Update 2025: Management of Non‑Small-Cell Lung Cancer

1Lung cancer has remained the leading cause of cancer-related mortality worldwide since the 1950s, posing a significant global health challenge. NSCLC, which constitutes the majority of lung cancer cases, has historically been associated with poor outcomes due to its often late diagnosis and limited treatment options. However, the landscape of NSCLC management has undergone exponential growth in recent years, driven by groundbreaking advancements in targeted therapies and immunotherapies. These innovations have ushered in a new era of precision medicine, allowing treatments to be tailored to the unique molecular and immunological profiles of patients, thereby improving efficacy and survival outcomes. Additionally, these advancements have redefined the standard of care, offering renewed hope to patients and clinicians alike. This review provides a comprehensive update on the evolving management strategies for NSCLC, with a focus on recent developments in screening, diagnostics, and therapeutic advancements in early-stage and advanced disease.

2Lung cancer screening with LDCT plays a pivotal role in detecting lung cancer at earlier, more treatable stages, as evidenced by a 20% reduction in mortality demonstrated in the National Lung Screening Trial (NLST) in 2013. This resulted in a Grade B recommendation by the United States Preventive Services Task Force (USPSTF) in 2013 for annual lung cancer screening in adults aged 55–80 years with a 30-pack-year smoking history, who are either current smokers or have quit within the last 15 years and a similar recommendation from the American Cancer Society (ACS) for adults aged 55–74 years old. In 2020, the NELSON study in the Netherlands and Belgium published a large, randomized lung cancer screening trial which not only confirmed the relative reduction in death rate by 20% but also reinforced the importance of early detection.

3These studies ultimately led to updated guidelines (Table 1) by the USPSTF in March 2021 and the ACS in November 2023, which have expanded eligibility for screening, targeting individuals aged 50–80 years with a 20 pack-year smoking history who are currently smoking or have quit within the past 15 years. These updates specifically aim to include underserved and lower socioeconomic status (SES) groups, as well as women and minorities who may face a heightened risk of lung cancer despite lower daily cigarette use. By reducing barriers to screening and enhancing early detection, these changes have resulted in a 61.1% relative increase in eligibility for the lowest SES quintile compared to a 49.6% increase for the highest SES quintile. However, further efforts are needed to allocate resources for tailored community outreach strategies and to address persistent barriers to screening for individuals from lower SES backgrounds. The ACS guidelines further emphasize shared decision-making and smoking cessation support to complement screening efforts, aiming to reduce lung cancer mortality and morbidity across diverse populations.

4While screening efforts focus on high-risk individuals with a smoking history, the increasing prevalence of lung cancer among never-smokers presents a critical area for future research and a significant public health consideration. Current risk prediction models inadequately address this population, necessitating the development of tools incorporating factors such as family history, second-hand smoke, occupational and environmental exposures, and genetic predispositions. Validating these models and assessing their cost-effectiveness will be essential for expanding screening efforts to never-smokers, potentially reducing lung cancer mortality in this growing demographic.

5The staging of NSCLC is continually refined through evidence-based iterations led by the International Association for the Study of Lung Cancer (IASLC). Following the widespread adoption of the 8th edition since 2017, which introduced more granular tumor (T) descriptors and refined stratification of metastatic (M) disease, the recently developed 9th edition has further enhanced the accuracy and clinical utility of NSCLC staging. Key modifications from the 8th to the 9th edition include the reclassification of stage groups based on a more refined nodal (N) category, as well as more nuanced M descriptors that better distinguish distinct patterns of metastatic spread. These refinements reflect an expanded global database, the incorporation of more nuanced prognostic data, and the consideration of emerging treatment modalities.

6Looking ahead, with the 10th edition already underway, efforts aim to build upon this trajectory by integrating emerging data sources, advanced imaging modalities, and molecular profiling tools, ultimately refining staging accuracy and better reflecting its prognostic value.

7Molecular profiling has emerged as a cornerstone in the management of NSCLC, revolutionizing the approach to diagnosis, prognosis, and personalized treatment. Advances in molecular testing based on next-generation sequencing (NGS) have enabled the identification of key driver mutations and genetic alterations, such as EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, NRG, KRAS, and ERBB2, that are critical for selecting targeted therapies. Additionally, the discovery of biomarkers such as PD-L1 expression and tumor mutational burden has expanded the landscape of immunotherapy in NSCLC, although their role as predictive biomarkers needs further investigation. Nonetheless, molecular profiling not only guides therapeutic decision-making but also provides insights into mechanisms of resistance, facilitating the development of novel treatment strategies. As molecular diagnostic technologies continue to evolve, their integration into clinical practice is essential for refining prognostic accuracy, optimizing treatment outcomes, and advancing the field of precision oncology in NSCLC. Additionally, emerging evidence suggests that circulating tumor DNA analysis may aid in minimal residual disease detection, though further validation is needed.

8Immunotherapy with or without chemotherapy has been a fundamental aspect of the management of metastatic NSCLC without AGA. In recent years, immunotherapy has expanded from late-stage treatment to earlier stages of disease, leading to FDA approvals in the perioperative and adjuvant settings (Table 2).

9In early-stage resectable NSCLC, two pivotal studies first demonstrated the benefit of adjuvant immunotherapy. The IMpower010 trial assessed atezolizumab as adjuvant therapy after adjuvant chemotherapy in resected stage IB-IIIA NSCLC. The result showed that, in the intention-to-treat population, atezolizumab improved disease-free survival (DFS) compared to best supportive care (HR, 0.81; 95% CI, 0.67–0.99; P = 0.04). The greatest benefit was observed in the stage II-IIIA population with PD-L1 ≥ 1% (HR 0.66; 95% CI, 0.50–0.88; P = 0.0039). Notably, stage II-IIIA patients with PD-L1 < 1% did not derive a DFS benefit with atezolizumab. The updated overall survival (OS) data from IMpower010 revealed an OS benefit of atezolizumab only in stage II-IIIA patients with PD-L1 ≥ 50% (HR 0.43; 95% CI, 0.24–0.78), while other subgroups did not show significant improvement.

10The PEARLS/KEYNOTE-091 compared pembrolizumab with placebo as adjuvant therapy in resected stage IB-IIIA NSCLC. In the overall population, pembrolizumab improved DFS compared to placebo (53.6 m vs. 42.0 m; HR 0.76; 95% CI, 0.63–0.91; P = 0.0014). Unlike the IMpower010 study, the PEARLS/KEYNOTE-091 study demonstrated a DFS benefit of pembrolizumab across all PD-L1 groups. The OS data for PEARLS/KEYNOTE-091 are still pending.

11Neoadjuvant immunotherapy was subsequently explored in resectable NSCLC without AGA due to several key advantages over adjuvant approaches: early control of micrometastatic disease, enhanced immune response, improved pathologic responses and reduced treatment delays. The CheckMate 816 is an open-label, randomized phase III trial that assessed neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in resectable stage IB to IIIA NSCLC. Adding nivolumab to chemotherapy prolonged event-free survival (EFS) (31.6 m vs. 20.8 m; HR 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005) and resulted in a higher pathologic complete response (pCR) (24% vs. 2.2%; OR 13.94; 99% CI, 3.49 to 55.75; P < 0.001).

12Following the establishment of neoadjuvant chemoimmunotherapy as a standard of care for resectable NSCLC based on the results of the CheckMate 816 trial, several phase III randomized trials have further evaluated the role of immunotherapy combined with chemotherapy in the perioperative setting.

13The CheckMate 77 T trial evaluated neoadjuvant nivolumab and chemotherapy compared to chemotherapy, followed by surgery and adjuvant nivolumab or chemotherapy for up to 1 year in resectable stage IIA and IIIB NSCLC. The result revealed significantly better median EFS (NR vs. 18.4 m; HR 0.58; 97.36% CI, 0.42–0.81; P < 0.001), pCR (25.3% vs. 4.7%; OR 6.64; 95% CI, 3.40–12.97) and major pathologic response (MPR) (35.4% vs.12.1%; OR 4.01; 95% CI, 2.48–6.49) in the nivolumab arm.

14The Keynote-671 trial demonstrated that perioperative pembrolizumab plus chemotherapy in resectable stage IIA-IIIB resulted in significantly longer 24-month EFS (62.4% vs. 40.6%; HR 0.58; 95% CI, 0.46–0.72; P < 0.001), pCR (18.1% vs.4.0%; difference 14.2%; 95% CI, 10.1–18.7; P < 0.0001) and MPR (30.2% vs. 11.0%; difference 19.2%; 95% CI, 13.9–24.7; P < 0.0001) were observed. The EFS benefit favored pembrolizumab and chemotherapy across all subgroups.

15The Neotorch trial assessed toripalimab versus placebo in combination with chemotherapy in the perioperative setting for stage II and III resectable NSCLC. The study demonstrated a benefit in the toripalimab arm with longer EFS (not estimable vs. 15.1 m; HR 0.40; 95% CI, 0.28–0.57; P < 0.001) and higher percentage of MPR (48.5% vs. 8.4%; difference 40.2%; 95% CI, 32.2–48.1; P < 0.001) as well as pCR (24.8% vs 1.0%; difference 23.7%; 95% CI, 17.6–29.8).

16The AEGEAN trial evaluated durvalumab vs. placebo in combination with chemotherapy in the perioperative setting for resectable stage II to IIIB NSCLC. The EFS was significantly longer in the durvalumab arm compared to placebo (HR 0.68; 95% CI, 0.53–0.88; P = 0.004). The pCR was also significantly higher, favoring durvalumab (17.2% vs. 4.3%; difference 13.0%; 95% CI, 8.7–17.6; P < 0.001).

17These studies collectively reinforce the efficacy of integrating immunotherapy into the perioperative setting and offer a multimodal strategy that requires early multidisciplinary discussions for resectable NSCLC. However, several important unanswered questions remain that require further investigation. For instance, determining the optimal patient selection for adjuvant therapy, including identifying prognostic factors such as pCR and MPR, is essential. In addition, there is a need to establish the correlation between surrogate endpoint and overall survival, which will require long-term follow-up for validation.

18For unresectable stage III NSCLC, concurrent chemoradiotherapy remains the standard of care as a definitive treatment. The PACIFIC trial demonstrated the survival benefit of durvalumab consolidation for up to 12 months post-chemoradiation and it was approved by the FDA in 2018. The 5-year updated results were consistent with the primary analysis. Median OS was significantly longer in the durvalumab arm (47.5 m vs. 29.1 m; HR 0.72; 95% CI, 0.59–0.89), with an estimated 5-year OS rate of 42.9% for durvalumab, compared to 33.4% for placebo. Median EFS was also longer in the durvalumab arm compared to placebo (16.9 m vs. 5.6 m; HR 0.55; 95% CI, 0.45–0.68), and 5-year PFS rate was 33.1% for durvalumab compared to 19.0% for placebo. Of note, the OS benefit favored durvalumab across most subgroups, but was less clear for the PD-L1 negative cohort (HR 1.15; 95% CI, 0.75–1.75) highlighting an unmet need in this population.

19For metastatic NSCLC without AGAs, immunotherapy, either alone or with chemotherapy, has remained the standard of care for frontline treatment. Updated long-term follow-up results from several landmark trials have demonstrated significant and durable survival benefits in this population.

20In the KEYNOTE-024 and KEYNOTE-042 studies, patients with PD-L1 ≥ 50% and PD-L ≥ 1%, respectively, and without EGFR or ALK alterations were randomized to receive pembrolizumab monotherapy versus platinum-based chemotherapy as frontline therapy. In KEYNOTE-024, the median OS was 26.3 months for pembrolizumab compared to 13.4 months for chemotherapy (HR 0.62; 95% CI, 0.48–0.81). The 5-year OS was estimated to be 31.9% for pembrolizumab versus 16.3% for the chemotherapy group. In KEYNOTE-042, the OS favored pembrolizumab over chemotherapy in patients with PD-L1 ≥ 50% (HR 0.68; 95% CI, 0.57–0.81), PD-L1 ≥ 20% (HR 0.75; 95% CI, 0.64–0.87), and PD-L1 ≥ 1% (HR 0.79; 95% CI, 0.70–0.89). The estimated 5-year OS was 16.6%-21.9% compared to 8.5%-10.1% across different PD-L1 groups. In the exploratory analysis, patients with PD-L1 score of 1–49% did not achieve a statistically significant OS benefit, indicating that additional treatment strategies are needed in this population.

21A similar OS benefit was observed with cemiplimab in metastatic NSCLC with PD-L1 ≥ 50% and without EGFR/ALK/ROS1 alterations in the frontline setting. Likewise, atezolizumab demonstrated OS superiority in metastatic non-squamous and squamous NSCLC with PD-L1 ≥ 1% and EGFR/ALK wild-type status. Long-term follow-up data are awaited to confirm the durability of these results.

22The combination of dual immunotherapy with ipilimumab and nivolumab was evaluated in the CheckMate 227 trial as a frontline treatment and included patients across all PD-L1 TPS scores. The 5-year follow-up revealed a significant survival benefit. In patients with PD-L1 ≥ 1%, the 5-year OS rate was 24% for ipilimumab plus nivolumab compared to 14% for chemotherapy (HR 0.77; 95% CI, 0.66–0.91). In PD-L1 negative patients, ipilimumab plus nivolumab also demonstrated an improved 5-year OS rates (19% vs. 7%; HR 0.65; 95% CI, 0.52–0.81).

23Long-term follow-up data from key chemoimmunotherapy trials—KEYNOTE-189, IMpower150, KEYNOTE-407, and CheckMate 9LA—have further established the role of immunotherapy combined with chemotherapy as a standard of care with durable benefit in metastatic NSCLC without AGA.

24In KEYNOTE-189, patients with untreated metastatic non-squamous NSCLC without EGFR or ALK alterations were randomized to receive pembrolizumab or placebo in combination with platinum and pemetrexed chemotherapy. The 5-year OS rate was 19.4 months for pembrolizumab plus chemotherapy versus 11.3 months for placebo plus chemotherapy (HR 0.60; 95% CI, 0.50–0.72). The OS benefit favored pembrolizumab plus chemotherapy across all PD-L1 groups.

25In the IMpower150 trial, patients with metastatic non-squamous NSCLC without EGFR or ALK alterations were randomized to receive atezolizumab-carboplatin-paclitaxel (ACP), atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP), or bevacizumab-carboplatin-paclitaxel (BCP). The ABCP regimen showed an OS benefit compared to the BCP regimen (19.5mo vs. 14.7mo; HR 0.80; 95% CI, 0.67–0.95). Exploratory analysis revealed that both ABCP and ACP demonstrated significantly longer OS compared to BCP in the PD-L1-high (30.0 m vs. 26.3 m vs.15.0 m) and PD-L1-positive (22.5mo vs. 24.4mo vs. 16.0mo) subgroups, but not the PD-L1-negative group. Notably, unlike most other trials where immunotherapy was continued for a maximum of 2 years, atezolizumab was continued until disease progression or unacceptable toxicity, suggesting a flexible approach without a definitive stopping point.

26For metastatic squamous NSCLC, the KEYNOTE-407 trial randomized patients to receive pembrolizumab or placebo in combination with carboplatin and paclitaxel or nab-paclitaxel for four cycles, followed by pembrolizumab or placebo. The estimated 5-year OS rates were 18.4% vs 9.7% (HR 0.71; 95% CI, 0.0.59–0.85), and the OS benefit favored pembrolizumab plus chemotherapy across all PD-L1 subgroups.

27In the CheckMate 9LA trial, metastatic NSCLC patients without sensitizing EGFR or ALK alterations were randomized to receive ipilimumab and nivolumab in combination with chemotherapy or chemotherapy alone. The 5-year OS favored the ipilimumab plus nivolumab plus chemotherapy regardless of PD-L1 status (5-year OS rates: 18% vs. 11%; HR 0.73; 95% CI, 062–0.85).

28Targeted therapies have revolutionized the management of NSCLC, most notably in the metastatic setting, and are now increasingly being studied for incorporation into earlier stages, including the neoadjuvant and adjuvant settings. We will explore how AGA-directed therapies are integrated into clinical decision-making across the spectrum of NSCLC and then examine the key genetic alterations guiding precision treatment in the metastatic setting.

29To date, the FDA has approved two targeted agents as adjuvant therapy —osimertinib for EGFR-mutated and alectinib for ALK-mutated tumors—for resectable, early-stage NSCLC with AGA. In the ADAURA trial, patients with stage IB–IIIA (AJCC 7th edition) NSCLC harboring EGFR exon 19 deletion or exon 21 L858R mutations who had undergone surgical resection were randomized to receive three years of osimertinib versus placebo. The osimertinib arm demonstrated a marked improvement in DFS, reaching 65.8 months compared to 28.1 months in the placebo group (HR 0.27; 95% CI 0.21–0.34), and a 5-year OS of 88% versus 78% (HR 0.49; 95% CI, 0.34–0.70). Similarly, the ALINA trial evaluated patients with resected stage IB–IIIA (AJCC 7th edition) ALK-positive NSCLC randomized to receive either two years of alectinib or four cycles of platinum-based chemotherapy. At three years, DFS in the alectinib arm was 88.7%, compared to 54.0% in the platinum-based chemotherapy group (HR 0.24; 95% CI, 0.13–0.43). Although immunotherapy has improved outcomes in many subsets of NSCLC, it is generally considered less effective in tumors harboring driver genomic alterations such as EGFR and ALK, further emphasizing the importance of molecularly targeted therapies in these settings.

30The LAURA study investigated the use of osimertinib until disease progression versus placebo in patients with unresectable stage III NSCLC harboring EGFR exon 19 deletion or exon 21 L858R mutations. Notably, PFS was significantly improved with osimertinib (39.1 m vs. 5.6 m; HR 0.16; 95% CI, 0.10–0.24), and at three years, OS was 84% versus 74% (HR 0.81; 95% CI, 0.42–1.56), findings that led to FDA approval of osimertinib in the adjuvant setting after chemoradiation. Although the indefinite treatment duration may be unsettling, these results highlight substantial patient benefit given the poor PFS in the placebo arm and the high incidence of distant metastases, including CNS involvement. Nevertheless, further efforts are needed in this adjuvant space to achieve a truly curative outcome.

31As molecular profiling becomes increasingly nuanced and comprehensive, a growing number of phase III trials have demonstrated the efficacy of targeted therapies for locally advanced and metastatic NSCLC, both as monotherapy and in combination with chemotherapy or other targeted agents (Table 3). These advancements extend beyond traditional tyrosine kinase inhibitors (TKI) to include emerging treatment modalities such as bispecific antibodies and ADCs further expanding the therapeutic arsenal for patients with AGA.

32Osimertinib, an irreversible EGFR TKI, has emerged as the mainstay of first-line therapy for EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC. Following the full approval of osimertinib based on the AURA3 study in patients who had progressed on a prior EGFR TKI with an exon 20 T790M mutation, the FLAURA study demonstrated superiority over earlier-generation EGFR TKIs (gefitinib and erlotinib) with an OS benefit of 38.6 months in the osimertinib group compared to 31.8 months in the comparator group (HR 0.8; 95% CI, 0.64–1). The trial also demonstrated a PFS benefit of 18.9 months in the osimertinib arm versus 10.2 months in the gefitinib or erlotinib arm (HR 0.46; 95%CI, 0.37–0.57). More recently, the FLAURA-2 study found that adding chemotherapy to osimertinib improved PFS from 16.7 to 25.5 months (HR 0.62).

33Beyond osimertinib, amivantamab—an EGFR-MET bispecific antibody—has shown promise in EGFR exon 20 insertion–positive disease: the PAPILLON study reported a PFS of 11.4 vs. 6.7 months (HR 0.4; 95%CI, 0.3–0.53) for amivantamab plus chemotherapy compared to chemotherapy alone as first-line therapy. Amivantamab plus lazertinib, a third generation of EGFR TKI, was also compared head-to-head with osimertinib in the MARIPOSA study which showed a PFS benefit of 23.7 vs. 16.6 months (HR 0.7; 95%CI, 0.58–0.85). However, a higher toxicity profile was observed in the amivantamab in combination plus lazertinib arm, with 75% vs. 43% of patients experiencing grade 3 or higher adverse events, leading to more frequent interruptions, dose adjustments, and treatment discontinuation. Additionally, the MARIPOSA-2 study explored amivantamab with or without lazertinib in combination with chemotherapy after osimertinib progression, reporting PFS of 8.3, 6.3, and 4.2 months for the triple combination, double combination (amivantamab and chemotherapy), and chemotherapy alone, respectively. These findings underscore the evolving treatment paradigm, with increasingly sophisticated EGFR-directed strategies and combination approaches improving outcomes for patients with EGFR-mutated advanced NSCLC.

34In ALK-rearranged advanced NSCLC, multiple first-line options have been approved, including crizotinib, alectinib, brigatinib, lorlatinib, and most recently, ensartinib. Crizotinib’s use has diminished over time due to its limited CNS penetration, making newer-generation ALK inhibitors more attractive. Notably, the CROWN study demonstrated that lorlatinib delivered a median PFS that was not yet reached at five years, compared to 9.1 months in the crizotinib arm (HR 0.19; 95% CI, 0.13–0.27). Similarly, ensartinib has also recently been FDA-approved in the first-line setting, showing a PFS of 25.8 months versus 12.7 months with crizotinib (HR 0.51; 95% CI, 0.35–0.72). As the treatment landscape evolves, the diverse efficacy and side effect profiles of ALK-targeted agents—including the impressive results demonstrated by lorlatinib—will play a pivotal role in guiding personalized therapy decisions and optimizing outcomes for each patient.

35Repotrectinib has expanded the treatment repertoire for ROS1-rearranged advanced NSCLC, joining entrectinib and crizotinib as an FDA-approved option. In the TRIDENT-1 phase I/II study, repotrectinib demonstrated a remarkable PFS of 35.7 months compared to 9 months for crizotinib, underscoring its potential as a highly effective therapy in this molecularly defined patient population.

36Encorafenib and binimetinib offer another therapeutic option for BRAF V600E-mutated NSCLC, demonstrating a 75% overall response rate (ORR) in untreated patients. However, treatment-related adverse events occurred in 24% of patients, leading to dose reductions or discontinuations, underscoring the need for larger studies to better understand tolerability and long-term outcomes.

37Tepotinib was approved in February 2024, demonstrating a PFS of 8.5 months and an OS of 17.1 months, showing promise for patients with MET exon 14 skipping mutations.

38Selpercatinib received approval based on the LIBRETTO-001 study with an ORR of 84% compared to 65% in the control group, and pralsetinib has also gained approval for RET-altered NSCLC with an ORR of 70% in the treatment naïve group.

39Entrectinib and larotrectinib remain viable options for patients harboring NTRK fusions, either as an initial treatment when no other alternatives exist or after prior therapies.

40Sotorasib and adagrasib have been approved based on the CodeBreaK200 and KRYSTAL-1 studies, respectively. However, sotorasib did not receive full approval in 2023 after its accelerated approval because, despite meeting the PFS endpoint (5.6 vs. 4.5 months), the OS was not improved (10.6 vs. 11.3 months), and concerns were raised regarding patient dropout in the docetaxel arm and early crossover to sotorasib before disease progression.

41Trastuzumab deruxtecan-nxki (TDxd) received tumor-agnostic approval for HER2-positive (IHC 3 +) solid tumors. This HER2-directed ADCs deliver deruxtecan payload, a topoisomerase I inhibitor, directly to HER2-expressing tumor cells. In the DESTINY-Lung01 phase II study, TDxd demonstrated an ORR of 55%, a median DOR of 9.3 months, and a PFS of 8.2 months, highlighting its efficacy in this subset of patients and offering an alternative in second line treatment.

42The recent approval of zenocutuzumab-zbco (zeno), based on the eNRGy study, presents an advancement for previously treated advanced NSCLC with NRG1 fusion. Zeno is a bispecific antibody targeting HER2/HER3 signaling, effectively inhibiting NRG1 binding. While the full publication is pending, the FDA has reported an ORR of 33% and a median DOR of 7.4 months in a cohort of 64 NSCLC patients. Previous abstract presentation showed 41 patients with NSCLC with an ORR 35% with good tolerability.

43The management of NSCLC has evolved remarkably over the past decade, reflecting a paradigm shift driven by advances in screening, molecular diagnostics, and targeted therapeutics. Enhanced screening protocols have enabled earlier detection, while ongoing refinements in staging ensure patients receive the most appropriate treatments based on precise risk stratification. The incorporation of molecular profiling and immunotherapy into both early-stage and advanced disease settings has expanded treatment options, improved survival outcomes, and set the stage for more personalized care (Fig. 1). Targeted therapies for EGFR, ALK, ROS1, and other actionable alterations have revolutionized the therapeutic landscape, and novel approaches—ranging from bispecific antibodies to ADCs—continue to emerge. Although challenges remain, the future of NSCLC management is increasingly defined by innovation and collaboration.