Thoracic Oncology in 2025: Evolving Standards and Practice-Changing Data From ASCO

Kriti Ahuja, MD Roswell Park Comprehensive Cancer Center

July 28, 2025

Lung anatomy with highlighted bronchi and surrounding structures in a digital medical illustration.
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Key Points

  • Perioperative immunotherapy continues to reshape resectable non–small cell lung cancer (NSCLC) treatment, with updated overall survival (OS) data from CheckMate 816 and new support for neoadjuvant approaches in EGFR- and ALK-driven cancers.

  • Osimertinib and alectinib show promising roles in the neoadjuvant and adjuvant settings, backed by ADAURA, ALINA, and NEOADAURA results.

  • For unresectable NSCLC, concurrent chemoradiation followed by consolidation with osimertinib (for EGFR-mutated) or durvalumab (for EGFR-wild type) remains the standard.

  • FLAURA2 versus MARIPOSA is now the key clinical decision point in EGFR-mutated metastatic NSCLC, with shared decision-making essential due to differences in delivery and toxicity.

  • For SCLC, lurbinectedin plus atezolizumab has moved into first-line maintenance (IMforte), and tarlatamab shows a 5-month OS benefit in the second-line setting (DeLLphi-304).

A host of precision oncology developments and evolving management strategies are making this an exciting era for thoracic oncology. At the recent Upstate NY Cancer Symposium, experts gathered to review current standard of care and highlight updates from the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Advances Across the NSCLC Spectrum

For stage IA NSCLC, the current management of surgical resection versus stereotactic body radiation therapy remains unchanged.1 Management strategies for stages IB to IIIA continue to evolve. In CheckMate 77T, perioperative chemoimmunotherapy (nivolumab) demonstrated a sustained improvement in event-free survival, and CheckMate 816 reported OS benefits with neoadjuvant chemoimmunotherapy.2,3 These ASCO updates add meaningful options to previously approved perioperative therapy per the KEYNOTE-671 (pembrolizumab) and AEGEAN (durvalumab) trials, adjuvant chemotherapy, and immunotherapy (IMpower010, KEYNOTE-091) for standard of care in non–EGFR/ALK-mutated cancers.4-7

Of note, the ninth edition TNM classification recognized subtypes N2 and M1C, and it will be interesting to see the real-world management implications of these updates.8 

Targeted Therapy’s Growing Role in Resectable Disease

For EGFR-mutated NSCLC, adjuvant osimertinib for 3 years improved OS (ADAURA); for ALK-rearranged NSCLC, adjuvant alectinib for 2 years (ALINA) improved disease-free survival, adding value through effective disease control and the convenience of oral administration.9,10 Studies focused on bringing these options to the neoadjuvant space continue, as NEOADAURA, a phase III study, demonstrated encouraging major pathological response (MPR) with neoadjuvant osimertinib in stage II to IIIB (resectable) EGFR-mutated cases.11 

Similarly, the phase II trial ALNEO explored the role of neoadjuvant alectinib in resectable stage III cancers with ALK rearrangements. The results presented at the 2025 ASCO Annual Meeting demonstrated achievement of MPR in patients with N2 disease, a population that would greatly benefit from maximal optimization of management strategies.12

Unresectable NSCLC: EGFR-Directed Consolidation

For unresectable NSCLC, current guidelines recommend concurrent chemoradiation followed by consolidation with osimertinib (LAURA) or durvalumab (PACIFIC), based on EGFR mutation status.13,14 Even in the metastatic setting, where treatment is typically given with palliative intent, there have been significant advances, especially for nonsmokers with tumors driven by actionable driver mutations. 

Frontline Options for Metastatic NSCLC With Actionable Drivers

Targeted therapies have been approved in the frontline setting for the following oncogenic drivers: EGFR mutations (including exon 20 insertions), ALK and ROS1 rearrangements, BRAF V600E mutations, NTRK 1/2/3 fusions, MET exon 14 skipping mutations, and RET rearrangements. EGFR L858R–mutated metastatic cancers have several options, with experts debating FLAURA2 versus MARIPOSA as the current question of the hour, making shared decision-making more crucial than ever.15,16 

As we evaluate these options with our patients and experts in the field, a few relevant details, such as the familiarity with adverse event profile and oral route of administration, favor osimertinib with amivantamab administered as an infusion and requiring prophylactic anticoagulation at least early on.15,16 This may evolve with the development of subcutaneous formulations of amivantamab and tailored prophylactic protocols for dermatologic adverse events continue to make headway with the COCOON study.17,18 

ALK, KRAS, HER2, MET, and NRG1: Expanding the Precision Toolkit

For first-line therapy in ALK-driven metastatic NSCLC, the 5-year update for lorlatinib (CROWN) demonstrated that the median progression-free survival (PFS) was not reached and provided benefit in patients with baseline brain metastases, as well as time to central nervous system progression, although crossover was not permitted as part of the trial design.19 

Of the oncogenic drivers for NSCLC, KRAS mutations are significant drivers, with KRAS G12C–targeted therapy currently approved in the second-line setting for metastatic NSCLC. The KRYSTAL-7 phase 2 data were presented at ASCO 2025, with encouraging results for advancing adagrasib, in combination with pembrolizumab, to the first-line setting.20 

For HER2-positive NSCLC, targeted therapy with trastuzumab deruxtecan continues to be approved in the second-line setting, with the field evolving toward development of oral tyrosine kinase inhibitors.21,22 Additionally, in the precision oncology era of NSCLC, telisotuzumab vedotin-tllv and zenocutuzumab have received approval for NSCLC with c-MET overexpression and NRG1 fusions, respectively, in the second-line setting.23-25 For NSCLC without driver mutations (frequently encountered with a smoking history), chemoimmunotherapy versus immunotherapy alone (contingent on PD-L1 expression), remain the standard of care.27,28 

SCLC: New Options for Limited and Extensive Disease

The field of small cell lung cancer has also seen tremendous progress in drug development and optimization of available therapies. For limited-stage disease, the current standard of care is concurrent chemoradiation (platinum-based), followed by consolidation with durvalumab for 2 years (ADRIATIC).29 Prophylactic cranial irradiation remains a contentious topic among the experts in the field and is considered on a case-by-case basis.30 

For tumors less than or equal to 5 cm without nodal involvement, up-front surgery followed by adjuvant platinum-based chemotherapy may be considered.31 Adjuvant radiation may also be considered if nodal involvement is identified intraoperatively.32 Until recently, extensive-stage disease was treated with chemoimmunotherapy followed by immunotherapy maintenance.33 

The IMforte data presented at ASCO 2025 move up lurbinectedin plus atezolizumab from the second line to first-line maintenance, delivering a statistically significant PFS and OS benefit.34 Rechallenge with platinum-based chemotherapy may be considered in the second line for disease recurrence beyond 6 months.35 Other existing options include topotecan and lurbinectedin (if not previously used in the first-line maintenance setting).36-37

Tarlatamab: A New Option With Immunotoxicity Considerations

The DeLLphi-304 data showed a statistically significant and meaningful OS benefit of 5 months with bispecific T-cell engager tarlatamab.38 The main adverse effect considerations are cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, for which institutional protocols and related training are imperative.39 

 References:

  1. Howington JA, Blum MG, Chang AC, Balekian AA, Murthy SC. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e278S-e313S. doi:10.1378/chest.12-2359
  2. Cascone T, Awad MM, Spicer J, et al. Perioperative nivolumab (NIVO) vs placebo (PBO) in patients (pts) with resectable NSCLC: updated survival and biomarker analyses from CheckMate 77T. J Clin Oncol. 2025;43(suppl 17):LBA8010. doi:10.1200/JCO.2025.43.17_suppl.LBA8010 
  3. Forde PM, Spicer J, Provencio M, et al. Overall survival with neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) in patients with resectable NSCLC in CheckMate 816. J Clin Oncol. 2025;43(suppl 17):LBA8000. doi:10.1200/JCO.2025.43.17_suppl.LBA8000
  4. Spicer JD, Garassino MC, Wakelee H, et al; KEYNOTE-671 investigators. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404 (10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
  5. Heymach JV, Harpole D, Mitsudomi T, et al. OA13.03 Perioperative durvalumab for resectable NSCLC (R-NSCLC): updated Outcomes from the Phase 3 AEGEAN Trial. J Thorac Oncol. 2024;19(suppl 10):38-39. doi:10.1016/j.jtho.2024.09.069
  6. Felip E, Altorki N, Zhou C, et al; IMpower010 investigators. Five-year survival outcomes with atezolizumab after chemotherapy in resected stage IB-IIIA non-small cell lung cancer (IMpower010): an open-label, randomized, phase III trial. J Clin Oncol. 2025;43(21):2343-2349. doi:10.1200/JCO-24-01681
  7. Oselin K, Shim BY, Okada M, et al. Pembrolizumab vs placebo for early-stage non‒small-cell lung cancer after resection and adjuvant therapy: subgroup analysis of patients who received adjuvant chemotherapy in the phase 3 PEARLS/KEYNOTE-091 study. J Clin Oncol. 2023;41(suppl 16):8520. doi:10.1200/JCO.2023.41.16_suppl.8520
  8. Faria N, Costa MI, Lacerda C, Sucena M. Impact of the ninth International Association for the Study of Lung Cancer TNM classification on endobronchial ultrasound for lung cancer staging. J Thorac Oncol. 2024;19(10):e53-e55. doi:10.1016/j.jtho.2024.07.010
  9. Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2023;389(2):137-147. doi:10.1056/NEJMoa2304594
  10. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in resected ALK-positive non-small-cell lung cancer. N Engl J Med. 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532
  11. He J, Tsuboi M, Weder W, et al. Neoadjuvant osimertinib for resectable EGFR-mutated non-small cell lung cancer. J Clin Oncol. Published online June 2, 2025. doi:10.1200/JCO-25-00883
  12. Leonetti A, Boni L, Gnetti L, et al. Alectinib as neoadjuvant treatment in potentially resectable stage III ALK-positive NSCLC: Final analysis of ALNEO phase II trial (GOIRC-01-2020-ML42316). J Clin Oncol. 2025;43(suppl 16):8015. doi:10.1200/JCO.2025.43.16_suppl.8015
  13. Lu S, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614
  14. Spigel DR, Faivre-Finn C, Gray JE, et al. (2022). Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 40(12):1301-1311. doi:10.1200/JCO.21.01308
  15. Jänne PA, Kobayashi K, Robichaux J, et al. FLAURA2: exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) ± platinum-pemetrexed. Cancer Res. 2024;84(suppl 7):CT017. doi:10.1158/1538-7445.AM2024-CT017
  16. Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: a secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504
  17. 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. J Clin Oncol. 2024;42(30):3605. doi:10.1200/JCO.24.01001
  18. Feldman JL, Cho BC, Li W, et al. Dermatologic prophylaxis and impact on patient-reported outcomes in first-line EGFR-mutant advanced NSCLC treated with amivantamab plus lazertinib: results from the phase 2 COCOON trial. J Clin Oncol. 2025;43(suppl 16):8641. doi:10.1200/JCO.2025.43.16_suppl.8641
  19. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200/JCO.24.00581
  20. Jänne PA, Theelen WSME,Garassino MC, et al. (2025). First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study. J Clin Oncol. 2025;43(suppl 16):8500. doi:10.1200/JCO.2025.43.16_suppl.8500
  21. Jänne PA, Goto Y, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non-small cell lung cancer (mNSCLC): final analysis results of DESTINY-Lung02. J Clin Oncol. 2024;42(suppl 16):8543. doi:10.1200/JCO.2024.42.16_suppl.8543
  22. Loong HH, Li L, WuL, et al. SOHO-01: Safety and efficacy of BAY 2927088 in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naïve to HER2-targeted therapy or had not received any treatment for advanced disease. J Clin Oncol. 2025;43(suppl 16):8504. doi:10.1200/JCO.2025.43.16_suppl.8504
  23. Goldman JW, Lu S, Bar J, et al. LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein-overexpressing non-squamous EGFR-wildtype advanced NSCLC: efficacy outcomes by prior therapy. J Clin Oncol. 2025;43(suppl 16):8618. doi:10.1200/JCO.2025.43.16_suppl.8618
  24. FDA grants accelerated approval to telisotuzumab vedotin-tllv for NSCLC with high c-MET protein overexpression. US Food and Drug Administration. May 14, 2025. Accessed July 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
  25. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022; 40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105
  26. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. US Food and Drug Administration. December 4, 2024. Accessed July 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic
  27. Garassino MC, Gadgeel S, Speranza G, et al. (2023). Pembrolizumab Plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-1998. doi:10.1200/JCO.22.01989
  28. Reck M, Rodríguez-Abreu D, Robinson AG, et al. (2021). Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non–small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%. J Clin Oncol. 2021;39(21):2339-2349. doi:10.1200/JCO.21.00174
  29. Cheng Y, Spigel DR, Cho BC, et al. Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 2024;391(14):1313-1327. doi:10.1056/NEJMoa2404873
  30. Edelman MJ. Prophylactic cranial irradiation for small-cell lung cancer: time for a reassessment. Am Soc Clin Oncol Educ Book. 2020;40:24-28. doi:10.1200/EDBK_281041
  31. Gergen AK, Scott CD, Mitchell JD. Surgery for limited stage small cell lung cancer. J Thorac Dis. 2020;12(10):6291-6297. doi:10.21037/jtd.2020.03.79
  32. Wong AT, Rineer J, Schwartz D, Schreiber D. Assessing the impact of postoperative radiation therapy for completely resected limited-stage small cell lung cancer using the National Cancer Database. J Thorac Oncol. 2016;11(2), 242-248. doi:10.1016/j.jtho.2015.10.011
  33. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and pd-l1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055
  34. Paz-Ares LG, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006
  35. Libre M, Lu M, Lessans S, Wu J, Bhatia S, Iams WT. Lurbinectedin versus platinum rechallenge in relapsed extensive stage small cell lung cancer: A retrospective cohort study. J Clin Oncol. 2024;42(suppl 16):e20110. doi:10.1200/JCO.2024.42.16_suppl.e20110
  36. Baize N, Monnet I, Greillier L, et al; Groupe Français de Pneumo-Cancérologie 01–13 investigators. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1224-1233. doi:10.1016/S1470-2045(20)30461-7
  37. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1
  38. Rudin CM, Mountzios GS, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008
  39. 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