Advances in immunotherapy for driver gene-positive non-small cell lung cancer: a narrative review

Introduction

Immunotherapy, particularly anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies, has recently revolutionized non-small cell lung cancer (NSCLC) treatment across all stages. Immunotherapy is now the standard of care for driver gene-negative advanced NSCLC. However, many issues remain for driver gene-positive NSCLC cases. However, substantial challenges persist for the ~30% of NSCLC patients with driver-positive mutations, who typically exhibit poor responses to immunotherapy monotherapy and even risk hyperprogression in certain subtypes. This review addresses critical unresolved controversies: (I) the biological basis for differential immunotherapy responses across molecular subtypes; (II) the role of immunotherapy (mono- or combination therapy) versus targeted therapy in the first-line setting; and (III) post-resistance strategies leveraging tumor microenvironment remodeling. Current evidence remains fragmented due to uneven data across mutations, limited prospective validation of targeted-immunotherapy sequencing/combinations, and heavy reliance on individualized experience for later-line decisions. To bridge these gaps, we synthesize the latest evidence to classify immunotherapy responses by driver gene, with in-depth analysis of epidermal growth factor receptor (EGFR) across treatment settings (frontline, later-line, perioperative) to inform broader applications, ultimately providing actionable strategies to optimize survival through integrated preclinical/clinical insights. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-684/rc).

Methods

This narrative review systematically and critically analyzes recently published literature on immunotherapy for driver gene-positive NSCLC, summarizing the currently available clinical studies, controversies, and future directions. Notably, this article emphasizes the comprehensive interpretation of literature and theoretical framework construction rather than rigorous selection and quantitative analysis. The literature search for this narrative review was conducted on 25 February 2025. Comprehensive searches were performed across major academic databases including PubMed, Web of Science, Scopus, and Google Scholar. Additionally, publications from leading journals and key conference proceedings were screened to ensure coverage of significant research outputs. The search strategy utilized specific search terms central to the review’s focus: “immunotherapy”, “non-small cell lung cancer”, and “driver gene-positive”. These terms were combined using Boolean operators (AND/OR) to construct precise and relevant search queries, aiming to capture the most pertinent literature. The review focused on literature published within a defined time frame spanning ten years, from 2015 to 2025. This period was selected to encompass the most recent advances and evolving paradigms in immunotherapy for driver gene-positive NSCLC. Strict inclusion and exclusion criteria were applied to ensure the quality and relevance of the selected literature. Inclusion criteria mandated that studies must have direct relevance to the review’s topic, contain findings from clinical studies or foundational basic research theories, and be published in peer-reviewed journals or influential conference proceedings. Conversely, exclusion criteria filtered out non-English literature, preprints or incomplete reports, and commentary articles lacking sufficient methodological details. The screening process was rigorous and involved three field experts. To ensure consistency, all reviewers received uniform training on the application of the inclusion/exclusion criteria and the overall screening protocol. Two reviewers independently screened each identified study for relevance and methodological quality. Studies where inclusion was uncertain were flagged for further discussion. Any discrepancies arising between the two primary reviewers during the screening phase were resolved through team discussions and, if necessary, consultation with a third reviewer. This collaborative and multi-step process continued until consensus was reached on all studies, resulting in the finalization of the literature list included in this review. The search strategy is presented in Table 1.

EGFR gene mutations

First-line immunotherapy for advanced NSCLC with EGFR gene mutations

EGFR mutations can participate in PD-L1 expression by abnormally activating pathways such as nuclear factor κB (NF-κB), phosphoinositide 3-kinase (PI3K), Janus kinase (JAK), mitogen-activated protein kinase (MAPK), and yes-associated protein (YAP). Simultaneously, tumor cells remodel the tumor microenvironment by secreting cytokines such as interleukin (IL)-6, IL-10, chemokine (C-C motif) ligand (CCL)-12/chemokine (C-X-C motif) ligand (CXCL)-10, as well as the hypoxia-induced metabolite adenosine. These factors enhance the effects of angiogenesis, thereby promoting the occurrence of immune escape (1). For treatment-naïve EGFR-mutant NSCLC, first-line immunotherapy is less effective than targeted therapy due to increased infiltration of regulatory T cells (Tregs), decreased number of CD8⁺ T-cells, and lower tumor mutation burden (TMB); it may even increase toxicities. Thus, first-line immunotherapy for EGFR-mutant advanced NSCLC is particularly challenging. The CheckMate 012 trial (2) evaluated the safety and efficacy of first-line nivolumab monotherapy and in combination with chemotherapy in the treatment of advanced non-squamous NSCLC. A total of 13 EGFR-mutant patients were included. Nivolumab monotherapy showed an objective response rate (ORR) of 14%, a median progression-free survival (mPFS) of 1.8 months, and a median overall survival (mOS) of 18.8 months (3); in contrast, the ORR, mPFS, and mOS were 17%, 4.8 months, and 20.5 months, respectively, in the nivolumab plus chemotherapy group (2), showing an efficacy significantly lower than that in patients without EGFR mutations. Multiple studies have explored the role of immunotherapy plus targeted therapy protocols. Clinical trials including CheckMate 012, KEYNOTE 021 (4), and TATTON (5) showed no significant survival benefits from first-line EGFR-tyrosine kinas inhibitors (TKIs) combined with PD-1/PD-L1 inhibitors in treating EGFR-mutant NSCLC; rather, these combinations caused serious toxicities. For example, osimertinib plus durvalumab resulted in a high incidence (38%) of interstitial pneumonia, and pembrolizumab plus erlotinib was associated with high-grade hepatotoxicity in 71.4% of patients treated.

Immunotherapy for EGFR-positive NSCLC with high PD-L1 expression

Prior studies have indicated varied therapeutic benefits from TKIs in advanced EGFR-mutant NSCLC patients with different PD-L1 expression levels (6-8). Treatment-naïve EGFR-positive NSCLC patients with high PD-L1 expression exhibit limited benefits from targeted therapy, with a poor prognosis. Several retrospective studies have linked high PD-L1 expression to primary resistance to EGFR-TKIs (7) and worse prognosis (6) in untreated, EGFR-mutant lung adenocarcinomas. Similar conclusions were also obtained from the third-generation TKIs. A study of 85 treatment-naïve, EGFR-mutant NSCLC patients on osimertinib also found high PD-L1 expression impacted the clinical efficacy of osimertinib; in addition, higher PD-L1 level (≥50%) correlated with worse PFS and OS in patients with EGFR-mutant advanced NSCLC (9). This clinical evidence suggests that high PD-L1 expression may serve as a useful predictor of primary resistance to targeted therapy.

EGFR-positive NSCLC patients with high PD-L1 levels show limited survival benefits from upfront immunotherapy monotherapy (10). A phase II trial (NCT02879994) enrolled 10 treatment-naïve EGFR-mutant, PD-L1-positive (and even highly positive) lung cancer patients, none of whom benefited from first-line pembrolizumab treatment. The trial was prematurely terminated due to poor results in the earlier stages. Furthermore, the incidence of adverse events (AEs) reached 86% in 7 patients receiving subsequent EGFR-TKIs. A review article analyzed the results of CheckMate 057, KEYNOTE-010, and POLAR and concluded PD-1/PD-L1 inhibitors were even less effective than docetaxel in EGFR-mutant NSCLC patients with high PD-L1 levels (11). Few studies have validated the efficacy of first-line chemoimmunotherapy for EGFR-positive NSCLC with high PD-L1 expression. Additionally, sequential EGFR-TKI therapy following first-line PD-1/PD-L1 inhibitors in EGFR-mutant advanced NSCLC significantly increases immune-related adverse events (irAEs). In a study conducted in the US, 15% of patients treated with sequential PD-1/PD-L1 inhibitors followed by osimertinib use for advanced NSCLC developed grade 3/4 irAEs; in contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-1/PD-L1 inhibitors (12). For EGFR-positive NSCLC with high PD-L1 expression, combination therapy may be preferable, although further research is needed to determine optimal treatment strategies.

Immunotherapy for non-classical EGFR-mutant NSCLC

Real-world studies have shown that most EGFR-mutant NSCLC subtypes (Ex19del and L858R) exhibit low immunogenicity, featured by lower PD-L1 and TMB expressions, higher proportion of immunosuppressive cells in the tumor microenvironment (TME), and a “colder” TME compared to wild-type tumors, aligning with prior literature. In addition to the common mutations, some rare EGFR mutations, including G719X mutations in exon 18, L861Q mutations in exon 21, S768I mutations in exon 20, and exon 20 insertions, account for 10–15% of all EGFR mutations. Although the first-, second-, and third-generation EGFR-TKIs are all effective against G719X, L861Q, and S768I mutations, the second- and third-generation TKIs are preferred as first-line treatment due to their higher efficacy. L861Q- and G719X-mutated tumors, with a higher TMB/TP53 co-mutation rate and a lower proportion of immunosuppressive cells in TME, may derive greater benefit from immune checkpoint inhibitor (ICIs) therapy due to their relatively higher immunogenicity (13). In a study of 24 EGFR-mutant patients treated with nivolumab, rare mutations predicted better treatment responses (14). The IMMUNOTARGET study showed improved efficacy with immunotherapy in patients with non-classical EGFR mutations, with the mPFS being 2.8 vs. 1.8 months and mOS being 12.8 vs. 4.9 months in patients with 19del mutations versus those with L858R mutations (15), respectively.

EGFR exon 20 insertion mutations (ex20ins) confer primary resistance to traditional EGFR-TKIs. The introduction of amivantamab (16) and sunvozertinib (17) as first-line therapies has dramatically increased survival benefits, addressing the treatment dilemma faced by patients with EGFR ex20ins. However, evidence suggests that immunotherapy has limited efficacy in treating patients with EGFR ex20ins. The proportions of tumors with TMB and PD-L1 expression ≥1% were significantly lower in patients with EGFR ex20ins compared with those with EGFR 19del/21L858R mutations (median TMB 3.4 vs. 3.5, P=0.001; PD-L1 expression ≥1%: 39% vs. 22%, P=0.02) and those without EGFR ex20ins (median TMB: 3.4 vs. 5.9, P<0.001; PD-L1 expression ≥1%: 60% vs. 22%, P<0.001), suggesting a potentially diminished response to immunotherapy in this patient group (18). A real-world study investigated the efficacy of immunotherapy for NSCLC with EGFR ex20ins: in the first-line setting, the outcomes of monotherapy (n=11) versus immunotherapy plus chemotherapy (n=16) were as follows: ORR, 9.1% vs. 18.8%; mPFS, 3.1 vs. 4.5 months; and mOS, 11.0 vs. 11.3 months, respectively. In contrast, the second-line immunotherapy in 32 patients only yielded an ORR of 3.1%, an mPFS of 3.3 months, and an mOS of 8.1 months (19). Another real-world study showed improved ORR with first-line chemoimmunotherapy versus chemotherapy alone (40.0% vs. 18.2%) but without significant difference in mPFS [6.53 vs. 5.93 months; hazard ratio (HR) =0.73, 95% confidence interval (CI): 0.38–1.39, P=0.48]. Despite first-line chemoimmunotherapy, the clinical outcomes were still poorer in NSCLC with EGFR ex20ins (mPFS: 4.5–6.53 months; ORR: 18.8–40.0%) than in driver gene-negative NSCLC (mPFS: 9.0 months; ORR: 48.3%) (20). Amivantamab exhibits targeted action while simultaneously recruiting immune effector cells, inducing NK cell-dependent antibody-dependent cellular cytotoxicity and macrophage-dependent trogocytosis. Results from the PAPILLON study demonstrated that with a median follow-up of 14.9 months, the amivantamab-containing chemotherapy regimen significantly outperformed chemotherapy alone in PFS, with median PFS of 11.4 months versus 6.7 months (HR =0.40; P<0.001). Concurrently, the amivantamab-chemotherapy combination regimen displayed a “tail effect” similar to that observed in immunotherapy-chemotherapy combination regimens (16).

Immunotherapy for TKI-treated EGFR-mutant advanced NSCLC

Although targeted therapies offer new options for driver gene-positive NSCLC, primary and secondary drug resistance remain common challenges. For patients with EGFR-TKI-resistant NSCLC, repeat biopsies and genetic testing are emphasized to guide subsequent treatments. Due to the complexity of EGFR-TKI resistance, immunotherapy has emerged as a novel option in the later-line treatments for NSCLC after EGFR-TKI resistance emerges, especially in those with unknown resistance mechanisms. Dynamic changes in the TME of EGFR-mutant NSCLC after TKIs resistance, especially if associated with macrophage-mediated inflammation, particularly through IL-6, can promote the EMT and contribute to T-cell exhaustion. Additionally, several factors secreted by M2 polarized TAMs (such as TGF-β, TNF-α, VEGF, IL-8, CCL-22, and CCL-18) (1). EGFR-TKI treatment can also promote CD8 T cell infiltration and major histocompatibility complex (MHC) I/II expression, decrease the amount and activity of Tregs, remodel the TME, and upregulate the expression of PD-L1, thereby potentially enabling later-line immunotherapy (21).

Immunotherapy monotherapy

Subgroup analyses of multiple phase III trials have indicated that EGFR-mutant NSCLC patients did not benefit from second- or later-line immunotherapy monotherapy (22-25). Two meta-analyses showed no OS benefit for immunotherapy monotherapy over docetaxel in EGFR-mutant NSCLC (26,27). The ATLANTIC study demonstrated that after multiple lines of EGFR-TKI therapy, durvalumab treatment in EGFR-mutant patients (even with high PD-L1 expression) resulted in a low ORR (12%) and short mPFS (2.9 months); however, an exploratory OS analysis revealed an mOS of 16.1 months for EGFR-mutant patients with PD-L1 level ≥25% (28). Thus, lung cancer patients with EGFR mutations and increased PD-L1 expression may benefit from immunotherapy monotherapy, although the efficacy remains inferior to that in EGFR wild-type patients. Additionally, dual-agent immunotherapy also fails to achieve the expected outcomes. A phase II trial of nivolumab plus ipilimumab in EGFR-mutant NSCLC after first-line EGFR-TKI failure showed poor efficacy (ORR: 6.3%; mPFS: 1.22 months), leading to early trial termination (29).

Chemoimmunotherapy

In a phase II single-arm multicenter open-label clinical study (CT18), toripalimab plus chemotherapy for EGFR-TKI-resistant, T790M-negative NSCLC achieved an ORR of 50.0% and a disease control rate (DCR) of 87.5%, suggesting that chemoimmunotherapy might have good short-term efficacy in this patient population (30). However, two international multi-center phase III randomized controlled trials (RCTs), namely, CheckMate 722 and Keynote 789, demonstrated that immunochemotherapy provided no PFS or OS benefit over platinum-based chemotherapy in EGFR-mutant NSCLC after the emergence of EGFR-TKI resistance (31,32). Given the negative results of these two large phase III trials, immunotherapy plus chemotherapy is not recommended for EGFR-mutant NSCLC following EGFR-TKI resistance. The ILLUMINATE study found that the dual-agent immunotherapy plus chemotherapy (durvalumab-tremelimumab plus platinum-based chemo doublets) was more effective in T790M-negative patients (ORR: 31%; mPFS: 6.5 months), warranting further phase III investigations (33). Amivantamab, while not fully equating to traditional immunotherapy, possesses critical immunomodulatory functions. The MARIPOSA-2 study investigated the efficacy of amivantamab combined with chemotherapy ± lazertinib in patients with advanced EGFR-mutated NSCLC who progressed after osimertinib therapy, showing a numerical improvement in overall survival (OS) without reaching statistical significance (34). Different mutation types benefit from immunotherapy to varying degrees. A meta-analysis concluded that patients harboring EGFR L858Rf mutations (but without T790M mutations) were more likely to benefit from immunotherapy plus chemotherapy with or without additional antiangiogenic therapy (35).

Immunotherapy combined with anti-angiogenic therapy

Only small-sample studies have investigated the combinations of immunotherapy with anti-angiogenic therapy. The ML41256 trial explored the atezolizumab plus bevacizumab regimen but was discontinued prematurely because only three patients achieved partial response (PR) (36). The ALTER-L038 study evaluated the efficacy and safety of the combination of benmelstobart, an anti-PD-L1 antibody, and anlotinib in EGFR-positive advanced NSCLC patients who progressed after EGFR-TKI therapy and showed an mPFS of up to 8.97 months and an immature mOS (currently 28.9 months); however, the ORR was only 25.5%, below the expected value. Subsequent phase III trials are needed to identify patient sub-populations that may benefit most from the combination (37).

Immunotherapy combined with chemotherapy and anti-angiogenic therapy

The IMpower150 study enrolled patients with EGFR-mutant NSCLC, comprising 11% of the total study population. The subgroup analysis revealed survival benefits for a 4-drug combination in this sub-population, offering hope of immunotherapy for patients with EGFR mutations after targeted therapy resistance (38). However, head-to-head comparison in the subsequent IMpower151 study (with 53% of patients with EGFR mutations) showed no significant PFS improvement with the 4-drug regimen versus chemotherapy plus bevacizumab (no statistically significant difference in mPFS) (39). In the ORIENT-31 study of pembrolizumab, lenvatinib, and chemotherapy for TKI-resistant, EGFR-mutant NSCLC, 18 patients achieved an ORR of 40% and an mPFS of 11.9 months (OS data immature). The study divided EGFR-mutant NSCLC patients into 3 arms: quadruple therapy, immunochemotherapy, and chemotherapy alone. It was found that both quadruple therapy and immunochemotherapy significantly prolonged mPFS over the platinum-based doublet chemotherapy in EGFR-mutant NSCLC patients; however, the subsequent interim analysis showed no significant difference in OS among all 3 groups (40). Similarly, the phase III ATTLAS trial also demonstrated that the quadruple therapy improved PFS but not OS compared to platinum-based combinations in EGFR-mutant NSCLC (41). Therefore, all the currently available clinical studies have indicated that although quadruple therapy improves mPFS, it does not confer an OS benefit and has a high incidence of treatment-related adverse events (TRAEs)/serious adverse events (SAEs), necessitating cautious patient selection. The increased drug variety in clinical practice often correlates with decreased patient tolerance to side effects. Consequently, many patients struggle to continue their treatments, often requiring dose reductions or medication changes, which potentially compromises treatment efficacy. Furthermore, the quadruple combinations may impair quality of life, reduce patients’ tolerance of side effects, limit subsequent treatment options, and ultimately hinder further OS prolongation. However, despite negative OS results in the ORIENT-31 study, subgroup analysis indicated greater benefit from quadruple therapy in patients with L858R mutations, T790M-negative status, and those previously treated with only 1 TKI (40). A Hong Kong-based single-arm study of atezolizumab plus chemotherapy and low-dose bevacizumab showed similar efficacy but significantly reduced AEs compared to the IMpower150 study (42). The BGB-A317-2001 study also utilized low-dose bevacizumab, yielding improved survivals with an incidence of grade 3/4 AEs of only 31.5% (43). The phase III HARMONi-A study demonstrated that ivonescimab [a novel anti-PD-1/vascular endothelial growth factor A (VEGF-A) bispecific antibody] plus chemotherapy significantly prolonged PFS compared to platinum-based doublet chemotherapy in EGFR-TKI-resistant, EGFR-mutant non-squamous NSCLC. In addition, it showed a trend to improve OS, although the data were not immature (44). In a phase II study, the novel PD-L1/VEGFA bispecific antibody PM8002/BNT327 demonstrated promising results (ORR: 54.7%; DCR: 92.9%) in 64 EGFR-resistant NSCLC patients when used in combination with chemotherapy, with the incidence of grade 3 or higher TRAEs being 54.7% (45). The data are summarized in Table 2.

Immunotherapy for EGFR-mutant early/locally advanced NSCLC

Despite EGFR mutations being the most common oncogenic driver event in NSCLC, progress in neoadjuvant therapy remains challenging. In some recent studies (e.g., NEOS and another phase II multicenter trial), neoadjuvant targeted therapy failed to achieve satisfactory pathological responses in EGFR-mutant NSCLC patients (46,47). The CTONG1103 study found that the OS benefit of neoadjuvant targeted therapy in EGFR-mutant NSCLC was lower than anticipated (48). The results of the NeoADAURA study were also not particularly promising. The major pathological response (MPR) rates were approximately 25% in the osimertinib monotherapy and osimertinib combination therapy groups, while the MPR rate in the chemotherapy-alone group was only 2%. The pathologic complete response (pCR) rates were 4% and 9% in the osimertinib monotherapy group and the combination therapy group, respectively (49). In a multi-center retrospective study involving 40 patients receiving neoadjuvant immunotherapy for driver gene-positive, resectable NSCLC, 37.5% of the patients achieved MPR and 12.5% achieved pCR; in the EGFR-mutant subgroup, the rates of MPR and pCR were 42.1% and 10.5%, respectively, surpassing prior neoadjuvant targeted therapy protocols (50). The study also showed no significant correlation between PD-L1 expression and MPR; however, immunosuppression in primary tumors and hyperinflammatory response in lymph nodes might correlate with better outcomes. The NEOTIDE (CTONG2104) study provided data supporting the application of neoadjuvant immunotherapy for EGFR-mutant NSCLC. In patients with resectable stage II_B–III_BEGFR-mutant NSCLC, neoadjuvant sintilimab plus chemotherapy achieved an MPR of 34.3% and a pCR of 11.4%, with no correlation between baseline PD-L1 expression and pathological responses, demonstrating clinical feasibility and good safety profile (51). Despite a lower overall pathological response rate than in wild-type NSCLC, the combinations of immunotherapy and chemotherapy demonstrated superior efficacy compared to prior neoadjuvant targeted therapy alone. Circulating tumor DNA (ctDNA) testing revealed that EGFR-mutant NSCLC patients who were highly nonresponsive to immunochemotherapy had high CCR8⁺ Treg/low CXCL13⁺ Tex infiltration and TCR clonal proliferation, which might serve as potential biomarkers for immunotherapy response and guide the development of new combination strategies to overcome the intrinsic tumor resistance to immunotherapy.

Both the IMpower010 study and the KEYNOTE-091 study showed no definite benefit of adjuvant immunotherapy in EGFR-mutant NSCLC patients (52,53). A meta-analysis indicated that adjuvant targeted therapy might confer superior DFS to immunotherapy for resectable, PD-L1-positive EGFR-mutant NSCLC (54). Based on the ADAURA study data, adjuvant therapy with osimertinib demonstrated statistically significant and clinically meaningful OS benefits compared to placebo treatment in patients with stage IB–IIIA EGFR mutation-positive NSCLC. The 5-year OS rate in the overall population (stage IB–IIIA) reached 88%, with an HR of 0.49 (P<0.0001). For postoperative adjuvant therapy in EGFR-positive patients, targeted therapy may be a more suitable option (55).

Adjuvant/neoadjuvant therapies have brought long-term benefits to driver gene-negative NSCLC patients; accordingly, the “sandwich” model of perioperative immunotherapy plus chemotherapy has been explored in EGFR-positive patients. In the KEYNOTE-671 study, subgroup analysis of 33 EGFR-mutant NSCLC patients showed significantly improved PFS and a trend towards OS benefit (56). The AEGEAN study enrolled 51 EGFR-mutant NSCLC patients; compared to the modified intent-to-treat (mITT) group [defined as without known EGFR mutations or anaplastic lymphoma kinase (ALK) fusions], these EGFR-mutant NSCLC patients showed numerical improvements in event-free survival (EFS), pCR, and MPR, although no statistically significant difference was reached (57). Unfortunately, both studies had small EGFR-positive subgroups, yielding inconclusive subgroup analyses. Although current evidence suggests that some EGFR-positive patients may benefit from perioperative immunotherapy, further follow-up data and clinical studies are warranted to clarify the potential value of immunotherapy for early/locally advanced EGFR-mutant lung cancer in neoadjuvant/adjuvant settings.

ALK mutations

ALK mutations in NSCLC patients have been associated with low TMB level and high T cell immunoglobulin mucin-3 (TIM3) expression compared to other alternations (58). In addition, ALK-TKI treatment may further diminish tumor immunogenicity. However, the combinations of ALK-TKI with immunotherapy for NSCLC offer no better efficacy than TKI alone; rather, they significantly increase toxicities. Alectinib combined with atezolizumab in the first-line setting caused grade 3 or higher AEs in up to 57% of the patients (59). In the CheckMate370 study, crizotinib plus nivolumab regimen resulted in severe hepatotoxicity in 38% of cases, including 2 deaths (60). Ceritinib plus nivolumab was attempted in both first- and later-line settings, resulting in grade 3+ AEs in up to 86% of patients and grade 3+ hepatotoxicity in with 31% of patients (61). In later-line treatment, SAEs were recorded in 39.3% of the patients receiving lorlatinib-avelumab combination in the Javelin Lung 101 trial (62). Neoadjuvant alectinib has shown significant efficacy. The ALNEO trial enrolled 25 patients with stage III ALK-positive NSCLC. Among the 18 cases who had received neoadjuvant alectinib, 17% achieved MPR and 17% achieved pCR. Thus, neoadjuvant alectinib has potentially superior PCR and MPR rates over chemoimmunotherapy, along with more significant treatment benefits than EGFR-TKIs (63). The ALINA study demonstrated significant efficacy and safety benefits of alectinib over chemotherapy in the adjuvant setting for ALK-positive NSCLC (64). Conversely, the IMpower010 trial found no DFS benefit for atezolizumab as adjuvant therapy in ALK-positive NSCLC. Based on the currently available clinical evidence, targeted therapy demonstrates greater benefit than immunotherapy across all stages (i.e., early, locally advanced, and advanced) of ALK-positive NSCLC, with the optimal immunotherapy mode for ALK-positive NSCLC deserving further investigations.

Receptor tyrosine kinase (ROS1) mutations

For c-ROS oncogene 1, ROS1-positive NSCLC patients, the PD-L1 expression level may be upregulated by activating extracellular signal-regulated protein kinases (ERK). A multi-center retrospective study showed that in ROS1-positive NSCLC patients treated with immunotherapy monotherapy, the median time to disease progression (TTD) was 2.1 months and the ORR was 13%; in contrast, immunotherapy plus chemotherapy yielded TTD of 10 months and an ORR of 83% (65). Therefore, NSCLC patients with ROS1 fusion may benefit from immunotherapy, with combination therapy showing greater promise, although more research is needed to confirm the superiority of immunotherapy over targeted therapy.

Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutations

A meta-analysis revealed that KRAS mutations correlated with increased proportions of PD-L1⁺/tumor-infiltrating lymphocytes (TILs)⁺ NSCLC, and KRAS-mutant tumors had more T cell infiltration and heightened immunogenicity, suggesting potential for ICIs therapy (66). Subgroup analyses across multiple studies indicate that patients with KRAS mutations may benefit from immunotherapy, especially in those with high PD-L1 expression. In the KEYNOTE-042 study, patients with KRAS mutations treated with pembrolizumab achieved higher ORR and improved PFS/OS compared to platinum-based chemotherapy (67). According to the KEYNOTE-189 study, pembrolizumab plus platinum-based doublet chemotherapy significantly improved PFS and showed a trend toward OS benefit in KRAS-mutant patients compared to chemotherapy alone (68). In both studies, KRAS co-mutated with serine/threonine kinase 11 (STK11) or Kelch-like ECH-associated protein 1 (KEAP1) showed reduced immunotherapy benefit but remained superior to chemotherapy. In the IMpower150 study, a 4-drug regimen was shown to be more beneficial than a 3-drug combination for patients with KRAS mutations (38). Notably, different KRAS mutations exhibit distinct biological features and respond variably to immunotherapy. In patients with KRAS G12C mutation, both monotherapy immunotherapy (HR =0.61, P=0.04) and chemoimmunotherapy (HR =0.59, P=0.03) significantly improved OS compared to chemotherapy alone. For KRAS G12D, neither immunotherapy alone (HR =0.74, P=0.53) nor chemoimmunotherapy (HR =0.73, P=0.42) improved OS compared to chemotherapy alone (69).

Mutant-specific KRAS inhibition reshapes the tumor microenvironment by reducing immune-suppressive cells while increasing the infiltration and activation of lymphoid populations and pro-inflammatory M1 macrophages. This remodeling involves both direct tumor cell-intrinsic and indirect effects. Cancer cells under KRAS inhibition exhibit reduced secretion of monocyte and neutrophil chemoattractants, particularly CXCR2 ligands, leading to decreased infiltration of these immunosuppressive cells. Conversely, KRAS inhibition-treated tumors show increased secretion of T cell chemoattractant cytokines, such as CXCL9 and CXCL10. This correlates with enhanced infiltration of CD8⁺ T cells, CD4⁺ T cells, and Tregs. These cytokines originate from multiple sources, including cancer cells themselves and antigen-presenting cells (APCs). KRAS inhibition enhances IFNγ responses within cancer cells, boosting the expression of IFN-responsive genes. These include genes encoding chemokines (CXCL9, CXCL10) and antigen-presenting machinery. Simultaneously, the increased cancer cell death resulting from KRAS inhibition elevates the pool of available antigens. This promotes APC activation. The resulting enhancement in antigen presentation, by both cancer cells and APCs, improves T cell recognition and activation (70). Among the immunotherapy plus targeted therapy protocols, the concurrent use of sotorasib and pembrolizumab has been shown to result in a high incidence (about 80%) of grade 3 or higher AEs (71,72). The rates of grade 3+ liver enzyme elevations exceeded 80% at a dose of 720 mg/960 mg quaque die (qd). However, subsequent studies using similar drugs have not revealed the additive toxicity of KRAS inhibitors when used in combination with immunotherapy. In the KRYSTAL-7 study, adagrasib 400 mg bisin die (bid) (the approved monotherapy dose is 600 mg bid) combined with pembrolizumab achieved an ORR of 63% and a DCR of 84% in the KRAS G12C-mutated and TPS50 population. The incidence of grade 3 and higher AEs was 55%, including liver enzyme elevations (glutamic pyruvic transaminase and glutamic oxaloacetic transaminase elevations were 10% and 14% respectively), and thus the safety profile was manageable (73). In the LOXO-RAS-20001 study, the second-generation KRAS G12C inhibitor olomorasib demonstrated initial efficacy in KRAS-mutant NSCLC. Olomorasib combined with pembrolizumab achieved an ORR of 77% and a DCR of 88% in the first-line treatment of NSCLC, with minor adverse reactions, although further follow-up data are still on the way (74). Iterative updating of targeted therapy drugs, particularly combinations with immunotherapy, are poised to revolutionize treatment strategies for KRAS-mutant cancers.

Human epidermal growth factor receptor 2 (HER2) alterations

HER2 alterations in NSCLC include mutations, amplification, and overexpression, which occur in approximately 4%, 10–20%, and 6–35% of NSCLC, respectively. In HER2-mutant NSCLC patients, low PD-L1 and TMB levels (15) resulted in reduced immunotherapy benefit compared to patients with other mutations. Exon 20 insertions are the most common HER2 mutation and confer primary resistance to EGFR-TKIs. First-line treatment for these patients, mimicking those for driver gene-negative NSCLC, is primarily immunotherapy combined with chemotherapy. A retrospective study found that patients with HER2 mutations had TMB and PD-L1 tumor cell proportion score (TPS) levels similar to those with EGFR alterations, potentially explaining the comparable efficacy and survival benefits of immunotherapy in these 2 patient subsets; notably, the response to immunotherapy monotherapy was suboptimal (75). Another retrospective study compared the efficacy of platinum-based chemoimmunotherapy versus platinum-based chemotherapy in patients with EGFR/HER2 exon 20 insertion (Ex20ins) mutations. No significant difference in mPFS was observed between these two groups (76). In contrast, patients without ex20ins have higher TMB and may benefit from immunotherapy. When treated with immunotherapy, patients without ex20ins had longer mPFS (13.0 vs. 3.6 months) and OS (27.5 vs. 8.1 months) than those with ex20ins (77).

Recent studies suggest HER2-targeting antibody-drug conjugates (ADCs) may synergize with ICIs in inducing tumor cell death and enhancing tumor immunogenicity. Prior DESTINY-Lung serial studies have demonstrated trastuzumab deruxtecan (T-DXd) has superior efficacy and a good safety profile in HER2-mutant NSCLC. DESTINY-Lung02, a global multi-center phase II trial, revealed a 50% ORR and 10-month mPFS with T-DXd 5.4 mg/kg in previously-treated HER2-mutant advanced NSCLC (78). The DESTINY-Lung05 trial, a bridging study in China, showed consistent benefits in Chinese patients with HER2-mutant NSCLC, demonstrating an independent central review (ICR)-confirmed ORR of 58.3% and a 12-month PFS rate of 55.1%, aligning with global trends (79). DESTINY-Lung01 investigated the efficacy and safety of T-DXd monotherapy in HER2-overexpressing (IHC 3+ or IHC 2+) NSCLC. Cohort 1a (5.4 mg/kg; n=41) showed a 34.1% ICR-confirmed ORR, 6.7-month mPFS, and an 11.2-month mOS. In particular, the IHC 3+ subgroup exhibited better efficacy: ORR, 52.9%; mPFS, 7.5 months; and mOS, 12.5 months (80). The ongoing DESTINY-Lung03 study (81) further confirmed the efficacy of T-DXd monotherapy in HER2-overexpressing advanced NSCLC: part 1 assessed the value of the combination of T-DXd monotherapy with durvalumab (data not yet publicly available), whereas parts 3 and 4 aimed to assess the role of T-DXd plus bispecific antibodies. The results are expected to inform future monotherapy and combination therapy strategies. In the DS8201-A-U106 study, T-DXd plus pembrolizumab yielded ORRs of 54.5% vs. 66.7% and mPFS of 15.1 vs. 11.3 months in immunotherapy-naïve HER2-expression (including overexpression) or HER2-mutant NSCLC patients, respectively. Preliminary safety results were consistent with known profiles of each drug: the incidence of grade 3 or higher TRAEs was 22.7% and 48.5%, respectively; drug-related interstitial lung disease/pneumonia was mostly grade 2 and recovered well (82). Thus, T-DXd is poised to be central in combination therapies for HER2-positive NSCLC. Its preliminary combinations with immunotherapy have been promising, and subsequent study results are anticipated.

Immunotherapy for NSCLC with other mutations

NSCLC patients with rearranged during transfection (RET) fusion tend to have low immunogenicity, although the immune microenvironments vary by fusion type. A retrospective analysis suggested that female patients with KIF5B-RET fusions may benefit from immunotherapy due to high PD-L1 expression (83).

NSCLC patients with B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations exhibited higher PD-L1, TMB, and tumor immunogenicity, suggesting potential immunotherapy benefit (84). For BRAF-mutant advanced NSCLC, although targeted therapy has been recommended by Chinese and international guidelines, chemoimmunotherapy protocols have also been advised. A retrospective study found no significant difference in PFS between first-line dabrafenib plus trametinib and immunotherapy for BRAF-mutant NSCLC (85). In patients with the BRAF V600E mutation, pooled data for PD-1/PD-L1 inhibitor monotherapy used in the first-line or later (1L+) setting showed an objective response rate (ORR) of 26.1%, a median progression-free survival (PFS) ranging from 5.3 to 9.79 months, and a median overall survival (OS) ranging from 20.83 to 33.9 months. In contrast, patients with an unspecified line of therapy receiving the same treatment had a median PFS of only 1.8 months and a median OS of 8.2 months (86).

NSCLC patients with mesenchymal-epithelial transition factor exon 14 (METex14) skipping mutation exhibit adaptively upregulated PD-L1, low TMB, and high heterogeneity of the tumor immune microenvironment. A retrospective study divided METex14 mutations into 4 subtypes, among which subtype C showed the features of an immune-activated subtype, with higher infiltration of T cells and macrophages, suggesting potential immunotherapy benefit in this subtype (87). In a retrospective study, 36 patients with MET mutations receiving immune monotherapy exhibited an ORR of 16%, with median PFS and OS of 3.4 and 18.4 months, respectively (15). A retrospective cohort study analyzed the baseline characteristics and efficacy in 147 NSCLC patients with MET exon 14 skipping mutations. PD-L1 expression was evaluable in 111 patients, among whom 41% had PD-L1 >50%. However, the ORR for immunotherapy was low (17%), with a median PFS of 1.9 months (88). Compared to targeted therapy or platinum-based chemotherapy, immune monotherapy outcomes in this cohort were inferior. Patients with MET exon 14 skipping mutations exhibit poor response to immunotherapy. Nevertheless, combining targeted therapy with immunotherapy represents a potential direction for treating these patients. Research has found that MET-TKIs may synergize with ICIs. In a renal cancer cohort, MET-TKI inhibitors were identified as key to overcoming ICI resistance and maximizing the efficacy of immunotherapy (89). Another preclinical study suggests that combining MET-TKIs with ICIs might enhance responsiveness to immunotherapy even beyond the context of MET-dependent tumors (90).

Conclusions

This article reviews recent advances in immunotherapy for NSCLC with the mutations of common driver genes. For EGFR-mutant advanced NSCLC, first-line targeted therapy is recommended; however, high PD-L1 level indicates a high rate of primary resistance to targeted therapy and predicts poor prognosis, and its optimal treatment deserves further investigations. Notably, nonclassical EGFR mutations may benefit from immunotherapy. For EGFR-TKI-resistant patients, re-biopsy is prioritized to identify the resistance mechanism, and immunotherapy may be initiated for those without treatable targets. The combination of immunotherapy, chemotherapy and anti-angiogenesis can prolong PFS but does not improve OS. How to screen for the benefit subgroups remains to be explored. The neoadjuvant immunotherapy combined with chemotherapy regimen is currently in the exploratory stage for EGFR-positive patients, and the level of evidence-based medicine needs to be improved. For advanced NSCLC with KRAS mutations, the first-line treatment is currently recommended to be immunotherapy combined with chemotherapy. The combination of targeted therapy and immunotherapy has shown certain therapeutic effects, but the toxicity mechanism is not clear. How to predict and prevent it needs further exploration. STK11/KEAP1 co-mutations lead to immune resistance and require drug reversal strategies. For HER variations, the combination of T-Dxd and immunotherapy is currently being explored to further improve efficacy. Non-ex20ins patients have significant benefits from immunotherapy, but ex20ins patients have poor efficacy. How to optimize stratification requires further research. Immunotherapy for NSCLC with positive driver genes needs to achieve refined combination through molecular typing, resistance mechanism analysis, and toxicity stratification. The future direction is to develop predictive biomarkers, explore new therapies such as bispecific antibodies/ADCs, and prioritize patient quality of life. However, this narrative review may be limited by the following potential biases: (I) the search scope was limited to English-language databases, with some important non-English articles excluded; (II) some of the conclusions were highly subjective and relied heavily on the authors’ interpretation; and (III) no quantitative methods (e.g., meta-analysis) were used to assess the strength of evidence. Future clinical and basic research is expected to improve immunotherapy for driver gene-mutant NSCLC.

This review emphasizes that driver gene types are the central factor determining the efficacy of immunotherapy. Clinically, strategies should be formulated based on mutation types, promoting standardized biomarker testing and establishing re-biopsy systems after drug resistance. Future research must address three critical issues: exploring combination immunotherapy strategies and predictive biomarkers post-resistance; accelerating therapeutic development for rare mutations; and optimizing toxicity management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-684/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-684/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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