Top Lung Cancer Advances From 2025

Chinmay Jani, MD University of Miami Health System | Ali Al Sbihi, MD Sylvester Comprehensive Cancer Center | Gilberto Lopes, MD Sylvester Comprehensive Cancer Center, University of Miami

January 25, 2026

1. Doctor explaining lung cancer scan results to patient with lung model and medical images on computer screen, in a clinical setting.
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The thoracic oncology landscape in 2025 marked a moment of long-awaited clarity. After years of anticipation, pivotal clinical signals matured, shifting the field decisively beyond debates centered on progression-free survival (PFS) toward end points that matter most—meaningful and durable improvements in overall survival (OS). In this moment of reckoning, several long-emerging strategies crossed the threshold from expectation to evidence. This article reflects on the most defining developments that collectively reshaped the clinical and therapeutic infrastructure of thoracic oncology over the past year.

The Rise of Combination Strategies in EGFR-mutant NSCLC

For years, the gold standard for EGFR-mutant non-small cell lung cancer (NSCLC) was defined by osimertinib monotherapy.1 The thoracic oncology community debated whether the added toxicity of combination therapies justified the clinical gains. In 2025, that debate reached a turning point.

The MARIPOSA trial evaluated the bispecific antibody amivantamab in combination with the tyrosine kinase inhibitor (TKI) lazertinib. While PFS gains were established early (23.7 months in the amivantamab plus lazertinib arm vs 16.6 months in the osimertinib arm; HR, 0.7), the 2025 maturity of OS data confirmed that this regimen offers a survival advantage, marking a historic challenge to the “osimertinib-only” frontline approach. This trial finally delivered a statistically significant OS benefit over osimertinib in the first-line setting. The MARIPOSA combination targets EGFR through dual mechanisms; extracellular binding and intracellular kinase inhibition, while also leveraging MET inhibition to delay resistance. Overall, better outcomes were met with the combination despite the toxicity and logistics barriers.2 Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer OS than osimertinib monotherapy; 3-year OS was 60% and 51%, respectively (HR, 0.75), indicating a 25% reduction in the risk of death. At the 3.5-year mark, 56% of patients in the combination arm were alive compared with 44% in the osimertinib arm.2

However, the combination is associated with higher rates of grade 3 or greater adverse events (AEs) and treatment discontinuation, largely driven by amivantamab. AEs include dermatologic toxicity, edema, hypoalbuminemia, and infusion-related reactions (IRRs), particularly during the first infusion (often about 60%–70%), although most are grade 1–2 and occur early. In addition, infusion burden is also a consideration as amivantamab requires intravenous administration, with split dosing and prolonged chair time during cycle 1, plus ongoing infusions thereafter, thus introducing a logistical burden for patients and infusion centers.2

Simultaneously, the FLAURA2 trial reinforced the value of adding platinum-pemetrexed chemotherapy to frontline osimertinib. Initial analyses demonstrated a robust and clinically meaningful improvement in PFS in the chemo-osimertinib arm versus osimertinib monotherapy (25.5 months vs 16.7 months, respectively; HR, 0.62). Importantly, in 2025, it was shown that the PFS advantage translated into a statistically significant final OS benefit (47.5 vs 37.6 months; HR, 0.77) reinforcing the biologic rationale of early combination therapy. The OS benefit appeared most pronounced in patients with adverse prognostic features, including high tumor burden, central nervous system involvement, L858R mutations, and rapidly progressive or symptomatic disease.3 As such, FLAURA2 expands the frontline therapeutic framework, offering a validated option for patients in whom maximizing early disease control and survival outweighs concerns about added grade 3 AEs. In the combination arm, AEs led to discontinuation of osimertinib, pemetrexed, or platinum for 12%, 50%, and 17% of patients, respectively. Seven percent of patients discontinued osimertinib in the monotherapy arm.4

Subcutaneous Amivantamab: Improving Treatment Delivery 

While much of the progress in 2025 centered on efficacy, advances in treatment delivery also proved clinically meaningful. The FDA approval of subcutaneous amivantamab represented a pragmatic but impactful step forward based on data from the PALOMA-3 study that demonstrated pharmacokinetic equivalence between subcutaneous and intravenous formulations, with a markedly lower incidence of IRRs and substantially reduced administration time. Comparing the subcutaneous versus the intravenous arms, objective response rate was 30% versus 33%; PFS was 6.1 months versus 4.3 months; and 12-month OS was 65% versus 51%, respectively (HR, 0.62). Less toxicity was observed in the subcutaneous arm (IRRs 13% vs 66%; venous thromboembolism 9% vs 14%, respectively). Median administration time for the first infusion was reduced to 4.8 minutes compared with 5 hours.5,6 These improvements are particularly relevant as amivantamab moves earlier in the disease course and into combination regimens. Reduced chair time and improved tolerability enhance feasibility for both patients and infusion centers, especially as combination strategies become more common.

New Targeted Agents in HER2-Mutant NSCLC

The accelerated approvals of next-generation oral TKIs in 2025 signaled a renewed confidence in targeted therapy beyond antibody–drug conjugates (ADCs). In August 2025, zongertinib received accelerated approval based on the Beamion LUNG-1 phase 1b trial, demonstrating a median PFS of 12.4 months in pretreated patients, while median PFS was not yet reached in the treatment-naive cohort; OS data remain immature.7,8 This was followed in November 2025 by the accelerated approval of sevabertinib, supported by the SOHO-01 phase 1/2 trial, which reported a median PFS of 8.3 months in pretreated patients and a not-reached median PFS in treatment-naive patients, with OS data likewise pending maturation.9,10

EGFR Exon 20 Insertions: Incremental but Meaningful Progress 

Progress in EGFR exon 20 insertion-mutated NSCLC, a historically challenging subset, continues, with sunvozertinib approved in July 2025 in the post-platinum setting, providing a much-needed targeted option for this molecular alteration.11 Based on the WE-KONG1B phase 1/2 trial results, the PFS was approximately 10.8 months to 11.5 months for sunvozertinib in the platinum-pretreated population with a median duration of response of 11.1 months, while OS has not yet been reached.12

ADCs and Expression-Based Targeting in MET-Overexpressing NSCLC

A milestone in MET-high NSCLC was reached in May 2025 with the accelerated approval of telisotuzumab vedotin, an ADC.13 The phase 1/2 LUMINOSITY trial showed a PFS of 5.5 months for c-MET high overexpression (50% or greater of cells with 3+ staining) and 6 months for intermediate expression (25%-50% or greater with 3+ staining) in addition to an OS benefit of 14.4 and 14.2 months, respectively.14 This approval highlights two important trends: protein expression is becoming a clinically actionable biomarker alongside genomic alterations, and ADCs are now firmly embedded in routine lung cancer treatment decisions.15

Breakthrough in Small Cell Lung Cancer

SCLC has historically been one of the most challenging areas in thoracic oncology drug development. In November 2025, the landscape evolved with the full approval of tarlatamab, a DLL3-targeted bispecific T-cell engager (BiTE), based on results from the DeLLphi-304 phase 3 trial in patients with platinum-refractory extensive stage SCLC. In this randomized study, tarlatamab demonstrated a statistically significant and clinically meaningful improvement in OS compared with standard chemotherapy in patients whose disease progressed on or after platinum-based therapy (median OS 13.6 vs 8.3 months, respectively; HR, 0.6), despite only a modest improvement in PFS (median PFS 4.2 months vs 3.2 months, respectively).16,17 The demonstration of an OS benefit in this heavily pretreated population represents an important therapeutic advance in SCLC. These findings have also renewed interest in bispecific antibody platforms, particularly BiTE, as a promising therapeutic strategy within thoracic oncology. 

Combination Immunotherapy 

The LATIFY trial evaluating ATR inhibition with ceralasertib plus durvalumab failed to meet its OS end pointcompared with docetaxel chemotherapy, proving that biological plausibility must still survive the rigors of phase 3 testing.18 This negative study showcases that mechanistic rationale and early-phase activity do not guarantee phase 3 success. As the field matures, survival end points and biomarker-driven trial design are becoming essential filters for advancing immunotherapy combination strategies. 

Pillars of Therapy Selection

One of the defining features of lung cancer care in 2025 is the inseparability of therapy from diagnostics. Nearly every major approval this year was paired with a companion or validated diagnostic assay, including HER2 TKD mutations, MET protein expression, and EGFR exon 20 insertions. As a result, the testing strategy is no longer ancillary. Assay selection, tissue adequacy, and turnaround time directly determine patient access to life-prolonging therapies. In the future, advances in disease monitoring are expected to further refine treatment sequencing and durability of benefit. The integration of longitudinal minimal residual disease assessment, along with routine use of high-sensitivity liquid biopsy and tissue-based next-generation sequencing, is poised to enable earlier detection of molecular relapse, more precise identification of resistance mechanisms, and improved personalization of therapy across lines of treatment.19

AI Moves Into Infrastructure

Throughout 2025, artificial intelligence (AI) quietly crossed a threshold, transitioning from an experimental tool to clinical infrastructure. AI-assisted CT interpretation improved lung nodule detection, reduced radiologist workload, and enhanced follow-up of incidental findings.20 Risk prediction models using routine imaging demonstrated high accuracy in identifying individuals at elevated future lung cancer risk, offering opportunities for more personalized screening strategies. Importantly, AI remains assistive rather than autonomous, augmenting clinician judgment rather than replacing it. Nonetheless, its integration into lung cancer workflows is now tangible and accelerating.

Future Directions and Global Impact

By 2025, previously suggested overall survival benefits in lung cancer became supported by sufficiently mature and reproducible data to inform clinical decision-making. For the first time, the concept of an optimal first-line strategy has evolved from a single standard to a set of evidence-based alternatives, enabling treatment selection to be guided by molecular subtype, disease burden, and patient-specific clinical characteristics. This shift reflects a broader transition toward biologically stratified care rather than empiric regimen selection. 

In parallel, health systems face growing pressure to operationalize precision oncology at scale, given the associated increases in treatment complexity, cost-effectiveness of the medications, and diagnostic requirements. Studies, such as ours, highlight the importance of evaluating the cost-effectiveness of cancer therapies alongside their clinical efficacy and survival benefits.21 

Looking ahead to 2026, therapeutic development is increasingly focused on rare and previously undruggable molecular targets, accompanied by a rapid expansion of ADCs and bispecifics. Collectively, these developments highlight a durable shift in lung cancer care toward greater molecular resolution, biologic rationality, and sustained clinical benefit. The incremental but substantive progress observed in 2025 is likely to have a lasting effect on standards of care.

References

  1. Lorenzi M, Ferro A, Cecere F, et al. First-line osimertinib in patients with EGFR-mutant advanced non-small cell lung cancer: outcome and safety in the real world: FLOWER study. Oncologist. 2022;27(2):87-e115. doi:10.1002/onco.13951
  2. Yang JC, Lu S, Hayashi H, et al. Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC. N Engl J Med. 2025;393(17):1681-1693. doi:10.1056/NEJMoa2503001
  3. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308
  4. Planchard D, Jänne PA, Kobayashi K, et al. First-line osimertinib + chemotherapy versus osimertinib monotherapy in EGFRm advanced NSCLC: FLAURA2 final overall survival. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 1956.
  5. FDA approves amivantamab and hyaluronidase-lpuj for subcutaneous injection. U.S. Food and Drug Administration. Updated December 17, 2025. Accessed January 21, 2026. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-and-hyaluronidase-lpuj-subcutaneous-injection
  6. Leighl NB, Akamatsu H, Lim SM, et al. Subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in refractory epidermal growth factor receptor–mutated non–small cell lung cancer: primary results from the phase III PALOMA-3 study. JClin Oncol. 2024;42(30):3593-3605. doi:10.1200/JCO.24.01001
  7. Heymach JV, Ruiter G, Ahn M-J, et al. Zongertinib in previously treated HER2-mutant non–small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
  8. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. U.S. Food and Drug Administration. Updated August 8, 2025. Accessed January 18, 2026. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
  9. Le X, Kim TM, Loong HH, et al. Sevabertinib in advanced HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;393(18):1819-1832. doi:10.1056/NEJMoa2511065
  10. FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. U.S. Food and Drug Administration Updated July 2, 2025. Accessed January 18, 2026. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sunvozertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20
  11. Sangwan K, Agarwal G. Sunvozertinib: a promising oral EGFR inhibitor approved for NSCLC with EGFR Ex20ins mutations. Invest New Drugs. 2025;43(5):1177-1189. doi:10.1007/s10637-025-01588-7
  12. Yang JCH, Wang M, Doucet L, et al. Phase II dose-randomized study of sunvozertinib in platinum-pretreated non–small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations (WU-KONG1B). J Clin Oncol. 2025;43(29):3198-3208. doi:10.1200/JCO-25-00788
  13. Zhao C, Lu D, Gao J. Telisotuzumab vedotin: The first-in-class c-Met-targeted antibody-drug conjugate granted FDA accelerated approval for treatment of non-squamous non-small cell lung cancer (NSCLC). Drug Discov Ther. 2025;19(4):275-276. doi:10.5582/ddt.2025.01058
  14. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein–overexpressing advanced nonsquamous EGFR-wildtype non–small cell lung cancer in the phase II LUMINOSITY trial. J Clin Oncol. 2024;42(25):3000-3011. doi:10.1200/JCO.24.00720
  15. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-Met protein overexpression. U.S. Food and Drug Administration. Updated May 14, 2025. Accessed January 18, 2026. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
  16. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361. doi:10.1056/NEJMoa2502099
  17. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. U.S. Food and Drug Administration. Updated November 19, 2025. Accessed January 18, 2026. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
  18. Update on LATIFY Phase III trial of ceralasertib plus Imfinzi  in previously treated advanced non-small cell lung cancer. AstraZeneca. Updated December 22, 2025. Accessed January 18, 2026. www.astrazeneca.com/media-centre/press-releases/2025/update-on-latify-Phase-iii-trial-of-ceralasertib.html 
  19. Boukouris, A. E., Michaelidou, K., Joosse, S. A., Charpidou, A., Mavroudis, D., Syrigos, K. N., & Agelaki, S. (2025). A comprehensive overview of minimal residual disease in the management of early-stage and locally advanced non-small cell lung cancer. NPJ Precis Oncol. 2025;9(1):178. doi:10.1038/s41698-025-00984-9
  20. Basu Roy, U. (2025). Artificial intelligence in lung cancer early detection and risk stratification. LUNGevity Foundation.
  21. Jani CT, Manoharan A, Han S, et al. Cost-effectiveness analysis of durvalumab in limited-stage small cell lung cancer in the united states. JCO Glob Oncol. 2025;11:e2500225. doi:10.1200/GO-25-00225