Shanghai Pulmonary Hospital, Department of Thoracic Surgery, Dedicated to Advancing Neoadjuvant Surgical Treatment for Lung Cancer

— Significantly Improving Surgical Resection Rates for Locally Advanced Lung Cancer, Providing More Patients with Surgical Treatment Opportunities

Shanghai Pulmonary Hospital, Department of Thoracic Surgery, has rigorously defined surgical indications after confirming the efficacy of targeted therapy, chemotherapy, and immunotherapy. Leveraging their deep technical expertise, they have made significant strides in neoadjuvant surgical treatment for lung cancer, improving a critical component of comprehensive lung cancer treatment. As of June 2023, they have performed a total of 1,044 neoadjuvant surgical procedures for lung cancer, including open surgery, thoracoscopic surgery, and da Vinci robot-assisted surgery.

Neoadjuvant Treatment

Lung cancer remains a leading cause of cancer-related deaths in both China and worldwide. Approximately 20-25% of patients diagnosed with non-small cell lung cancer (NSCLC) have the opportunity for curative surgery. However, 30-55% of patients undergoing radical resection experience recurrence and ultimately succumb to the disease^1-3. Neoadjuvant treatment refers to an approach aimed at enhancing curability through treatment administered before local interventions. The goal of neoadjuvant treatment is to address subclinical micrometastatic disease, improve R0 resection rates, and ultimately enhance prognosis. However, compared to surgery alone, preoperative chemotherapy only raises the 5-year survival rate of stage IB-III NSCLC by 5%^4-6. In recent years, biomarker-driven treatment strategies have improved therapeutic outcomes and survival benefits for advanced NSCLC. Consequently, there is renewed attention to neoadjuvant treatment strategies for locally advanced lung cancer. Several clinical trials employing targeted therapy and immunotherapy alone or in combination with chemotherapy have had a positive impact on the treatment of locally advanced NSCLC⁷.

Neoadjuvant EGFR-Targeted Therapy

Neoadjuvant EGFR-targeted therapy for resectable EGFR-mutant NSCLC is still in its early stages. Given the therapeutic potential of EGFR-TKIs in late-stage EGFR-mutant NSCLC, they have been applied to neoadjuvant treatment for locally advanced, resectable EGFR-mutant NSCLC. Many centers are exploring the potential therapeutic effects of combining neoadjuvant targeted therapy with surgery, a clinical strategy that is currently under investigation.

In resectable NSCLC, most data on targeted therapy have been obtained in populations with EGFR mutations, although trials involving other molecular subgroups (such as the ALINA trial for ALK-rearranged NSCLC [NCT03456076]) are also underway. Some studies on neoadjuvant EGFR-TKIs have been published. EMERGING-CTONG110323 is the only published randomized controlled trial (RCT) to date, comparing neoadjuvant and adjuvant erlotinib with neoadjuvant and adjuvant platinum-based doublet chemotherapy in 72 patients with stage III-N2 EGFR-mutant NSCLC. While this study did not meet its primary endpoint of objective response rate (ORR), erlotinib showed a statistically significant improvement in progression-free survival compared to platinum-based doublet chemotherapy (21.5 months vs. 11.4 months)⁸. The erlotinib group had a 9.7% rate of significant pathological response (MPR), while the chemotherapy group had none. Three small single-arm phase II studies involving neoadjuvant gefitinib or erlotinib demonstrated ORRs of 42.1% to 61.5% and MPR rates of 7.7% to 24.2%^9-11.

It's important to note that not all patients in these four trials successfully underwent curative surgery. The trial with the lowest R0 resection rate included only stage III-N2 lesions, and 43 patients ultimately received definitive chemoradiation therapy as an alternative. Additionally, ORRs for EGFR-TKIs in these studies seem lower than what is observed in advanced-stage patients, possibly due to the duration and types of EGFR-TKIs affecting MPR. Larger studies are needed to confirm these findings and further understand the determinants of response rates and resistance to develop optimal strategies for neoadjuvant EGFR-TKI treatment.

Two phase II single-arm trials investigated the feasibility of using third-generation EGFR-TKIs, such as osimertinib, as neoadjuvant treatment for resectable EGFR-mutant NSCLC^12-14. The NCT03433469 study included 13 EGFR-mutant stage I-IIIA resectable NSCLC patients who received 1-2 cycles (28 days per cycle) of osimertinib before surgery. The results showed partial responses (PR) in six cases (46%), stable disease (SD) in seven cases, and a disease control rate (DCR) of 100%. Postoperative pathology revealed that two cases (15%) achieved MPR, with no pathologic complete responses (pCR). The pathology and lymph node downstaging rates were 69% and 80%, respectively. Similar to first-generation EGFR-TKIs, neoadjuvant osimertinib exhibited good tolerability, with no significant adverse events observed and no unexpected delays in surgery or surgical complications. The NEOS study updated its results at the 2022 European Lung Cancer Congress (ELCC), reporting an ORR of 71.1% for neoadjuvant osimertinib, with a 94% R0 resection rate. Among the 28 patients who underwent pathological assessment, three cases (11%) achieved MPR, including one case (4%) with pCR, and 13 cases (46%) achieved over 50% pathological regression. Moreover, preoperative osimertinib was well-tolerated and did not result in any significant perioperative complications. Currently, the ongoing phase III NeoADAURA study aims to explore the efficacy and safety of osimertinib as neoadjuvant monotherapy or in combination with chemotherapy for resectable EGFR-mutant NSCLC patients. The NeoADAURA study defines neoadjuvant treatment for a duration of 9 weeks, with the primary endpoint being MPR. Details and results of the study are pending.

The clinical research team at Shanghai Pulmonary Hospital, Department of Thoracic Surgery, is currently conducting four clinical trials for neoadjuvant targeted therapy, including Investigator-Initiated Trials (IIT) and Good Clinical Practice (GCP) trials. These trials involve domestic second- and third-generation EGFR-TKIs as neoadjuvant drugs, and the neoadjuvant trial for first-generation EGFR-TKIs has completed patient recruitment. After neoadjuvant treatment, patients are evaluated for surgical eligibility and referred to various clinical teams within the Department of Thoracic Surgery at Shanghai Pulmonary Hospital for surgical treatment. Further assessment of adjuvant treatment plans is conducted after surgical recovery.

Neoadjuvant EGFR-Targeted Therapy

After achieving remarkable treatment outcomes with single immunotherapy and chemo-immunotherapy in advanced non-oncogene-driven NSCLC, especially in patients identified by PD-L1 as a predictive biomarker, neoadjuvant immunotherapy has gained considerable attention in the field of lung cancer neoadjuvant therapy⁷. Various clinical trials have been conducted to explore the effectiveness of new adjuvant treatments using PD-1 and PD-L1 inhibitors either as monotherapy or in combination with platinum-based chemotherapy agents or CTLA-4 inhibitors^15-26.

The groundbreaking study by Forde et al. demonstrated promising results, showing good tolerability for two cycles of neoadjuvant nivolumab, with an objective response rate (ORR) of 9.5%, a major pathological response (MPR) of 45.0%, and a complete pathological response (cPR) of 10.0%. Similar studies utilizing other PD-1 or PD-L1 inhibitors as monotherapy before surgery have also shown varying degrees of therapeutic effects^21-23. According to the latest results from the phase II LCMC3 trial, which has the largest sample size in neoadjuvant phase II studies related to PD-1/PD-L1 inhibitors, resectable stage IB-IIIB NSCLC patients who received atezolizumab as neoadjuvant treatment followed by surgery and postoperative atezolizumab adjuvant therapy had prolonged disease-free survival (DFS) and showed a trend toward extended overall survival (OS) compared to patients who did not receive atezolizumab adjuvant therapy. Specifically, among the MPR population (n=137), patients who received atezolizumab adjuvant therapy (n=53) achieved a 3-year DFS of 83%, while patients who did not receive atezolizumab adjuvant therapy had a 3-year DFS of 64%. With a median follow-up of 3.1 years (range: 0.15-4.7), the 3-year OS for patients receiving atezolizumab adjuvant therapy reached 89%, while the 3-year OS for patients not receiving atezolizumab adjuvant therapy was 77%. In the non-MPR population, the 3-year DFS for patients receiving atezolizumab adjuvant therapy was 80%, compared to 62% for patients not receiving atezolizumab adjuvant therapy. The respective 3-year OS rates were 87% and 75%. Among the MPR population (n=137), the overall 3-year DFS and OS rates were 72% and 82%, respectively. The DFS and OS rates were similar among patients at different stages. The 3-year DFS rate for stage I/II patients (n=70) was 75%, while it was 70% for stage III patients (n=67). The potential benefits were consistent among different subgroups.

Given the low response rates with monotherapy, the role of neoadjuvant combination immunotherapy has been explored. NEOSTAR, a phase II randomized controlled trial (RCT) involving 44 patients, aimed to compare the therapeutic effects of neoadjuvant nivolumab in combination with ipilimumab versus monotherapy nivolumab, with MPR as the primary endpoint¹⁹. The combination therapy significantly improved MPR (38.1% for combination vs. 21.7% for monotherapy) and cPR (28.6% for combination vs. 8.7% for monotherapy) compared to monotherapy, with no increase in drug toxicity.

Exploration of neoadjuvant chemo-immunotherapy (including various chemo-based regimens and different PD-1 and PD-L1 inhibitors) has also shown significant promise, with objective response rates (ORR) ranging from 46.2% to 76.1%, MPR exceeding 80%, and cPR surpassing 60%. CheckMate-816, a phase III clinical trial, was the first to evaluate the safety and efficacy of neoadjuvant nivolumab (PD-1 inhibitor) in combination with chemotherapy (NC group) compared to chemotherapy alone (C group) for treating resectable NSCLC. The study revealed that the NC group significantly increased cPR (24.0% in the NC group vs. 2.2% in the C group)²⁰. MPR also improved, with rates of 36.9% in the NC group and 8.9% in the C group, as well as an ORR of 53.6% in the NC group versus 37.4% in the C group. Additionally, the median event-free survival (EFS) in the NC group was 31.6 months (95% confidence interval [CI]: 30.2-undetermined), compared to 20.8 months in the C group (95% CI: 14.0-26.7). The risk ratio was 0.63 (97.38% CI: 0.43-0.91, p=0.005). Both the NC and C groups had 1-year progression-free survival (PFS) rates of 76.1% and 63.4% and 2-year PFS rates of 63.8% and 45.3%, respectively. Neither group reached the median overall survival (OS) time (risk ratio 0.57, 99.67% CI: 0.3-1.07, p=0.008). The AEGEAN study is the first phase III trial to investigate the efficacy and safety of the “neoadjuvant chemo-immunotherapy + surgery + adjuvant immunotherapy” treatment approach, targeting patients with operable stage II-IIIB NSCLC. This study involves four cycles of neoadjuvant chemo-immunotherapy and twelve cycles of adjuvant immunotherapy. A total of 802 patients were enrolled in this study, and the mid-term analysis was conducted with a median follow-up of 11.7 months, up to November 10, 2022²⁷. Among the study and control groups, 366 and 374 patients were included, with the shortest follow-up time being 6.7 months. In the surgical treatment phase, the proportions of patients who underwent surgery were 80.6% and 80.7% in the two groups, with 77.6% and 76.7% of patients completing surgery, and R0 resection rates of 94.7% and 91.3%, respectively. The median EFS for the study and control groups was not reached and 25.9 months, respectively, with a hazard ratio (HR) of 0.68 (95% CI: 0.53-0.88, p=0.0039). The EFS results for various subgroups all demonstrated a trend toward therapeutic benefits in the study group. Furthermore, regardless of baseline PD-L1 expression levels, EFS benefits were observed. Different neoadjuvant platinum-based chemotherapy regimens did not affect EFS benefits. The study group and control group had a pathological complete response (pCR) of 17.2% and 4.3%, with a difference of 13% (95% CI: 8.7%-17.6%, p=0.000036), and an MPR of 33.3% and 12.3%, with a difference of 21% (95% CI: 15.1%-26.9%, p=0.000002). Subgroups also showed benefits in pCR. No significant differences in safety were observed between the two groups. Furthermore, other neoadjuvant immunotherapy trials are currently ongoing, including the Neotorch study (investigating the combination of tislelizumab, a PD-1 inhibitor, with placebo in neoadjuvant + surgery + adjuvant phase III clinical research) and the IMpower030 study (examining atezolizumab, a PD-L1 inhibitor, in combination with neoadjuvant chemotherapy in a phase III research setting). We await the release of future results.

In comparison to neoadjuvant EGFR-TKIs treatment, neoadjuvant immunotherapy has been associated with a higher incidence of grade 3 or higher adverse events, particularly when combined with chemotherapy^16,17,19. Additionally, immune-related side effects, such as pneumonia and endocrine disorders, can lead to delayed or canceled surgeries, making perioperative assessment and treatment more complex, especially when corticosteroids are required to manage these side effects.

The clinical research team at Shanghai Pulmonary Hospital, Department of Thoracic Surgery, is currently conducting enrollment for two neoadjuvant monotherapy trials and more than ten neoadjuvant chemo-immunotherapy trials (including both Investigator-Initiated Trials [IIT] and Good Clinical Practice [GCP] trials). Patients are evaluated, treated, and reassessed by the thoracic surgery neoadjuvant treatment team before transitioning to the clinical teams at Shanghai Pulmonary Hospital, Department of Thoracic Surgery, for surgical treatment. After surgical recovery, further assessment is carried out for the adjuvant treatment plan. This comprehensive treatment process aims to provide a seamless and precise management approach for patients, eliminating any confusion or additional burdens on their part.

SCLC Neoadjuvant Mode Exploration

The clinical research team at Shanghai Pulmonary Hospital, Department of Thoracic Surgery, is currently exploring three neoadjuvant chemo-immunotherapy + surgery + adjuvant chemo-immunotherapy treatment modes for SCLC. While these modes are showing a trend of therapeutic benefit, we eagerly await the publication of the final study results, which will provide high-level evidence for the comprehensive treatment of SCLC.

Neoadjuvant Radiotherapy

Research into neoadjuvant radiotherapy primarily focuses on evaluating its combination with chemotherapy for locally advanced lesions. Patients with potentially resectable tumors receiving preoperative neoadjuvant therapy involving whole-body treatment plus radiotherapy have seen an increased rate of tumor regression and local control^28-34. When compared to neoadjuvant chemotherapy alone, the addition of radiotherapy has resulted in a higher rate of pathologic downstaging, allowing more patients to achieve MPR. However, this outcome has not consistently translated into improved survival rates across various studies^30-32.

In two studies comparing neoadjuvant chemoradiotherapy + surgery to curative chemoradiotherapy, no survival benefit was observed^33,34. Nevertheless, patients receiving trimodal therapy had fewer local recurrences than those undergoing curative chemoradiotherapy. This highlights the importance of identifying patients at risk of local recurrence and determining which patients would benefit more from surgery. In this regard, radiation resistance biomarkers like KEAP1 and NFE2L2 indicate a high risk of local recurrence after radiotherapy and can be used to guide patient selection³⁵.

Presentation of Representative Achievements in Neoadjuvant Research at the Department of Thoracic Surgery, Shanghai Pulmonary Hospital

The research and results of LungMate-001, LungMate-002, and LungMate-004 have been mentioned in the previous section titled “Clinical Research Thriving with Order at the Department of Thoracic Surgery, Shanghai Pulmonary Hospital”.

In 2022, the team at the Department of Thoracic Surgery at Shanghai Pulmonary Hospital reported the results of sleeve resection after neoadjuvant chemotherapy and immunotherapy for locally advanced NSCLC and double sleeve resection after neoadjuvant chemotherapy for central-type NSCLC. This included perioperative and oncological outcomes, which provided preliminary validation for the feasibility of sleeve or double sleeve resection in patients with locally advanced NSCLC after receiving neoadjuvant treatment36-37. In 2023, the team reported the results of the largest global study on sleeve pulmonary lobectomy after neoadjuvant therapy for locally advanced lung cancer, assessing the feasibility and safety of sleeve pulmonary lobectomy after neoadjuvant treatment. The study included 613 patients, with 124 of them having received prior neoadjuvant treatment. The results showed that neoadjuvant treatment did not significantly increase the postoperative complication rate, and the complete pathologic response (cPR) with neoadjuvant chemotherapy and immunotherapy was significantly better than with neoadjuvant chemotherapy alone. This large-scale study provided the first substantial evidence for the safety of sleeve pulmonary lobectomy after neoadjuvant treatment. The related paper was published in the top-tier international journal “J Thorac Cardiovasc Surg”, providing a theoretical basis for further promoting the “neoadjuvant combined with surgery” treatment model for locally advanced lung cancer. Once again, this demonstrates the leadership of Chinese thoracic surgery in advancing innovative treatment approaches for locally advanced lung cancer on a global scale.

In 2022, the Department of Thoracic Surgery team at Shanghai Pulmonary Hospital published a real-world observational study in the international core journal “Lung Cancer”. This study included 76 resectable NSCLC patients who had undergone neoadjuvant chemotherapy and immunotherapy. The results revealed an MPR (major pathologic response) of 64% and a cPR (complete pathologic response) of 37% in patients who received neoadjuvant chemotherapy and immunotherapy. Among clinical N2 patients, 69% achieved lymph node downstaging, with pathological diagnoses of N0 in 39 cases and N1 in 3 cases. For stage III patients, the 1-year progression-free survival (PFS) was 91%. Furthermore, it was found that neoadjuvant chemotherapy and immunotherapy did not increase the rate of postoperative complications compared to neoadjuvant chemotherapy alone³⁸. Additionally, the team conducted an assessment of the perioperative outcomes for NSCLC patients who underwent neoadjuvant chemotherapy and immunotherapy followed by surgical resection. When compared to neoadjuvant EGFR-TKI treatment and neoadjuvant chemotherapy, the results were similar, and no unexpected perioperative complications occurred. Both of these studies provided valuable evidence for the perioperative safety of the “neoadjuvant chemotherapy and immunotherapy followed by surgery” treatment model for locally advanced lung cancer, contributing to the body of evidence supporting comprehensive treatment approaches for locally advanced lung cancer.

Professor Chang Chen's team at Shanghai Pulmonary Hospital has established an artificial intelligence model for predicting the efficacy of neoadjuvant immunotherapy in NSCLC, with the results published in EBioMedicine. Further details about this research can be found in the previous section titled “Introduction to the Series of Multidisciplinary Research Achievements in Artificial Intelligence”. In addition, Professor Chang Chen's team designed and conducted a multicenter study to explore the predictive performance of SUVmax values in PET-CT scans for neoadjuvant chemotherapy and immunotherapy. The results showed that ΔSUVmax% and post-treatment SUVmax could effectively predict MPR in NSCLC patients undergoing neoadjuvant immunotherapy. Importantly, the predictive performance was not influenced by the specific neoadjuvant treatment regimen. This study further enhances the significance of PET-CT scans in predicting the efficacy of neoadjuvant therapy for NSCLC and was published in the international core journal “Lung Cancer”. Furthermore, Professor Chang Chen's team also investigated the predictive value of inflammatory biomarkers in peripheral blood for MPR after neoadjuvant treatment. The study found that the systemic immune inflammation index (SII) was independently associated with MPR and recommended further prospective research for evaluation. This research was published in “Cancer Immunology, Immunotherapy”³⁸. These three studies approach the prediction of neoadjuvant treatment efficacy from different angles, providing important insights to enhance the assessment system for the efficacy of neoadjuvant treatment in NSCLC.

Summary

The development of neoadjuvant and adjuvant treatments for NSCLC is still in its early stages and requires a wealth of clinical trial results and long-term survival data. Due to the heterogeneity of NSCLC, especially in stage III disease, treatment strategies need to be personalized to improve efficacy. Close multidisciplinary collaboration and rigorous patient selection remain key principles for the success of neoadjuvant treatments. As research continues to advance, neoadjuvant treatment approaches are expected to play an increasingly significant role.

1. Liang Y, Wakelee HA. Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. Oct 2013;2(5):403-10. doi:10.3978/j.issn.2218-6751.2013.07.01

2. Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res. Aug 2014;3(4):242-9. doi:10.3978/j.issn.2218-6751.2013.12.05

3. Taylor MD, Nagji AS, Bhamidipati CM, et al. Tumor recurrence after complete resection for non-small cell lung cancer. Ann Thorac Surg. Jun 2012;93(6):1813-20; discussion 1820-1. doi:10.1016/j.athoracsur.2012.03.031

4. Group NM-aC. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. May 3 2014;383(9928):1561-71. doi:10.1016/S0140-6736(13)62159-5

5. Hellmann MD, Chaft JE, William WN, Jr., et al. 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. Jan 2014;15(1):e42-50. doi:10.1016/S1470-2045(13)70334-6

6. Waser NA, Adam A, Schweikert B, et al. 1243P Pathologic response as early endpoint for survival following neoadjuvant therapy (NEO-AT) in resectable non-small cell lung cancer (rNSCLC): Systematic literature review and meta-analysis. Annals of Oncology. 2020;31:S806. doi:10.1016/j.annonc.2020.08.116

7. Saw SPL, Ong BH, Chua KLM, Takano A, Tan DSW. Revisiting neoadjuvant therapy in non-small-cell lung cancer. Lancet Oncol. Nov 2021;22(11):e501-e516. doi:10.1016/S1470-2045(21)00383-1

8. Zhong WZ, Chen KN, Chen C, 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. Sep 1 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075

9. Xiong L, Li R, Sun J, 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. Feb 2019;24(2):157-e64. doi:10.1634/theoncologist.2018-0120

10. Zhang Y, Fu F, Hu H, et al. Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non-small cell lung cancer: A phase II study. J Thorac Cardiovasc Surg. Feb 2021;161(2):434-442 e2. doi:10.1016/j.jtcvs.2020.02.131

11. Tan A, Chua KP, Takano A, et al. P1.17-07 Neoadjuvant Gefitinib in Resectable Early Stage EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): A Window-of-Opportunity Study. Journal of Thoracic Oncology. 2019/10/01/ 2019;14(10, Supplement):S609-S610. doi:https://doi.org/10.1016/j.jtho.2019.08.1281

12. Aredo JV, Urisman A, Gubens MA, et al. Phase II trial of neoadjuvant osimertinib for surgically resectable EGFR-mutated non-small cell lung cancer. Journal of Clinical Oncology. 2023/06/01 2023;41(16_suppl):8508-8508. doi:10.1200/JCO.2023.41.16_suppl.8508

13. Lyu C, Fang W, Jiao W, et al. 81MO Osimertinib as neoadjuvant therapy in patients with EGFR mutated resectable stage II-IIIB lung adenocarcinoma (NEOS): Updated results. Annals of Oncology. 2022;33:S71-S72. doi:10.1016/j.annonc.2022.02.091

14. Lv C, Fang W, Wu N, 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. 2023/04/01/ 2023;178:151-156. doi:https://doi.org/10.1016/j.lungcan.2023.02.011

15. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. May 24 2018;378(21):1976-1986. doi:10.1056/NEJMoa1716078

16. Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. Jun 2020;21(6):786-795. doi:10.1016/S1470-2045(20)30140-6

17. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. Nov 2020;21(11):1413-1422. doi:10.1016/S1470-2045(20)30453-8

18. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Journal of Clinical Oncology. 2021/05/20 2021;39(15_suppl):8500-8500. doi:10.1200/JCO.2021.39.15_suppl.8500

19. Cascone T, William WN, Jr., Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. Mar 2021;27(3):504-514. doi:10.1038/s41591-020-01224-2

20. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. May 26 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170

21. Carbone D, Lee J, Kris M, et al. OA06.06 Clinical/Biomarker Data for Neoadjuvant Atezolizumab in Resectable Stage IB-IIIB NSCLC: Primary Analysis in the LCMC3 Study. Journal of Thoracic Oncology. 2021;16(3):S115-S116. doi:10.1016/j.jtho.2021.01.294

22. Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol. May 2020;15(5):816-826. doi:10.1016/j.jtho.2020.01.017

23. Wislez M, Mazieres J, Lavole A, et al. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO). J Immunother Cancer. Oct 2022;10(10)doi:10.1136/jitc-2022-005636

24. Besse B, Adam J, Cozic N, et al. 1215O - SC Neoadjuvant atezolizumab (A) for resectable non-small cell lung cancer (NSCLC): Results from the phase II PRINCEPS trial. Annals of Oncology. 2020;31:S794-S795. doi:10.1016/j.annonc.2020.08.1417

25. Zinner R, Axelrod R, Solomides CC, et al. Neoadjuvant nivolumab (N) plus cisplatin (C)/pemetrexed (P) or cisplatin /gemcitabine (G) in resectable NSCLC. Journal of Clinical Oncology. 2020;38(15_suppl):9051-9051. doi:10.1200/JCO.2020.38.15_suppl.9051

26. Rothschild SI, Zippelius A, Eboulet EI, et al. SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small-Cell Lung Cancer-A Multicenter Single-Arm Phase II Trial. J Clin Oncol. Sep 10 2021;39(26):2872-2880. doi:10.1200/JCO.21.00276

27. Heymach JV, Mitsudomi T, Harpole D, et al. Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Clin Lung Cancer. May 2022;23(3):e247-e251. doi:10.1016/j.cllc.2021.09.010

28. Vokes EE, Herndon JE, 2nd, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. May 1 2007;25(13):1698-704. doi:10.1200/JCO.2006.07.3569

29. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. Mar 21 2007;99(6):442-50. doi:10.1093/jnci/djk093

30. Thomas M, Rube C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. Jul 2008;9(7):636-48. doi:10.1016/S1470-2045(08)70156-6

31. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. Sep 12 2015;386(9998):1049-56. doi:10.1016/S0140-6736(15)60294-X

32. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. Dec 15 2012;118(24):6126-35. doi:10.1002/cncr.26689

33. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. Aug 1 2009;374(9687):379-86. doi:10.1016/S0140-6736(09)60737-6

34. Eberhardt WE, Pottgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. Dec 10 2015;33(35):4194-201. doi:10.1200/JCO.2015.62.6812

35. Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition. Cancer Discov. Dec 2020;10(12):1826-1841. doi:10.1158/2159-8290.CD-20-0282

36. Dai J, Zhu X, Li D, et al. Sleeve resection after neoadjuvant chemoimmunotherapy in the treatment of locally advanced non-small cell lung cancer. Transl Lung Cancer Res. Feb 2022;11(2):188-200. doi:10.21037/tlcr-22-56

37. Bao Y, Jiang C, Wan Z, et al. Feasibility of double sleeve lobectomy after neoadjuvant chemotherapy in patients with non-small-cell lung cancer. Interact Cardiovasc Thorac Surg. Jul 9 2022;35(2)doi:10.1093/icvts/ivac103

38. Zhao D, Xu L, Wu J, et al. Comparison of perioperative outcomes among non-small cell lung cancer patients with neoadjuvant immune checkpoint inhibitor plus chemotherapy, EGFR-TKI, and chemotherapy alone: a real-world evidence study. Transl Lung Cancer Res. Jul 2022;11(7):1468-1478. doi:10.21037/tlcr-22-476

39. Li C, Wu J, Jiang L, et al. The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study. Cancer Immunology, Immunotherapy. 2023/03/01 2023;72(3):783-794. doi:10.1007/s00262-022-03262-w