trials exists regarding the use of these agents in the neoadjuvant or adjuvant setting for early-stage NSCLC. This represents a substantial evidence gap, especially considering the curative potential in resectable disease and the biological plausibility of benefit in the micrometastatic setting.

Several retrospective studies have also reported outcomes of neoadjuvant TKI therapy in ROS1 fusion-positive NSCLC. An et al. described that among patients with ALK or ROS1 rearrangements who received a median of 4.1 months of targeted therapy, a MPR rate of 34.2% was achieved (54). Additionally, documented cases have demonstrated favorable responses to neoadjuvant lorlatinib or crizotinib in patients with ROS1-rearranged NSCLC (55,56). The NAUTIKA1 trial (NCT04302025), a multicohort phase II study, is currently investigating neoadjuvant entrectinib in patients with ROS1 or NTRK fusion-positive resectable NSCLC. Primary endpoints include MPR and pCR, with secondary endpoints focused on radiologic response and survival outcomes. While this study represents a pivotal step, its single-arm, non-randomized design and anticipated small sample sizes will limit the generalizability of findings. A phase 3, multicenter, double-blind, randomized trial is currently ongoing, comparing the investigational agent taletrectinib versus placebo in patients with resectable, ROS1 fusion-positive stage IB to IIIA NSCLC (NCT07154706), with DFS as the primary endpoint. As the first randomized controlled study evaluating perioperative targeted therapy in this molecular subset, its results are anticipated to provide robust evidence regarding the feasibility and efficacy of adjuvant treatment following surgical resection. In terms of immunotherapy, monotherapy with ICIs has shown limited efficacy in patients with ROS1- or NTRK-altered NSCLC. One study investigating neoadjuvant chemoimmunotherapy in an AGA cohort which included rare mutations such as ROS1, KRAS G12C, and HER2 reported a pCR rate of approximately 20% (57). However, these findings are derived predominantly from retrospective studies with small sample sizes and heterogeneous molecular subgroups; thus, the robustness of these conclusions requires further validation.

Taken together, the perioperative treatment of ROS1- and NTRK-fusions NSCLC should prioritize TKI-based strategies, with future research focusing on randomized validation, treatment optimization, and integration of MRD biomarkers to guide personalized therapeutic decisions.

BRAF V600E mutations

BRAF V600E is an oncogenic mutation in the MAPK pathway which results in constitutive activation of the BRAF kinase and downstream ERK signaling, driving tumor proliferation and survival (58,59). Unlike KRAS, which is more common and genetically diverse, BRAF V600E represents a clearly defined, targetable mutation (58). In advanced NSCLC, the development of dual BRAF and MEK inhibition has significantly improved outcomes. The combination of dabrafenib and trametinib demonstrated an ORR of 64% and median PFS of 10.8 months in treatment-naïve patients with BRAF V600E mutations, leading to FDA approval in this population (19). However, no randomized or prospective trials have been published evaluating the perioperative application of BRAF or MEK inhibitors in BRAF-mutant NSCLC.

Previous case reports have described patients with stage IIIA BRAF V600E-mutant NSCLC who received a 2-month course of neoadjuvant targeted therapy with combined BRAF and MEK inhibitors before surgery, achieving a MPR or even a pCR upon postoperative assessment (59,60). Notably, evidence from melanoma where perioperative BRAF-targeted strategies have been more extensively studied may inform treatment approaches in NSCLC. For instance, neoadjuvant dabrafenib plus trametinib in melanoma could achieve high pathological response rates; however, RFS benefits were comparable to those achieved with adjuvant targeted therapy alone (61). These findings underscore the potential value of incorporating targeted therapy in the perioperative setting.

Another major consideration is the aggressive biological behavior inherent to BRAF-mutant NSCLC. Retrospective analyses have indicated an elevated risk of early recurrence and brain metastases, underscoring a high-risk phenotype that may derive particular benefit from adjuvant systemic therapy (62). Furthermore, BRAF-mutant tumors exhibit heterogeneous responses to ICIs, suggesting that immunotherapy alone may be inadequate in the perioperative setting (63-66). In the NeoTrio trial involving resectable stage III BRAF V600-mutant melanoma, the control arm received pembrolizumab monotherapy, while experimental arms received either sequential targeted therapy (dabrafenib plus trametinib followed by pembrolizumab) or concurrent triple therapy. Although the concurrent regimen yielded a higher pathological response rate (80% vs. 50% with sequential), it was also associated with increased toxicity and a higher incidence of early recurrence, suggesting that combining targeted therapy with neoadjuvant immunotherapy may attenuate the long-term curative potential of immunotherapy (67). These findings provide important insights for designing perioperative strategies for BRAF V600E-mutant NSCLC, emphasizing the need to balance efficacy and safety to improve patient outcomes.

Given these considerations, it is imperative to develop clinical trials evaluating the efficacy of BRAF/MEK inhibition in resectable BRAF V600E-mutant NSCLC. While BRAF-mutant NSCLC represents an immunologically hot subtype amenable to immunotherapy, BRAF/MEK inhibitors may be more appropriate in the neoadjuvant setting due to their rapid tumor response. Combining ICIs with BRAF/MEK inhibitors preoperatively could further enhance efficacy. Postoperatively, ICIs may offer a better safety profile, making them a favorable adjuvant option, though the choice between TKIs and ICIs should ultimately be guided by PD-L1 expression levels.

KRAS G12C mutations

The KRAS G12C mutation, which leads to a cysteine substitution at codon 12, represents the most common activating alteration among KRAS-mutant NSCLCs (68,69). Furthermore, KRAS G12C-mutant tumors frequently co-occur with alterations in STK11, KEAP1, or TP53, which significantly shape treatment sensitivity and clinical outcomes (70,71). The development of KRAS G12C-specific inhibitors, such as sotorasib and adagrasib, represents a major breakthrough in targeting what was once considered an “undruggable” oncogene. In the advanced setting, both agents have demonstrated clinically meaningful efficacy, with ORRs ranging from 37.1% to 42.9% and median PFS of approximately 6.5 to 6.8 months among pretreated patients (12,72). These outcomes have led to accelerated regulatory approvals and spurred interest in evaluating these therapeutics in earlier stages of the disease. Several clinical trials are currently investigating KRAS G12C inhibitors in the perioperative management of NSCLC. A phase II single-arm trial (NCT05118854) is evaluating the efficacy, safety, and tolerability of neoadjuvant sotorasib combined with cisplatin (or carboplatin) and pemetrexed chemotherapy for four cycles in patients with resectable stage IIA–IIIB non-squamous NSCLC harboring a KRAS p.G12C mutation, with MPR as the primary endpoint.

Given the potential sensitivity of KRAS G12C-mutant tumors to immunotherapy, additional studies are exploring whether combining adjuvant KRAS G12C inhibition with ICIs can improve outcomes in resected NSCLC. The rationale for combining KRAS G12C inhibitors with ICIs is supported by preclinical evidence indicating that KRAS inhibition may promote T-cell infiltration and attenuate immunosuppressive signaling, thereby potentiating response to ICIs (73). Furthermore, KRAS-mutant tumors frequently exhibit elevated PD-L1 expression and increased tumor-infiltrating lymphocytes, consistent with an inflammatory tumor microenvironment (74). Besides, tumors harboring concurrent KRAS and TP53 mutations often demonstrate high TMB, elevated PD-L1 expression and enhanced tumor cell proliferation (75). However, co-mutations in STK11 or KEAP1, which are common in KRAS G12C-mutant NSCLC, have been linked to primary resistance to immunotherapy (76,77). One such effort is a phase III, multicenter, double-blind, placebo-controlled study (NCT06890598), which is assessing the efficacy and safety of adjuvant olomorasib plus pembrolizumab for up to one year, followed by olomorasib monotherapy for up to three years, compared with placebo plus pembrolizumab followed by placebo alone in patients with resected KRAS G12C-mutant NSCLC. Furthermore, other investigations are examining the efficacy of neoadjuvant KRAS G12C inhibitor monotherapy or in combination with immunotherapy. The Neo-Kan trial (NCT05472623), a phase II study, is evaluating neoadjuvant adagrasib with or without nivolumab in patients with stage IIB–IIIB KRAS G12C-mutant NSCLC. This trial aims to assess pCR as the primary endpoint, with secondary endpoints including surgical feasibility, radiographic response, and immune microenvironment modulation.

Overall, perioperative strategies for KRAS G12C-mutant NSCLC should be guided by PD-L1 status and the presence of STK11/KEAP1 co-mutations. While KRAS G12C inhibitors hold promise in the neoadjuvant setting, caution is advised with adjuvant use, especially in PD-L1-high tumors where ICIs may suffice.

HER2 mutations

HER2 mutations represent a distinct molecular subset of NSCLC. The most prevalent alteration is an in-frame insertion in exon 20, resulting in constitutive activation of the HER2 tyrosine kinase domain (78). In contrast to HER2 overexpression or amplification observed in breast cancer, HER2-mutant NSCLC is primarily driven by activating mutations where most commonly is the A775_G776insYVMA variant and requires detection via DNA- or RNA-based sequencing, as immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are generally inadequate for reliable identification (79,80). Trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate (ADC), has substantially expanded the therapeutic landscape for HER2-altered NSCLC. The DESTINY-Lung02 trial, T-DXd at 5.4 mg/kg demonstrated a high ORR of 53.8% with the incidence of interstitial lung disease (ILD) being 5.9% (24). Based on these results, the FDA granted accelerated approval to T-DXd at the 5.4 mg/kg dose for previously treated, HER2-mutant metastatic NSCLC, establishing it as the first targeted therapy approved for this molecular subset (10). Additionally, trastuzumab rezetecan, another HER2-directed ADC, has shown promising efficacy in HER2-mutant NSCLC patients who progressed after platinum-based chemotherapy and ICIs, reporting an ORR of 73%, a time to response of 1.5 months, a median PFS of 11.5 months, and a manageable safety profile (81). Sevabertinib demonstrated an ORR of 71% and a DOR of 11 months in treatment-naïve NSCLC patients with HER2 mutations (82).

Despite these advances, the role of HER2-directed therapy in the perioperative setting remains almost untested. In a retrospective study evaluating neoadjuvant immunochemotherapy in stage III NSCLC with driver gene mutations, both included HER2-altered patients achieved PR following treatment. One of these two patients underwent curative resection, and pathological assessment confirmed a pCR (56). Neovision, a prospective, single-arm, multicenter, phase II clinical study (NCT06734182), is currently evaluating the efficacy and safety of neoadjuvant envafolimab (a PD-L1 inhibitor) in combination with disitamab vedotin (a HER2-directed ADC) and carboplatin in patients with resectable, HER2-mutant, stage II–IIIB NSCLC. Enrolled patients are to receive four cycles of the combination therapy followed by surgical resection 4–6 weeks after the last neoadjuvant dose. The primary endpoint is MPR, and the secondary endpoints include pCR, ORR, survival outcomes, and molecular response or progression as assessed by ctDNA-based MRD monitoring.

In summary, ADCs and TKIs should form the cornerstone of perioperative treatment in HER2-mutant NSCLC, with ADCs favoring neoadjuvant use and TKIs preferred postoperatively. The role of immunotherapy remains limited, and the optimal duration of adjuvant TKI therapy requires further investigation.

Key challenges and future directions

Although numerous clinical trials into perioperative therapy for NSCLC with rare mutations are currently underway, several critical challenges remain unresolved. The development and validation of targeted therapies for rare molecular subtypes have expanded treatment possibilities in the metastatic setting; however, their translation into the perioperative landscape faces biological, clinical, and methodological barriers. Among these, the scarcity of large, prospective, randomized trials poses a fundamental limitation, largely due to the low prevalence of individual mutations and the difficulty of conducting biomarker-driven studies in early-stage populations. Another key limitation is the heterogeneity in endpoints across current trials. While OS remains the gold standard, it is often impractical in the perioperative context due to long follow-up times (83). Surrogate endpoints such as DFS, MPR, and pCR have been variably adopted, but their correlation with long-term outcomes in the context of targeted therapy remains to be fully validated (84-87). Besides, the advent of ctDNA and MRD assessment offers a promising means to monitor treatment efficacy, detect early relapse, and guide therapy escalation or de-escalation (88,89). Yet, its integration into clinical trial design and real-world clinical practice is still evolving, with questions remaining about assay standardization, optimal timepoints, and interpretation of MRD positivity.

ctDNA and MRD in perioperative management

The emergence of ctDNA-based assays for MRD detection represents a transformative development in the management of early-stage NSCLC. In the perioperative setting, ctDNA provides a molecular window into residual disease that remains invisible to imaging or pathology. In multiple studies, postoperative ctDNA positivity has been strongly associated with disease recurrence and inferior survival outcomes. In the landmark TRACERx study, patients with detectable ctDNA following curative resection experienced relapse with a median lead time of 70 days before radiographic progression (90). Similarly, the NADIM trial showed that persistent or rising ctDNA levels post-treatment were predictive of recurrence, whereas ctDNA clearance correlated with improved outcomes (91). Despite robust signals in immunotherapy-based trials, evidence for ctDNA in the context of targeted therapies, especially in rare mutations, is limited. Most MRD studies have focused on classical EGFR mutations or unselected populations. For instance, the post hoc analysis of the ADAURA trial revealed that molecular recurrence, defined by detectable MRD, preceded clinical recurrence or death by a median lead time of 4.7 months across both study groups (92). The majority of DFS or MRD events occurred following discontinuation or completion of osimertinib therapy. These findings suggest that while osimertinib may effectively reduce or eliminate micrometastatic disease in certain patients, persistent MRD detection during post-adjuvant surveillance could help identify a high-risk subgroup that might benefit from additional treatment. In this context, MRD holds particular promise for patients with rare oncogenic drivers, many of whom lack standardized perioperative treatment protocols. For example, in METex14 or RET-rearranged tumors, the utility of MRD monitoring remains undefined, though its potential to identify micrometastatic persistence could inform adjuvant use of MET or RET inhibitors.

Current ctDNA technologies fall into two broad categories: tumor-informed assays, which use matched tissue sequencing to track patient-specific mutations, and tumor-agnostic panels, which apply fixed NGS panels to plasma DNA (93,94). While tumor-informed methods offer higher sensitivity, they require longer turnaround times and greater cost, which may limit applicability in real-time clinical decisions. Nevertheless, the establishment of clinically validated thresholds for defining MRD positivity, along with the determination of optimal sampling schedules such as immediate postoperative assessment versus longitudinal monitoring during adjuvant therapy, remains an active area of investigation and standardization. From a clinical trial design perspective, MRD status could serve as a stratification or enrichment biomarker, particularly for rare subtypes where event rates are low and large sample sizes are impractical. The MERMAID-2 trial (NCT04642469) is a phase III, randomized study evaluating adjuvant durvalumab in patients with completely resected stage II–III NSCLC who exhibit positive MRD as detected by ctDNA analysis following curative-intent surgery. The primary endpoint is DFS. Similar concepts could be extended to rare-mutant populations using targeted agents. Several key barriers remain. False negatives due to low tumor shedding, especially in early-stage or indolent subtypes such as RET fusion may limit sensitivity (95,96). False positives can arise from clonal hematopoiesis or technical artifacts (97). Moreover, regulatory frameworks for MRD-based decision-making are still evolving, and ctDNA remains a research-only biomarker in most perioperative contexts.

To enhance clinical utility, MRD-guided perioperative trials should adopt adaptive designs that adjust treatment based on ctDNA status. Patients with detectable or rising MRD may benefit from escalation strategies such as prolonged targeted therapy or added immunotherapy, while MRD-negative patients could be considered for therapy de-escalation. In parallel, standardization of assay methods (e.g., tumor-informed vs. tumor-agnostic), sampling timepoints, and ctDNA threshold definitions is essential to ensure consistency and enable regulatory acceptance (98,99).

Standardized assessment of pathological response to perioperative targeted therapy

Pathologic response assessment has become a principal surrogate endpoint for predicting long-term clinical outcomes in the neoadjuvant and perioperative treatments (85,100). Two key histopathologic measures are now routinely employed: MPR which is characterized by 10% or fewer residual viable tumor cells and pCR which denotes the total absence of viable tumor cells. These endpoints are increasingly utilized as primary indicators of efficacy in contemporary perioperative clinical trials, including CheckMate 816, KEYNOTE-671, AEGEAN, and CheckMate 77T, which have contributed to defining new standards of paradigm of neoadjuvant chemo-immunotherapy (3-5,27). However, the applicability and interpretation of pathologic response in the context of neoadjuvant targeted therapy, especially for NSCLC with rare oncogenic drivers, remains uncertain. Most pathologic response standards were validated in cytotoxic regimens, where tumor necrosis is extensive and uniformly distributed. Chemotherapy-induced necrosis primarily results from direct genotoxic and cytotoxic effects, which provokes inflammatory responses and subsequent immune activation (101). In contrast, TKI-mediated cell death operates through precise interference with oncogenic signaling pathways (102). This targeted inhibition can engage multiple programmed cell death mechanisms including apoptosis and regulated necrosis. Additionally, the efficacy and mode of TKI-induced cell death are influenced by tumor-specific genetic backgrounds and the emergence of resistance mutations (103).

In EGFR-mutant NSCLC, several neoadjuvant trials involving EGFR TKIs have shown low rates of MPR or pCR, despite high radiologic response rates. For instance, the phase II EMERGING-CTONG1103 trial reported a radiologic response rate of 54.1% with neoadjuvant erlotinib, yet only 9.7% of patients achieved MPR (104). Similarly, results from the NeoADAURA trial indicated that osimertinib, either alone or in combination with chemotherapy, significantly improved MPR rates compared to chemotherapy alone. However, the observed MPR rate of approximately 25% remains substantially lower than those achieved with neoadjuvant chemoimmunotherapy in driver-negative NSCLC populations, raising questions regarding the applicability of MPR as a universal surrogate endpoint across divergent therapeutic modalities (105). This disparity may be even more pronounced in rare driver mutation populations, where no validated histopathologic response standards exist. For instance, in METex14, RET, or HER2-mutated NSCLC, no perioperative trials to date have published MPR or pCR outcomes. Moreover, the baseline histologic diversity of these tumors adds additional complexity to response interpretation.

Another limitation is the lack of standardized sampling protocols and central pathology review in early-phase trials. Heterogeneity in specimen handling, number of tumor sections reviewed, and pathologist expertise can lead to interobserver variability (106). Guidelines published by the International Association for the Study of Lung Cancer (IASLC) recommend systematic sampling of the tumor bed and standardized scoring methods, but implementation across trials remains inconsistent (107). To mitigate these issues, subsequent perioperative trials incorporating targeted agents should adopt several evidence-based strategies: histologic response criteria adapted to TKI-specific mechanisms such as incorporating measures of cytostatic effect or fibrosis rather than relying exclusively on conventional MPR or pCR thresholds; integration of radiologic-pathologic correlations to improve quantification of partial responses; longitudinal ctDNA monitoring as a complementary endpoint to enhance correlation with pathologic outcomes and recurrence risk; implementation of centralized pathology review using unified criteria, especially in multicenter studies involving rare molecular subtypes; and biomarker-driven substudies to account for distinct patterns of treatment response across molecularly defined cohorts.

The reliability of surrogate endpoints in perioperative targeted therapy

In perioperative clinical trials for NSCLC, surrogate endpoints such as DFS, MPR and pCR have gained prominence as practical alternatives to OS, which requires extended follow-up and large sample sizes (87). These surrogate markers enable earlier readouts of clinical benefit and are particularly useful in early-stage disease (108). However, their predictive value for long-term outcomes in the context of targeted therapy, especially for rare driver mutations, remains inadequately validated. DFS has been widely accepted as a primary endpoint in adjuvant trials evaluating EGFR TKIs. The ADAURA trial revealed a significant improvement in DFS with osimertinib in patients with resected stage IB–IIIA EGFR-mutant NSCLC, leading to its early regulatory approval and integration into clinical practice (6). However, uncertainty persisted regarding whether this DFS benefit would translate into an OS advantage until updated results in 2023 confirmed a statistically significant OS improvement (109). In contrast, the ADJUVANT/CTONG 1104 trial demonstrated significantly prolonged DFS with gefitinib compared to adjuvant chemotherapy (median DFS: 30.8 vs. 19.8 months), yet this advantage did not yield a 5-year OS benefit (53% vs. 51%) (110). These findings suggest that the surrogacy of DFS for OS in the adjuvant setting for classical EGFR-mutation NSCLC requires further validation, and its generalizability to other rare molecular subtypes remains even more uncertain. Although MPR and pCR have demonstrated strong correlation with EFS in patients receiving neoadjuvant chemoimmunotherapy for NSCLC, their association with OS remains to be further validated (100). Furthermore, these endpoints may hold limited utility in perioperative studies investigating targeted therapies. As discussed in section “Standardized assessment of pathological response to perioperative targeted therapy”, EGFR TKIs and other targeted agents often induce cytostatic rather than cytotoxic effects, resulting in low rates of MPR despite meaningful radiologic or molecular responses. This calls into question the use of pathologic regression alone as a reliable measure of therapeutic efficacy in TKI-based perioperative regimens.

To further optimize surrogate endpoint evaluation in rare oncogenic drivers, future perioperative trials should consider several mutation-specific strategies. First, for immune-cold genotypes such as EGFRex20ins, HER2 mutations, RET fusions, and NTRK fusions, traditional pathological endpoints like MPR or pCR may systematically underestimate clinical benefit due to the cytostatic mechanism of action of targeted therapies. In these populations, early ctDNA clearance or longitudinal molecular response kinetics may serve as more sensitive indicators of residual disease eradication. Second, for mutations associated with higher immunogenicity such as KRAS G12C or BRAF V600E composite endpoints integrating MPR, radiographic response, and ctDNA dynamics could provide a more holistic assessment of treatment efficacy. Third, incorporating functional imaging [e.g., positron emission tomography-computed tomography (PET-CT)] alongside pathologic review may help discriminate between viable tumor and treatment-related fibrosis, especially in TKI-treated tumors with low MPR. Given the heterogeneity of pathologic regression with targeted therapies, establishing standardized response criteria and centralized review procedures is essential for consistent interpretation across trials. Finally, because trial enrollment for rare subtypes is inherently challenging, Bayesian adaptive designs that allow interim reassessment of surrogate-OS correlations across genotypes may accelerate validation without compromising statistical power (111).

Conclusions

The perioperative treatment landscape for resectable NSCLC harboring rare oncogenic alterations is rapidly evolving, driven by the clinical success of targeted therapies in advanced disease. However, translating these therapies into the perioperative setting remains challenging due to the biological heterogeneity of molecular subtypes, limited patient populations, and the scarcity of high-level prospective data. Current evidence suggests that perioperative strategies should move beyond a uniform model and adopt a precision oncology framework that accounts for the specific biological features of each genotype. For molecular subsets such as METex14, BRAF V600E, and KRAS G12C mutations, which are often associated with an immunologically active tumor microenvironment, ICIs may play a meaningful role when used alone or in combination with targeted agents. In contrast, tumors with EGFRex20ins, HER2 mutations, RET, ROS1, and NTRK fusions generally exhibit immune-cold phenotypes and are less likely to respond to immunotherapy, making them more suitable for TKI- or ADC-based perioperative strategies. Nonetheless, emerging immunotherapeutic platforms such as bispecific T-cell engagers, engineered cytokine fusions, and next-generation ADCs are being actively investigated to overcome immune resistance in these genotypes. Preclinical and early clinical studies have shown promise in enhancing antitumor activity in immune-cold tumors by redirecting immune effector cells or modifying the tumor microenvironment, offering potential avenues for future perioperative exploration (112,113). Notably, the cytostatic nature of many targeted therapies limits the reliability of traditional surrogate endpoints such as MPR or pCR, which were originally validated in cytotoxic regimens. As such, radiographic response, functional imaging, and ctDNA-based MRD assessment should be increasingly integrated into efficacy evaluation to capture the true therapeutic impact in these populations.

Moreover, the design of perioperative strategies for rare oncogenic drivers should also consider rational combination and sequencing approaches. While TKI remains the backbone for most of these subtypes, emerging strategies such as combining TKIs with ICIs, or sequential integration of TKIs with chemotherapy or ADCs have shown early signs of synergistic potential. However, these regimens carry increased risks of overlapping toxicity, particularly hepatic, dermatologic, and pulmonary adverse events, which may be amplified in the perioperative setting. Moreover, real-world feasibility remains uncertain, especially in older or comorbid patients who may not tolerate multi-modality regimens. Therefore, future trials should not only focus on efficacy endpoints but also incorporate detailed toxicity profiling, quality-of-life assessments, and feasibility metrics to guide treatment selection in clinical practice.

Several priorities need to be addressed to close existing evidence gaps. Subtype-enriched perioperative clinical trials are essential to clarify the efficacy of targeted therapies in early-stage disease, especially for ultra-rare mutations. Harmonized and composite surrogate endpoints that incorporate pathologic, radiologic, and molecular markers are critical to accurately reflect treatment benefit. Furthermore, standardized MRD assays and longitudinal ctDNA monitoring could provide a powerful framework for risk stratification, escalation or de-escalation of adjuvant therapy, and real-time tracking of recurrence dynamics. Adaptive trial designs and regulatory engagement will be pivotal in accelerating the validation of these tools and establishing new standards.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2202/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2202/coif). The authors have no 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.

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