Induction chemoimmunotherapy and surgery for unresectable stage III non-small cell lung cancer

Introduction

The standard of care for resectable locally advanced non-small cell lung cancer (NSCLC) had been neoadjuvant chemotherapy prior to the paradigm-shifting CheckMate-816 trail (1), although the improvement of 5-year recurrence-free survival and overall survival (OS) rate brought by neoadjuvant chemotherapy over surgery alone is only 5–6% (2). CheckMate-816 trial marked a milestone, presenting an increment of 2-year event-free survival (EFS) and OS of 18.5% and 12.1% respectively in neoadjuvant chemoimmunotherapy arm compared to chemotherapy alone (1). In subsequent trials, namely KEYNOTE-671, AEGEAN, and Neotorch trials, perioperative programmed cell death protein-1 (PD-1)/programmed cell death protein ligand-1 (PD-L1) antibody plus chemotherapy also showed advantage over neoadjuvant chemotherapy (3-5). However, for unresectable locally advanced NSCLC, surgery was debatable in several phase III randomized trials without showing significant OS benefit compared with radiotherapy (6-11). Concurrent chemoradiotherapy followed by durvalumab is widely recommended based on the results of PACIFIC trial which enrolled unresectable stage III NSCLC patients whose disease did not progress after chemoradiotherapy (6,12). The durvalumab consolidation arm of PACIFIC trial obtained a 5-year OS rate of 42.9%, exceeding the corresponding 33.4% in placebo arm (13). GEMSTONE-301 is also a successful phase 3 trial similar to PACIFIC except that it enrolled unresectable stage III NSCLC patients both after concurrent and sequential chemoradiotherapy, and the consolidation PD-L1 antibody was sugemalimab (14).

Resection for initially unresectable locally advanced NSCLC after induction therapy stirs ongoing debate. Moghanaki and colleagues believe unresectable stage III NSCLC should remain classified as unresectable even downstaging is obtained, considering the safety concerns and a risk of a higher R1/R2 resection rate than in initially resectable diseases (15). However, emerging research showed promising data in resection of unresectable NSCLC after induction chemoimmunotherapy, both in retrospective studies (16-19) and prospective clinical trials (20-22). In those studies, most surgical types were lobectomies, accounting for 60% to more than 90%, and the surgery related death was very rare (16-22). R0 resection rate exceeded 90% in four studies (17,18,20,21). The major pathological response (MPR) rate and pathological complete response (pCR) rate in the resected initially unresectable diseases were 56.5–72.7% and 34.8–63.6% respectively (16-19,21,22). Those studies were limited by small sample sizes, including 11~64 initially inoperable NSCLC patients underwent surgery. In addition, most of those patients underwent short-time follow-up. To date, no phase 3 clinical trial concerning induction immunotherapy/chemoimmunotherapy followed by surgery for unresectable stage III NSCLC has been published.

To further assess the efficacy and safety of induction chemoimmunotherapy plus surgery in initially unresectable stage III NSCLC patients, we retrospectively collected the data of stage I–III NSCLC patients underwent neoadjuvant/induction chemoimmunotherapy plus surgery, and categorized the whole study population into initially resectable and unresectable cohorts and compared the two cohorts both in efficacy and safety. This is the largest cohort study of unresectable NSCLC using the therapeutic strategy of induction chemoimmunotherapy plus surgery so far. The results substantiate the need to investigate the potential to convert the unresectable NSCLCs into operable ones. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-369/rc).

Methods

Data source

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of Shanghai Pulmonary Hospital (No. K24-009). Individual consent for this retrospective cohort study was waived. NSCLC patients underwent neoadjuvant/induction chemoimmunotherapy plus surgery were reviewed from the electronic medical records from January 2019 to December 2022 in Shanghai Pulmonary Hospital. Patients meeting the following criteria were included for analysis: (I) NSCLC diagnosed via histologic or cytologic examination; (II) stage IB-III disease according to the 8th edition of TNM staging criteria released by American Joint Committee on Cancer; (III) receipt of at least one cycle of neoadjuvant/induction chemoimmunotherapy and surgery; (IV) no other malignancies in the preceding five years; (V) having electronic medical records of baseline chest computed tomography (CT), brain magnetic resonance imaging or CT, abdominal CT or ultrasonography, whole body bone imaging or FDG-PET/CT; (VI) having at least one radiological response assessment using chest CT during neoadjuvant/induction therapy phase. At baseline, pathological examination via endobronchial ultrasound guided mediastinal lymph node puncture and ultra sound guided supraclavicular lymph node puncture were conducted per clinician’s discretion.

The details of treatment of PD-1/PD-L1 antibody and chemotherapy including the drug, dose, cycle, etc. were determined by the attending doctors, those who had no progressive disease after neoadjuvant/induction therapy were assessed for surgery. Multidisciplinary team discussed before the decision of each treatment mainly abiding by National Comprehensive Cancer Network guidelines or Chinese Society of Clinical Oncology guidelines, also considering the clinical course and preference of patients.

Study variables

Clinical variables were collected from electronic records including age, sex, smoking history, clinical stage (cStage), histological type, PD-L1 (E1L3N) expression, gene mutation, PD-1/PD-L1 antibody, neoadjuvant/induction therapy cycle, radiological response, baseline body mass index (BMI), preoperative BMI, surgical approach, surgical type. The variable we focus on is resectability at the time of diagnosis, which was stratified into resectable and unresectable. Radiological response was evaluated according to the edition 1.1 of Response Evaluation Criteria in Solid Tumors. As this a retrospective study, the resectability was classified according to the retrospective review of the patients’ imaging data by the researchers. Unresectable disease should be stage III and met one of the following criteria (20): (I) T4 invading root of the main vessels, trachea or other unresectable organs; (II) multistational N2; (III) stage IIIB or IIIC.

Endpoints and follow-up

The primary endpoint was the survival outcome of the study cohort, focusing on EFS, disease-free survival (DFS), and OS. EFS was defined as the beginning of diagnosis of NSCLC to recurrence, progression, or all-cause death. DFS was defined as the interval between surgery and recurrence or all-cause death whichever occured first. OS was calculated from the beginning of diagnosis of NSCLC to all-cause death. The second endpoints encompassed surgical results and safety metrics including downstaging of nodal status, MPR, pCR, surgical margin, surgical time, blood loss in surgery, length of hospital stay after surgery, 30-day mortality, and 90-day mortality. MPR denoted that the residual viable tumor in primary tumor bed is 10% or less, and pCR was defined as no residual tumor cell found both in primary tumor bed and resected lymph nodes. Data were collected via electronic medical records and telephone follow-up. Survival outcome lost to follow-up was deemed as censored data. The latest follow-up was August 23, 2024.

Statistical analysis

Continuous variables were presented as median [interquartile range (IQR)] and compared employing Mann-Whitney U test. Categorical variables were listed as number (percentage) and compared via χ² test or Fisher’s exact test as appropriate. EFS/DFS/OS curves were plotted using Kaplan-Meier method and the log-rank test was used to calculate P value. Propensity score matching (PSM) with a caliper of 0.05 and a ratio of 1:1 was used to diminish the difference of baseline characteristics between resectable and unresectable cohort. Covariables including age, sex, smoking history, cStage, histological type, PD-L1 (E1L3N) expression, gene mutation, PD-1/PD-L1 antibody, neoadjuvant/induction therapy cycle, radiological response, baseline BMI, preoperative BMI, surgical approach, and surgical type were adjusted in PSM between resectable and unresectable cohort. cStage was not adjusted in PSM because this variable highly correlated with resectability. A standardized mean difference of the baseline characteristics less than 0.1 was thought to be good balance. Univariable and multivariable Logistic regression were conducted to seek out the characteristics related to MPR/pCR. Similarly, univariable and multivariable Cox regression were performed to screen the prognostic factors of DFS/OS. Variables with P value <0.1 in univariable logistic/Cox regression were put into the multivariable logistic/Cox regression. The DFS/OS difference between unresectable and resectable cohort were also explored in subgroups of the covariables. In addition, sensitivity analysis was performed via comparation between resectable cohort and unresectable cohort with more advanced disease of cStage IIIB, IIIC or N3 separately. R, version 4.3.2 (R Project for Statistical Computing) was used for statistical analysis and plotting. A two-sided P<0.05 was thought to be statistical significance.

Results

Patient characteristics

Between January 2019 and December 2022, a total of consecutive 640 NSCLC patients were included in intention-to-treat analysis (EFS and OS), and a total of consecutive 425 NSCLC patients receiving surgery after neoadjuvant/induction chemoimmunotherapy were identified for DFS and OS comparation, comprising of 147 in initially resectable cohort and 278 in initially unresectable cohort (Figure 1). In the resectable cohort, 24 patients did not undergo surgery after neoadjuvant therapy, among whom 3 cases were due to disease progression, 2 cases were unresectable, and 19 cases refused surgery. In the unresectable cohort, 191 patients did not undergo surgery after induction therapy. Among them, 22 cases were due to disease progression, 4 cases were due to death, 106 cases remained unresectable, and 59 cases refused surgery. Age was categorized into <65 and ≥65 years old, and BMI was divided into <18.5, 18.5–24.9, and >24.9. The baseline characteristics including age, sex, smoking history, histological type, gene mutation, radiological response, baseline BMI, preoperative BMI, surgical approach, and surgical type had no statistical difference between resectable and unresectable cohort. However, the unresectable cohort had more advanced cStage, higher proportion of pembrolizumab or nivolumab use, and larger neoadjuvant/induction therapy cycle (Table 1). cStage was not adjusted in PSM given this variable highly correlated with resectability. After PSM, 122 patients were selected in both cohorts, and except for cStage, the baseline characteristics were all balanced with P value >0.3 (Table 1), and the standardized mean difference were all less than 0.1 or very close to 0.1 (Figure S1).

Figure 1 Flowchart of study cohort selection. NSCLC, non-smal l cell lung cancer.

Survival outcomes

The median follow-up time for the study cohort was 28.9 [95% confidential interval (CI): 27.4–29.9] months. Patients with unresectable disease showed worse EFS than those with resectable disease in the intention-to-treat population (Figure 2A). However, no significant difference in OS was observed in the intention-to-treat population (Figure 2B). In patients underwent surgery, the log-rank test exhibited no significant difference between unresectable and resectable cohort in DFS and OS both before and after PSM (Figure 3). Before PSM, the 1-, 2-, 3-year DFS rate for unresectable vs. resectable cohort were 85.2% vs. 90.4%, 74.7% vs. 74.0%, 68.7% vs. 66.2%, and the corresponding OS rates were 96.7% vs. 96.6%, 91.1% vs. 92.0%, 87.8% vs. 89.3%. After PSM, the 1-, 2-, 3-year DFS rate for unresectable vs. resectable cohort were 84.9% vs. 90.9%, 73.9% vs. 77.2%, 66.0% vs. 67.4%, and the corresponding OS rates were 95.0% vs. 95.9, 88.0% vs. 91.2%, 88.0% vs. 89.2%. Figure 4 demonstrated better DFS in patients who obtained MPR vs. non-MPR (P<0.001) and pCR vs. non-pCR (P<0.001), and significant different OS was observed in MPR vs. non-MPR (P=0.01) and pCR vs. non-pCR (P=0.04).

Figure 2 Survival outcome stratified by unresectable and resectable cohort in intention-to-treat population. Kaplan-Meier estimates of EFS (A) and OS (B) stratified by unresectable and resectable cohort before PSM. EFS, event-free survival; OS, overall survival; PSM, propensity score matching.

Figure 3 Survival outcome stratified by unresectable and resectable cohort in patients underwent surgery after neoadjuvant/induction chemoimmunotherapy. Kaplan-Meier estimates of DFS stratified by unresectable and resectable cohort before (A) and after (B) PSM, OS for study cohort before (C) and after (D) PSM. DFS, disease-free survival; OS, overall survival; PSM, propensity score matching.

Figure 4 Survival outcome stratified by pathological response. Kaplan-Meier estimates of DFS (A) and OS (B) stratified by non-MPR and MPR, DFS (C) and OS (D) stratified by non-pCR and pCR. DFS, disease-free survival; MPR, major pathological response; OS, overall survival; pCR, pathological complete response.

Characteristics related to DFS/OS/MPR/pCR

In the univariable Cox regression for DFS before and after PSM, the unresectable cohort achieved a point hazard ratio (HR) very close to 1 [HR before PSM: 0.95 (0.65–1.38), P=0.77; HR after PSM: 1.08 (0.66–1.76), P=0.75] (Table 2 and Table S1). In the univariable Cox regression for OS before and after PSM, no significant difference was observed [HR before PSM: 1.07 (0.57–2.02), P=0.83; HR after PSM: 1.40 (0.63–3.09), P=0.41] (Table 2 and Table S1). In the multivariable Cox regression for DFS/OS, the independent prognostic factors for DFS were histological type and PD-1/PD-L1 antibody, while none for OS (Table S1).

In the univariable Logistic regression for MPR/pCR, the unresectable cohort was more likely to achieve MPR [odds ratio (OR) before PSM: 1.37 (0.91–2.05), P=0.13; OR after PSM: 1.49 (0.90–2.48), P=0.12] or pCR [OR before PSM: 1.45 (0.94–2.25), P=0.09; OR after PSM: 1.40 (0.82–2.40), P=0.22] but without statistical significance (Table 2 and Table S2). In the multivariable logistic regression for MPR/pCR, the independent related variables were histological type, PD-L1 expression, gene mutation, PD-1/PD-L1 antibody, radiological response, and baseline BMI for MPR, and the corresponding variables were sex, histological type, PD-L1 expression, gene mutation, PD-1/PD-L1 antibody, and surgical approach for pCR (Table S2).

Subgroup and sensitivity analysis for DFS/OS

The forest plot indicated no significant DFS/OS difference between unresectable and resectable cohort in all subgroups (Figures S2,S3). In the sensitivity analysis, there were also no obvious contrast in DFS/OS between unresectable cohort with more advanced disease of cStage IIIB/IIIC or N3 compared with resectable cohort respectively (Figure S4).

Surgical and safety results

Only one patient underwent video-assisted thoracotomy exploration and was found to be unresectable. This patient underwent radiotherapy subsequently, and experienced disease progression 7.5 months after the end of radiotherapy, and the patient was still alive at the last follow-up (26.8 months). As shown in Table 3, of all the surgical and safety results, only downstaging of nodal status (P<0.001) and surgical time (P=0.001) were significantly different between unresectable and resectable cohorts. Both cohorts had the highest proportion of downstaging from N2 to N0, while the unresectable cohort had 32 patients with N3 disease downstaged to N0/1/2 which was not seen in resectable cohort, and the unresectable cohort presented less downstaging from N1 to N0. Surgical time in unresectable cohort was only 15 minutes longer than resectable cohort which is acceptable. The MPR rate in unresectable and resectable cohort were 60.1% vs. 52.4%, and the corresponding pCR rates were 36.0% vs. 27.9%, both higher in the unresectable cohort with no statistical significance. In the unresectable cohort, only 1 of 277 patients (0.4%) underwent R1 resection, and all the resectable cohort had R0 resection. Blood loss in surgery and length of hospital stay after surgery in the two cohorts were both 50.0 (IQR: 50.0–100.0) mL and 5.0 (IQR: 4.0–7.0) days respectively. The 30-day and 90-day mortality rate in unresectable vs. resectable cohort were 1.1% vs. 0.7% and 1.8% vs. 0.7%.

Discussion

Only a few studies have investigated induction chemoimmunotherapy plus surgery in unresectable NSCLC, with sample sizes ranging from 11 to 112 (16-27). As far as we know, our study is the largest one in terms of the special therapeutic strategy with a sample size of 425 consisting 278 patients with unresectable NSCLC and 147 with resectable disease, adding more powerful evidence to the eligibility of reevaluation for resection after chemoimmunotherapy.

The breakthrough of PACIFIC trial makes the consolidation of durvalumab after concurrent chemoradiotherapy become the standard of care for unresectable stage III NSCLC, bringing a 1-, 3-, and 5-year OS rate of 83.1%, 56.7%, and 42.9% (13). Recently, Wu et al. reported induction chemoimmunotherapy plus definitive chemoradiotherapy could bring a median OS of 41.9 months for unresectable stage III NSCLC in a retrospective multicenter study (28). Although this number seemed to be smaller than 47.5 months in the consolidation therapy arm in PACIFIC trial, it should be noted that the PACIFIC trial only included patients who had partial/complete response or stable disease after concurrent chemoradiotherapy which was a selected population, while Wu et al.’s research included intention-to-treatment patients—in other words, patients achieved progressive disease in the induction phase were also put into the survival analysis. However, in some patients, induction chemoimmunotherapy could reverse the positive lymph nodes and eliminate the minimal metastasis systemically, rendering the chance of resection for those traditionally considered unresectable disease. Thus, the seeking for new therapeutic strategies to break the bottleneck of PACIFIC mode is needed. A recent retrospective study using National Cancer Database compared the OS between neoadjuvant chemoimmunotherapy plus surgery (N=93) and concurrent chemoradiation followed by immunotherapy (N=3,289) in stage T1–3N2M0 NSCLC, and found better OS in surgery group, however, most of the surgery group was with initially resectable disease instead of unresectable or more advanced NSCLC (29). No phase III trial can change the unbudgeable position of PACIFIC mode in unresectable stage III NSCLC right now, but the aforementioned small sample-sized trials and retrospective studies encourage us to make some exploration.

In the present study, the 1-, 2-, and 3-year DFS rates in the unresectable cohort receiving surgery were about 85.2%, 74.7%, and 68.7%, and the corresponding OS rates were 96.7%, 91.1%, and 87.8%. All those data were surprisingly high and comparable with those in resectable cohort receiving surgery. Previous studies reported a 2-year DFS rate of 55–88% (16,18,19,21,22) and a 2-year OS rate of 76–100% (17,20-22), aligning with our results. However, the 3-year DFS and 3-year OS were only reported in the 20 patients receiving surgery in Neo-Pre-IC trial which were 75% and 80% (21). Other studies did not show the 3-year DFS/OS because of short follow-up. The survival outcome after PSM presented that the point estimate of HR for unresectable vs. resectable cohort concerning DFS and OS were 1.08 (P=0.75) and 1.40 (P=0.41), showing no significant difference. The subgroup analysis in the whole study cohort displayed no evident contrast between the two cohorts in all subgroups, making the main results more solid. This comparation supported that the unresectable need not be considered unresectable persistently. After induction therapy, even the cStage IIIB, IIIC, and N3 with resectable disease in reevaluation obtained comparable DFS/OS to initially resectable tumors (Figure S4). Raman et al. investigated the stage N3 NSCLC data in the National Cancer Database, and found those underwent surgery had similar or worse short-term but better long-term OS compared with those had chemoradiation in the 935 pairs of patients (30). This study used data of NSCLC diagnosed in 2004–2015 when no PD-1/PD-L1 antibody had the U.S. FDA indication approval of first-line treatment in NSCLC. In the era of immunotherapy, uniting chemoimmunotherapy with surgery may further improve the long-term survival compared with chemoradiation for stage N3 disease.

To be noted, it is not all but part (278/469, Figure 1) of the initially unresectable stage III and oligometastatic IV NSCLCs underwent surgery after induction therapy, and the probability of resection rate was about 31–68%, while, in fact, the success rate of induction might be higher taking into account that some patients refused surgery at their own discretion after successful induction therapy (16-18,20-22). Some radiologists worried about the unresectable stage III NSCLC which were still unresectable or progressive disease after induction therapy might miss the standard care of chemoradiation per PACIFIC mode (15). But induction chemoimmunotherapy plus chemoradiation was also a good choice for those patients, demonstrated in Wu et al.’s Chinese multi-institutional investigation with a median OS of 41.9 months for the whole study cohort in which progressive disease after induction therapy was included (28). In Wu et al.’s study cohort, 16.5% achieved progressive disease, and at most only 7.0% of the study cohort missed the chance of definitive radiotherapy (28). In addition, most of the chemoradiation in the induction therapy arm in Wu et al.’s real-world study was sequential with a percentage of 63.3% because a large proportion of Chinese patients could not tolerate or accept the adverse effects of concurrent chemoradiation, although 66.7% of the GEMSTONE-301’s cohort received concurrent chemoradiation (14,28). That is to say, the real world might be different from the clinical trial. Overall, Wu et al.’s study was complementary with ours: for patients with initially unresectable stage III NSCLCs, after induction chemoimmunotherapy, those with tumor converted into resectable could be suggested to have surgery, while those with persistent unresectable disease or refused surgery could be evaluated for sequential or concurrent chemoradiation, and only a small proportion of the intention-to-treat patients might lose the opportunity for radical therapy which was acceptable.

As for the resection margin and safety concerns raised by Moghanaki et al. (15), our study presented only one patient underwent R1 resection in the unresectable cohort (N=278) with a median blood loss of 50 mL, a median length of hospital stay after surgery of 5 days, a 30- and 90-day mortality rate of 1.1% and 1.8%, indicating a high rate of complete resection and good safety. The median surgical time of the unresectable cohort was only 15 minutes longer than the resectable cohort which had no clinical significance.

Although the present study showed promising efficacy and safety in induction chemoimmunotherapy plus surgery for initially unresectable stage III NSCLC, some limitations have to be illustrated. First, the retrospective nature of this study might introduce confounding bias, so prospective clinical trial is needed to further validate the aforementioned results. Second, the unresectable cohort receiving surgery is a highly selected population for 40.7% of the unresectable cohort did not receive surgery, and the comparation between unresectable and the resectable cohort receiving surgery is only for reference and preliminarily exploring the survival outcome, although we used an initially resectable cohort as a control and adjusted the confounders using PSM and subgroup/sensitivity analysis. Third, the PD-L1 expression level could not be identified in about half of the patients. Fourth, long-term survival data could not be obtained currently.

Conclusions

Our study demonstrates that surgical resection can provide favorable survival outcomes and an acceptable safety profile for patients with initially unresectable stage III NSCLC following successful conversion to resectability through induction chemoimmunotherapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-369/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-369/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-369/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-369/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of Shanghai Pulmonary Hospital (No. K24-009). Individual consent for this retrospective cohort study was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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