Table Info

Table 1.

Ongoing phase III clinical trials of perioperative immunotherapy with PD-1/PD-L1 inhibitors in operable NSCLC

Trial	Stage	Treatment	Control	Primary endpoint	Primary Outcome
Neoadjuvant: CheckMate 816 [5]	IB–IIIA	Nivolumab + chemotherapy × 3 cycles	Chemotherapy	EFS	EFS: 31.6 months vs. 20.8 months
Adjuvant: IMpower010 [2]	IB (> 4 cm)–IIIA	Chemotherapy → atezolizumab 16 cycles	Chemotherapy → observation	DFS	DFS: HR = 0.81 (0.67–0.99)
Keynote-091 [3]	IB (> 4 cm)–IIIA	Chemotherapy (optional) → pembrolizumab 18 cycles	Chemotherapy (optional) → placebo	DFS	mDFS: 53.6 months vs. 42 months [HR = 0.76, 95% CI: 0.63–0.91]
BR.31 (NCT02273375)	IB (> 4 cm)–IIIA	Chemotherapy(optional) → durvalumab 12 months	Chemotherapy (optional) → placebo	DFS	N/A
ANVIL (NCT02595944)	IB (> 4 cm)–IIIA	Chemotherapy(optional) → nivolumab 16 cycles	Chemotherapy (optional) → observation	DFS, OS	N/A
MERMAID-1 (NCT04385368)	II–III	Durvalumab + SoC chemotherapy	Placebo + SoC chemotherapy	DFS	N/A
MERMAID-2 (NCT04642469)	II–III	Durvalumab 1 year	Placebo	DFS	N/A
ALCHEMIST (NCT04267848)	IB (> 4 cm)–IIIA	Chemotherapy → pembrolizumab 16 cycles; or chemotherapy + pembrolizumab 4 cycles → pembrolizumab 12 cycles	Chemotherapy → observation	DFS, OS	N/A
Perioperative: KEYNOTE-671 [43]	II–IIIA	Neoadjuvant Pembrolizumab + chemotherapy 4 cycles; adjuvant Pembrolizumab	Neoadjuvant chemotherapy; adjuvant placebo	EFS, OS	EFS at 24 months: 62.4% vs. 40.6% (HR = 0.58, 95% CI: 0.46–0.72); OS at 24 months: 80.9% vs. 77.6% (P = 0.02)
CheckMate-77T [7]	II–IIIB	Neoadjuvant nivolumab + chemotherapy 4 cycles; adjuvant nivolumab	Neoadjuvant chemotherapy; adjuvant placebo	EFS	EFS at 18 months: 70.2% vs. 50.0% (HR = 0.58, 97.36% CI: 0.42–0.91)
IMpower030 [44]	II–IIIB	Neoadjuvant Atezolizumab + chemotherapy 4 cycles; adjuvant atezolizumab 16 cycles	Neoadjuvant chemotherapy; adjuvant monitoring	EFS	N/A
AEGEAN [45]	IIA–IIIB	Neoadjuvant durvalumab + chemotherapy 4 cycles; adjuvant durvalumab 12 cycles	Neoadjuvant chemotherapy; adjuvant placebo	EFS, PCR	EFS at 12 months: 73.4% vs. 64.5% (HR = 0.68, 95% CI: 0.53–0.88); PCR: 17.2% vs. 4.3% (95% CI: 8.7 to 17.6)
RATIONALE-315 [46]	II–IIIA	Neoadjuvant tislelizumab + chemotherapy 3–4 cycles; adjuvant tislelizumab up to 8 cycles	Neoadjuvant chemotherapy; adjuvant placebo	EFS	Median EFS was not reached at 22 months for either arm; however, a statistically significant difference in EFS (HR = 0.56, 95% CI: 0.40–0.79)
JS001-029	IIIA	Neoadjuvant toripalimab + chemotherapy 4 cycles; adjuvant toripalimab 13 cycles	Neoadjuvant chemotherapy; adjuvant placebo	MPR, EFS	N/A
NCT05157776	IIIA	Neoadjuvant sintilimab + chemo 4 cycles	Neoadjuvant sintilimab + chemotherapy 2 cycles; adjuvant: optional Sintilimab + chemotherapy 2 cycles	PCR	N/A

DFS: disease-free survival; EFS: event-free survival; MPR: major pathological response; OS: overall survival; PCR: pathologically complete response; N/A: not applicable; HR: hazard ratio; CI: confidence interval; OS: overall survival; PD-1: programmed death 1; PD-L1: programmed death-ligand 1; NSCLC: non-small cell lung cancer

Declarations

Author contributions

RH and DJB: Conceptualization, Investigation, Supervision, Project administration, Writing—original draft, Writing—review & editing. ZLA and DP: Investigation, Writing—original draft, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

RH is a consultant for Targeted Oncology and Takeda and received honoraria from DAVA Oncology and The Dedham Group. DJB has the following disclosures: consulting or advisory role: Astellas, Eisai, Seagen; speakers’ bureau: Merck; travel and accommodations: Merck. Both other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Pignon J, Tribodet H, Scagliotti GV, Douillard J, Shepherd FA, Stephens RJ, et al.; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552–9. [DOI] [PubMed]

Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O, et al.; IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398:1344–57. Erratum in: Lancet. 2021;398:1686. [DOI] [PubMed]

O’Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, et al.; EORTC-1416-LCG/ETOP 8-15-PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022;23:1274–86. [DOI] [PubMed]

Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018;378:1976–86. Erratum in: N Engl J Med. 2018;379:2185. [DOI] [PubMed] [PMC]

Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, et al.; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386:1973–85. [DOI] [PubMed] [PMC]

Wakelee H, Liberman M, Kato T, Tsuboi M, Lee S, Gao S, et al.; KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389:491–503. [DOI] [PubMed] [PMC]

Cascone T, Awad MM, Spicer JD, He J, Lu S, Sepesi B, et al.; CheckMate 77T Investigators. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med. 2024;390:1756–69. [DOI] [PubMed]

Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohé C, et al.; ADAURA Investigators. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023;389:137–47. [DOI] [PubMed]

Wu Y, Tsuboi M, He J, John T, Grohe C, Majem M, et al.; ADAURA Investigators. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383:1711–23. [DOI] [PubMed]

10.

Herbst RS, Wu Y, John T, Grohe C, Majem M, Wang J, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023;41:1830–40. Erratum in: J Clin Oncol. 2023;41:3877. [DOI] [PubMed] [PMC]

11.

Wu Y, Dziadziuszko R, Ahn JS, Barlesi F, Nishio M, Lee DH, et al.; ALINA Investigators. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2024;390:1265–76. [DOI] [PubMed]

12.

Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res. 2014;3:242–9. [DOI] [PubMed] [PMC]

13.

Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ. 1995;311:899–909. [PubMed] [PMC]

14.

Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, et al.; Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003;95:1453–61. [DOI] [PubMed]

15.

Waller D, Peake MD, Stephens RJ, Gower NH, Milroy R, Parmar MKB, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg. 2004;26:173–82. [DOI] [PubMed]

16.

Douillard J, Rosell R, Lena MD, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006;7:719–27. Erratum in: Lancet Oncol. 2006;7:797. [DOI] [PubMed]

17.

Arriagada R, Bergman B, Dunant A, Chevalier TL, Pignon J, Vansteenkiste J, et al.; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–60. [DOI] [PubMed]

18.

Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol. 2010;28:29–34. [DOI] [PubMed] [PMC]

19.

Kang J, Kim KD, Chung KY. Prognostic value of visceral pleura invasion in non-small cell lung cancer. Eur J Cardiothorac Surg. 2003;23:865–9. [DOI] [PubMed]

20.

Choi J, Oh JY, Lee YS, Min KH, Shim JJ, Choi SI, et al. Clinical efficacy of adjuvant chemotherapy in stage IB (< 4 cm) non-small cell lung cancer patients with high-risk factors. Korean J Intern Med. 2022;37:127–36. [DOI] [PubMed] [PMC]

21.

Huang W, Deng H, Lin M, Xu K, Zhang Y, Yuan C, et al. Treatment Modality for Stage IB Peripheral Non-Small Cell Lung Cancer With Visceral Pleural Invasion and ≤3 cm in Size. Front Oncol. 2022;12:830470. [DOI] [PubMed] [PMC]

22.

Cheng Y, Chen Y, Liu C, Lin C, Tong S, Wang B. Adjuvant chemotherapy in pathological node-negative non-small cell lung cancer. Sci Rep. 2023;13:19137. [DOI] [PubMed] [PMC]

23.

Pathak R, Goldberg SB, Canavan M, Herrin J, Hoag JR, Salazar MC, et al. Association of Survival With Adjuvant Chemotherapy Among Patients With Early-Stage Non-Small Cell Lung Cancer With vs Without High-Risk Clinicopathologic Features. JAMA Oncol. 2020;6:1741–50. [DOI] [PubMed] [PMC]

24.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®): Non-Small Cell Lung Cancer [Internet]. National Comprehensive Cancer Network, Inc.; ©2024 [cited 2024 Mar 25]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

25.

Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30:1321–28. [DOI] [PubMed] [PMC]

26.

Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Front Immunol. 2022;13:823618. [DOI] [PubMed] [PMC]

27.

Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, Pawel Jv, et al.; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65. Erratum in: Lancet. 2017;389:e5. [DOI] [PubMed] [PMC]

28.

Herbst RS, Baas P, Kim D, Felip E, Pérez-Gracia JL, Han J, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50. [DOI] [PubMed]

29.

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123–35. [DOI] [PubMed] [PMC]

30.

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627–39. [DOI] [PubMed] [PMC]

31.

Herbst RS, Giaccone G, Marinis Fd, Reinmuth N, Vergnenegre A, Barrios CH, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020;383:1328–39. [DOI] [PubMed]

32.

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al.; KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379:2040–51. [DOI] [PubMed]

33.

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, Angelis FD, et al.; KEYNOTE-189 Investigators. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078–92. [DOI] [PubMed]

34.

Hellmann MD, Paz-Ares L, Caro RB, Zurawski B, Kim S, Costa EC, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019;381:2020–31. [DOI] [PubMed]

35.

Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M, Gogishvili M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397:592–604. [DOI] [PubMed]

36.

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al.; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823–33. [DOI] [PubMed]

37.

Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;40:1301–11. Erratum in: J Clin Oncol. 2022;40:1965. [DOI] [PubMed] [PMC]

38.

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al.; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. N Engl J Med. 2017;377:1919–29. [DOI] [PubMed]

39.

Bakos O, Lawson C, Rouleau S, Tai L. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J Immunother Cancer. 2018;6:86. [DOI] [PubMed] [PMC]

40.

Tang WF, Ye HY, Tang X, Su JW, Xu KM, Zhong WZ, et al. Adjuvant immunotherapy in early-stage resectable non-small cell lung cancer: A new milestone. Front Oncol. 2023;13:1063183. [DOI] [PubMed] [PMC]

41.

Mathieu LN, Larkins E, Sinha AK, Mishra-Kalyani PS, Jafri S, Kalavar S, et al. FDA Approval Summary: Atezolizumab as Adjuvant Treatment following Surgical Resection and Platinum-Based Chemotherapy for Stage II to IIIA NSCLC. Clin Cancer Res. 2023;29:2973–8. [DOI] [PubMed] [PMC]

42.

Felip E, Altorki N, Zhou C, Vallières E, Martínez-Martí A, Rittmeyer A, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023;34:907–19. [DOI] [PubMed]

43.

Aredo JV, Wakelee HA. Top advances of the year: Perioperative therapy for lung cancer. Cancer. 2024;[Epub ahead of print]. [DOI] [PubMed]

44.

Peters S, Kim AW, Solomon B, Gandara DR, Dziadziuszko R, Brunelli A, et al. IMpower030: Phase III study evaluating neoadjuvant treatment of resectable stage II-IIIB non-small cell lung cancer (NSCLC) with atezolizumab (atezo) + chemotherapy. Ann Oncol. 2019;30:ii30. [DOI]

45.

Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, et al.; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389:1672–84. [DOI] [PubMed]

46.

Yue D, Wang W, Liu H, Chen Q, Chen C, Liu L, et al. VP1-2024: RATIONALE-315: Event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC). Ann Oncol. 2024;35:332–3. [DOI]

47.

Duan H, Wang T, Luo Z, Tong L, Dong X, Zhang Y, et al. Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study. Transl Lung Cancer Res. 2021;10:1020–28. [DOI] [PubMed] [PMC]

48.

Hellmann MD, Chaft JE, Jr WNW, Rusch V, Pisters KMW, Kalhor N, et al.; University of Texas MD Anderson Lung Cancer Collaborative Group. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 2014;15:e42–50. [DOI] [PubMed] [PMC]

49.

Provencio M, Serna-Blasco R, Nadal E, Insa A, García-Campelo MR, Rubio JC, et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol. 2022;40:2924–33. Erratum in: J Clin Oncol. 2022;40:3785. [DOI] [PubMed] [PMC]

50.

Provencio M, Nadal E, González-Larriba JL, Martínez-Martí A, Bernabé R, Bosch-Barrera J, et al. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389:504–13. [DOI] [PubMed]

51.

Peng Y, Li Z, Fu Y, Pan Y, Zeng Y, Liu J, et al. Progress and perspectives of perioperative immunotherapy in non-small cell lung cancer. Front Oncol. 2023;13:1011810. Erratum in: Front Oncol. 2023;13:1163376. [DOI] [PubMed] [PMC]

52.

Spicer JD, Gao S, Liberman M, Kato T, Tsuboi M, Lee SH, et al. LBA56 Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Ann Oncol. 2023;34:S1297–8. [DOI]

53.

FDA approves neoadjuvant/ adjuvant pembrolizumab for resectable non-small cell lung cancer [Internet]. Silver Spring: Food and Drug Administration; c2024 [cited 2024 May 25]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-adjuvant-pembrolizumab-resectable-non-small-cell-lung-cancer

54.

Lu S, Wu L, Zhang W, Zhang P, Wang W, Fang W, et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phase III Neotorch study. J Clin Oncol. 2023;41:425126. [DOI]

55.

Cascone T, Leung CH, Weissferdt A, Pataer A, Carter BW, Godoy MCB, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med. 2023;29:593–604. [DOI] [PubMed] [PMC]

56.

Pass H, Kim AW, Felip E, Shu CA, Ferris A, Frueh M, et al. 970TiP SKYSCRAPER-05: Phase II study of neoadjuvant atezolizumab (Atezo) + tiragolumab (Tira) with or without platinum-based chemotherapy (CT) in patients (Pts) with locally advanced resectable stage II‒IIIB NSCLC. Ann Oncol. 2022;33:S990–1. [DOI]

57.

Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim D, John T, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36:841–9. [DOI] [PubMed]

58.

Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18:1307–16. [DOI] [PubMed]

59.

Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim D, et al.; ALEX Trial Investigators. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377:829–38. [DOI] [PubMed]

60.

Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383:813–24. [DOI] [PubMed] [PMC]

61.

Khozin S, Blumenthal GM, Jiang X, He K, Boyd K, Murgo A, et al. U. Oncologist. 2014;19:774–9. [DOI] [PubMed] [PMC]

62.

Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al.; FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020;382:41–50. [DOI] [PubMed]

63.

Hoy SM. Brigatinib: A Review in ALK-Inhibitor Naïve Advanced ALK-Positive NSCLC. Drugs. 2021;81:267–75. [DOI] [PubMed]

64.

Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19:1654–67. Erratum in: Lancet Oncol. 2019;20:e10. [DOI] [PubMed]

65.

Kelly K, Altorki NK, Eberhardt WEE, O’Brien MER, Spigel DR, Crinò L, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2015;33:4007–14. [DOI] [PubMed]

66.

Pennell NA, Neal JW, Chaft JE, Azzoli CG, Jänne PA, Govindan R, et al. SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. J Clin Oncol. 2019;37:97–104. Erratum in: J Clin Oncol. 2019;37:612. [DOI] [PubMed] [PMC]

67.

Janjigian YY, Park BJ, Zakowski MF, Ladanyi M, Pao W, D’Angelo SP, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol. 2011;6:569–75. [DOI] [PubMed] [PMC]

68.

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13:239–46. [DOI] [PubMed]

69.

Zhong W, Wang Q, Mao W, Xu S, Wu L, Shen Y, et al.; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19:139–48. [DOI] [PubMed]

70.

Zhong W, Wang Q, Mao W, Xu S, Wu L, Wei Y, et al. Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39:713–22. [DOI] [PubMed] [PMC]

71.

Yue D, Xu S, Wang Q, Li X, Shen Y, Zhao H, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med. 2018;6:863–73. [DOI] [PubMed]

72.

Yue D, Xu S, Wang Q, Li X, Shen Y, Zhao H, et al. Updated Overall Survival and Exploratory Analysis From Randomized, Phase II EVAN Study of Erlotinib Versus Vinorelbine Plus Cisplatin Adjuvant Therapy in Stage IIIA Epidermal Growth Factor Receptor+ Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;40:3912–7. [DOI] [PubMed]

73.

Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, et al. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018;29:1409–16. [DOI] [PubMed] [PMC]

74.

Solomon BJ, Mok T, Kim D, Wu Y, Nakagawa K, Mekhail T, et al.; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77. Erratum in: N Engl J Med. 2015;373:1582. [DOI] [PubMed]

75.

Govindan R, Mandrekar SJ, Gerber DE, Oxnard GR, Dahlberg SE, Chaft J, et al. ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non-Small Cell Lung Cancer. Clin Cancer Res. 2015;21:5439–44. [DOI] [PubMed] [PMC]

76.

FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer [Internet]. Silver Spring: Food and Drug Administration; c2024 [cited 2024 May 19]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alectinib-adjuvant-treatment-alk-positive-non-small-cell-lung-cancer

77.

He J, Su C, Liang W, Xu S, Wu L, Fu X, et al. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial. Lancet Respir Med. 2021;9:1021–9. [DOI] [PubMed]

78.

Lv C, Wang R, Li S, Yan S, Wang Y, Chen J, et al. Randomized phase II adjuvant trial to compare two treatment durations of icotinib (2 years versus 1 year) for stage II-IIIA EGFR-positive lung adenocarcinoma patients (ICOMPARE study). ESMO Open. 2023;8:101565. [DOI] [PubMed] [PMC]

79.

Han B, Xiong L, Sun J, Li R, Lou Y, Zhang Y, et al. Erlotinib as Neoadjuvant Treatment in Endobronchial Ultrasound Confirmed Stage IIIA-N2 Non-Small Cell Lung Cancer (NSCLC) Patients with Epidermal Growth Factor Receptor (EGFR) Mutation (EXON 19 OR 21) (NCT01217619, ESTERN): a Prospective, Single Arm, Phase Ii Clinical Trial. Ann Oncol. 2015;26:i24. [DOI]

80.

Xiong L, Li R, Sun J, Lou Y, Zhang W, Bai H, et al. Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study. Oncologist. 2019;24:157–e64. [DOI] [PubMed] [PMC]

81.

Zhong W, Chen K, Chen C, Gu C, Wang J, Yang X, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol. 2019;37:2235–45. [DOI] [PubMed]

82.

Zhong W, Yan H, Chen K, Chen C, Gu C, Wang J, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer: final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial. Signal Transduct Target Ther. 2023;8:76. [DOI] [PubMed] [PMC]

83.

Lv C, Fang W, Wu N, Jiao W, Xu S, Ma H, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial. Lung Cancer. 2023;178:151–6. [DOI] [PubMed]

84.

Tsuboi M, Weder W, Escriu C, Blakely C, He J, Dacic S, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol. 2021;17:4045–55. [DOI] [PubMed] [PMC]

85.

Levy A, Bardet E, Lacas B, Pignon J, Adam J, Lacroix L, et al. A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer. Oncotarget. 2017;8:15924–33. [DOI] [PubMed] [PMC]

86.

Zenke Y, Yoh K, Sakakibara-Konishi J, Daga H, Hosomi Y, Nogami N, et al. P1.18-04 Neoadjuvant Ceritinib for Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement: SAKULA Trial. J Thorac Oncol. 2019;14:S626–7. [DOI]

87.

Zhang C, Li S, Nie Q, Dong S, Shao Y, Yang X, et al. Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol. 2019;14:726–31. [DOI] [PubMed]

88.

Leonetti A, Minari R, Boni L, Gnetti L, Verzè M, Ventura L, et al. Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial. Clin Lung Cancer. 2021;22:473–7. [DOI] [PubMed]

89.

Zhong W, Yang X, Yan H, Zhang X, Su J, Chen Z, et al. Phase II study of biomarker-guided neoadjuvant treatment strategy for IIIA-N2 non-small cell lung cancer based on epidermal growth factor receptor mutation status. J Hematol Oncol. 2015;8:54. [DOI] [PubMed] [PMC]

90.

Aredo JV, Urisman A, Gubens MA, Mulvey C, Allen GM, Rotow JK, et al. Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR -mutated non-small cell lung cancer. J Clin Oncol. 2023;41:8508. [DOI]

91.

Deutsch JS, Cimino-Mathews A, Thompson E, Provencio M, Forde PM, Spicer J, et al. Association between pathologic response and survival after neoadjuvant therapy in lung cancer. Nat Med. 2024;30:218–28. [DOI] [PubMed] [PMC]

92.

Hines JB, Cameron RB, Esposito A, Kim L, Porcu L, Nuccio A, et al. Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC. J Thorac Oncol. 2024;S1556-086400117-5. [DOI] [PubMed]

93.

Yu A, Fu F, Li X, Wu M, Yu M, Zhang W. Perioperative immunotherapy for stage II-III non-small cell lung cancer: a meta-analysis base on randomized controlled trials. Front Oncol. 2024;14:1351359. [DOI] [PubMed] [PMC]

94.

Li N, Wang B, Li J, Shao Y, Li M, Li J, et al. Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non-small cell lung cancer. Cancer. 2022;128:708–18. [DOI] [PubMed]

95.

Felip E, Srivastava M, Reck M, Wakelee H, Altorki NK, Vallieres E, et al. 1O IMpower010: ctDNA status in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC). Immuno-Oncology and Technology. 2022;16:100106. [DOI]

96.

Gao Q, Yang L, Lu M, Jin R, Ye H, Ma T. The artificial intelligence and machine learning in lung cancer immunotherapy. J Hematol Oncol. 2023;16:55. [DOI] [PubMed] [PMC]

97.

Ren C, Li J, Zhou Y, Zhang S, Wang Q. Typical tumor immune microenvironment status determine prognosis in lung adenocarcinoma. Transl Oncol. 2022;18:101367. [DOI] [PubMed] [PMC]

98.

Lin H, Pan X, Feng Z, Yan L, Hua J, Liang Y, et al. Automated whole-slide images assessment of immune infiltration in resected non-small-cell lung cancer: towards better risk-stratification. J Transl Med. 2022;20:261. [DOI] [PubMed] [PMC]

99.

Harel M, Christopoulos P, Puzanov I, Bar J, Kamer I, Reinmuth N, et al. Abstract 1208: Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy. Cancer Res. 2024;84:1208. [DOI]

100.

Rakshit S, Molina JR. Immunotherapy in patients with autoimmune disease. J Thorac Dis. 2020;12:7032–8. [DOI] [PubMed] [PMC]

101.

Mollica V, Rizzo A, Marchetti A, Tateo V, Tassinari E, Rosellini M, et al. The impact of ECOG performance status on efficacy of immunotherapy and immune-based combinations in cancer patients: the MOUSEION-06 study. Clin Exp Med. 2023;23:5039–49. [DOI] [PubMed]

102.

Rizzo A, Cusmai A, Giovannelli F, Acquafredda S, Rinaldi L, Misino A, et al. Impact of Proton Pump Inhibitors and Histamine-2-Receptor Antagonists on Non-Small Cell Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis. Cancers (Basel). 2022;14:1404. [DOI] [PubMed] [PMC]

103.

Solomon BJ, Ahn JS, Dziadziuszko R, Barlesi F, Nishio M, Lee DH, et al. LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34:S1295–6. [DOI]

104.

Xu S, Xi J, Zhong W, Mao W, Wu L, Shen Y, et al. The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104). J Thorac Oncol. 2019;14:503–12. [DOI] [PubMed]

105.

Soo RA, de Marinis F, Han J, Ho JC, Martin E, Servidio L, et al. TARGET: A Phase II, Open-Label, Single-Arm Study of 5-Year Adjuvant Osimertinib in Completely Resected EGFR-Mutated Stage II to IIIB NSCLC Post Complete Surgical Resection. Clin Lung Cancer. 2024;25:80–4. [DOI] [PubMed]

106.

Wu YL, Zhong W, Chen KN, Chen C, Yang F, Yang XN, et al. CTONG1103: Final overall survival analysis of the randomized phase 2 trial of erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non–small cell lung cancer. J Clin Oncol. 2021;39:8502. [DOI]

107.

Grant C, Nagasaka M. Neoadjuvant EGFR-TKI therapy in Non-Small cell lung cancer. Cancer Treat Rev. 2024;126:102724. [DOI] [PubMed]

108.

2024 ASP drug pricing files [Internet]. Baltimore: CMS.gov; [cited May 24]. Available from: https://www.cms.gov/medicare/payment/part-b-drugs/asp-pricing-files

109.

Lemmon CA, Zabor EC, Pennell NA. Modeling the Cost-Effectiveness of Adjuvant Osimertinib for Patients with Resected EGFR-mutant Non-Small Cell Lung Cancer. Oncologist. 2022;27:407–13. [DOI] [PubMed] [PMC]