Abstract
Background
Neoadjuvant chemoimmunotherapy (nCIT) has become the standard-of-care for resectable non-small cell lung cancer (NSCLC), due to its significant improvements in event-free survival (EFS) and overall survival (OS). However, the feasibility of conversion chemoimmunotherapy (CIT) in potentially resectable NSCLC remains unclear. In this context, this study will provide more reliable real-world data to support the robust efficacy of CIT in patients with potentially resectable NSCLC.
Methods
This retrospective analysis enrolled patients with potentially resectable NSCLC who had no active oncogene mutation and underwent conversion therapy at four cancer centers between January 2021 and March 2024. All patients received either chemotherapy (CT) or CIT as conversion regimens. After 1:n propensity score matching (PSM), efficacy and safety were compared between groups using the following endpoints: surgical conversion rate, major pathological response (MPR) rate, pathological complete response (pCR) rate, EFS, and treatment-related adverse events (TRAEs).
Results
A total of 334 patients were enrolled, with 252 in the CIT group and 82 in the CT group. After PSM, the final cohort comprised 196 patients in the CIT group and 78 in the CT group. CIT treatment showed significantly higher surgical conversion rate vs. CT (73.5% vs. 60.3%; P=0.03). After PSM analysis in the surgical cohort, 131 patients were matched to the CIT group and 49 to the CT group. Compared with CT, CIT obtained higher rates of MPR (60.3% vs. 20.4%; P<0.001) and pCR (39.7% vs. 12.2%; P<0.001), as well as significantly improved EFS [hazard ratio (HR) =0.28; 95% confidence interval (CI): 0.14–0.55; P<0.001]. Subgroup analysis revealed more obvious EFS benefit with CIT among patients with younger age (HR =0.172; 95% CI: 0.081–0.364; P=0.001), squamous cell carcinoma (SCC) (HR =0.197; 95% CI: 0.094–0.411; P=0.001), N2–3 (HR =0.279; 95% CI: 0.136–0.571; P=0.001), and stage III diseases (HR =0.347; 95% CI: 0.187–0.644; P=0.001). The incidence of TRAEs was comparable between the two groups, with nausea (27.5% vs. 22.4%), neutropenia (22.1% vs. 12.2%), and anorexia (17.6% vs. 14.3%) being the most common in both groups, with no other clinically significant immune-related adverse events (irAEs) observed. Furthermore, in the subset of 184 patients who achieved R0 resection following CIT, MPR was identified as an independent predictor of improved EFS (HR =0.305; 95%CI: 0.086–0.978; P=0.04).
Conclusions
In this retrospective cohort, CIT was associated with higher surgical conversion rates, MPR, pCR, and improved EFS vs. CT, with comparable safety. These findings support prospective evaluation of CIT in potentially resectable NSCLC.
Keywords: Non-small cell lung cancer (NSCLC), conversion therapy, chemoimmunotherapy (CIT), chemotherapy (CT), propensity score matching (PSM)
Highlight box.
Key findings
• In potentially resectable non-small cell lung cancer (NSCLC), chemoimmunotherapy (CIT) showed superior surgical conversion rates, major pathological response rate, pathological complete response rate, and event-free survival, but comparable safety vs. chemotherapy.
What is known and what is new?
• Neoadjuvant CIT (nCIT) has become the standard-of-care for resectable NSCLC. However, the feasibility of conversion CIT in potentially resectable NSCLC remains unclear.
• CIT may become the preferred scheme for the conversion therapy of potentially resectable NSCLC.
What is the implication, and what should change now?
• Further validation through prospective multicenter clinical trials is warranted.
Introduction
Lung cancer remains the leading cause of cancer-related mortality worldwide (1,2). Non-small cell lung cancer (NSCLC) constitutes the predominant pathological subtype, representing 80–85% of all lung cancer cases (3). Surgery is considered the most important curative strategy for resectable NSCLC. However, approximately 20% of locally advanced NSCLC are diagnosed as potentially resectable due to the invasion of the tumor into vital structures (e.g., main vessel roots, trachea, or other unresectable organs) or the presence of multiple enlarged ipsilateral mediastinal lymph nodes (4-7). For these patients, direct radical resection of tumors is technically challenging, and conversion therapy is needed to downstage the tumors. Previously, chemotherapy (CT) was considered the standard strategy for conversion therapy. However, the pathological complete response (pCR) rates and the long-term postoperative survival after CT remain limited, with major pathological response (MPR) rates of <20%, pCR rates of only 6–8%, and a 5-year overall survival (OS) of less than 30% (8-11).
In recent years, immunotherapy based on programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has transformed the treatment landscape for resectable NSCLC (12-15). Extensive clinical evidence has demonstrated superior pathological response rates and event-free survival (EFS) of neoadjuvant chemoimmunotherapy (nCIT) over neoadjuvant CT (nCT), with MPR rates of 30–60% and pCR rates exceeding 20% (16-20). In patients with potentially resectable stage III NSCLC, two single-arm studies reported that preoperative sintilimab (PD-1 inhibitor) plus CT achieved a complete resection rate of 67–90% and a pCR rate of 22.2–40% (6,21). However, these studies had a very limited sample size (30–40 patients). Furthermore, there is a lack of comparative studies between chemoimmunotherapy (CIT) and CT regimens in this subpopulation.
Here, using the real-world data from 334 NSCLC patients with potentially resectable diseases, we systematically compared the efficacy and safety of CIT vs. CT as conversion therapy. We proposed that CIT would improve the surgical conversion rates compared with CT. We also evaluated the pathological response rates (MPR and pCR), R0 resection rates, and long-term survival outcomes (particularly EFS). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0561/rc).
Methods
Patients
This study enrolled potentially resectable NSCLC patients at Shandong Cancer Hospital and Institute, Public Health Clinical Center Affiliated to Shandong University, Qilu Hospital of Shandong University, and Shandong Provincial Hospital between January 2021 and March 2024. All the patients received CIT or CT as conversion therapy. Inclusion criteria are as follows: (I) histologically confirmed NSCLC [according to the World Health Organization (WHO) 2021 classification]; (II) stage II/III according to Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging standards (8th edition) and deemed potentially resectable by a multidisciplinary team (MDT); they were generally classified into the following four categories: (i) central Stage II tumors where the lesion is closely adherent to critical structures such as the main bronchus, pulmonary artery, or pericardium, precluding R0 resection via direct surgery (22); (ii) T1–2 with multi-station N2 disease (non-massive or non-invasive) or massive N2 disease; (iii) T3–4 with multi-station N2 disease (non-massive or non-invasive); (iv) T4 (invasive) with N0–1 or single-station N2 disease (non-massive or non-invasive) (23-28); (III) completion of at least one cycle of platinum-based doublet CT, consisting of albumin-bound paclitaxel plus platinum for squamous cell carcinoma (SCC) and pemetrexed plus platinum for non-squamous carcinoma, with or without PD-1/PD-L1 inhibitors (tislelizumab, sintilimab, camrelizumab, toripalimab, nivolumab, pembrolizumab, or atezolizumab). Patients were excluded if they met any of the following criteria: (I) prior anti-tumor treatment before admission; (II) a second primary tumor requiring treatment; (III) another condition that might affect survival; (IV) unavailability of detailed clinicopathologic and follow-up information.
Data collection
Initial evaluation and staging routinely include contrast-enhanced computed tomography (CT) of the neck, chest, abdomen, and pelvis, brain magnetic resonance imaging (MRI), and radionuclide bone scanning. For patients with suspected mediastinal lymph node metastasis, positron emission tomography-computed tomography (PET/CT) or endobronchial ultrasound-guided biopsy (EBUS) is performed. Baseline demographic and clinical characteristics, including age, sex, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status, clinical stage (AJCC 8th edition), histologic subtype, PD-L1 expression level, and disease progression, were collected from electronic medical records. Information was also gathered for conversion therapy and surgical procedures, including treatment regimen, number of cycles, extent of resection, surgical margin status, and pathological staging (ypTNM). Treatment-related adverse events (TRAEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (No. SDTHEC202411001) and was approved by all participating institutions. Due to the retrospective nature of the study, the ethics committee granted an exemption from the requirement for informed consent.
Conversion therapy and pathological evaluation
Conversion therapy was defined as a treatment strategy aimed at achieving R0 resection in patients with potentially resectable NSCLC. R0 resection and pathological response were assessed according to the 2020 International Association for the Study of Lung Cancer (IASLC) consensus criteria. R0 resection was defined as complete tumor excision with microscopically negative margins, systematic nodal dissection, and negative highest mediastinal lymph nodes. pCR was defined as the absence of viable tumor cells in both the primary lesion (ypT0) and resected lymph nodes (ypN0). MPR was defined as ≤10% viable tumor cells remaining in the primary tumor bed.
Surgical procedures
The predominant surgical approaches in this study were video-assisted thoracoscopic (VATS) lobectomy and conventional open lobectomy, both accompanied by systematic mediastinal lymph node dissection. In accordance with the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines, anatomical lobectomy with systematic lymph node dissection was the standard procedure for all resectable cases. Following the IASLC recommendations, systematic lymphadenectomy required dissection of at least six lymph node stations, including three or more mediastinal (N2) stations with mandatory inclusion of the subcarinal station (station 7), and the highest mediastinal lymph node was required to be pathologically negative.
Clinical endpoints
The primary endpoints included surgical conversion rate (defined as the proportion of patients with borderline resectable or initially unresectable disease who achieved R0 resection after conversion therapy), and EFS [defined as the time from treatment initiation (baseline) to the first occurrence of any of the following events: disease progression rendering the patient inoperable, unresectability at the time of planned surgery, postoperative local or distant recurrence, or death from any cause; for patients who were alive and event-free at the last follow-up, data were censored at that time point]. Secondary endpoints encompassed pCR rate, MPR rate, R0 resection rate [defined as microscopically negative margins according to the College of American Pathologists (CAP) protocol], pathological downstaging rate [reduction of ≥1 tumor-node-metastasis (TNM) stage category based on the IASLC 8th edition criteria], and safety. The subgroup analysis focuses on examining potential biomarker associations with clinical outcomes, including genomic alterations, PD-L1 tumor proportion score (TPS), and histopathological differentiation patterns.
Statistical analysis
Statistical analysis was performed using SPSS Statistics version 27.0 (IBM SPSS, IBM Corp.; Armonk, NY, USA), GraphPad Prism (version 9.0), and R version 4.1.3 (R Foundation for Statistical Computing). Baseline categorical variables were compared using the Chi-squared test or Fisher’s exact test, and results are presented as frequencies and percentages. Propensity score matching (PSM) was performed to control confounding factors. The propensity score for the CIT vs. CT groups was calculated using a logistic regression model with covariates including age, sex, smoking history, histology, pretreatment clinical stage, KRAS/TP53 gene status, PD-L1 expression level, and treatment cycle. To maximize statistical power while maintaining rigorous confounding control, we adopted variable-ratio matching with a strict caliper of 0.05 of the logit of the propensity score. Finally, patients who underwent conversion therapy and those in the surgery cohort were matched at actual ratios of 1:2.51 and 1:2.67, respectively. The quality of the matches was assessed by comparing the standardized mean differences (SMDs) of covariates between the pre-matching and post-matching groups. The matched cohorts were then used to compare conversion rates, postoperative pathological response rates, and long-term survival between the two groups. In the matched cohort, between-group comparisons were performed using unpaired statistical tests, with the Chi-squared test or Fisher’s exact test applied to categorical variables and the independent-samples t-test or Wilcoxon rank-sum test applied to continuous variables, as appropriate. EFS was analyzed through the Kaplan-Meier method and compared using the log-rank test. Subgroup analysis forest plots were generated using R version 4.1.3. Univariate and multivariate Cox regression analyses were used to calculate hazard ratios (HRs) for EFS and to explore prognostic clinical factors. Statistical significance was set at P<0.05.
Results
Patient enrollment
This retrospective study analyzed 334 patients with potentially resectable NSCLC at four collaborating institutions (Shandong Cancer Hospital and Institute, Public Health Clinical Center Affiliated to Shandong University, Qilu Hospital of Shandong University, and Shandong Provincial Hospital; January 2021–March 2024). Potentially resectable status was determined through MDT assessment based on imaging, pathological, and clinical criteria. The choice of conversion therapy (CIT vs. CT alone) was individualized according to performance status, tolerability, drug availability, and financial considerations, rather than a predefined protocol. This real-world allocation may have introduced selection bias, which was subsequently addressed by PSM. Of the 334 patients, 252 received conversion CIT and 82 received CT (Figure 1). Following PSM, the final cohort comprised 196 patients in the CIT group and 78 in the CT group. As shown in Table 1, both cohorts demonstrated comparable baseline characteristics. A majority of patients in CIT and CT groups were male (92.5% vs. 86.6%), had an ECOG performance status of 0–1 (99.2% vs. 100.0%), and staged III before treatment (AJCC 8th edition; 95.2% vs. 92.7%). SCC was the most common histologic subtype in both cohorts (CIT 76.6% vs. CT 56.1%). Genetic profiling revealed a similar prevalence of KRAS (4.0% vs. 6.1%) and TP53 (3.6% vs. 3.7%) mutations between groups. After PSM, all covariates had SMDs below 0.2, and the majority were below 0.1, indicating adequate balance (Table 1).
Figure 1.
Methodological diagram of the study. CIT, chemoimmunotherapy; CT, chemotherapy; NSCLC, non-small cell lung cancer; PSM, propensity score matching.
Table 1. Clinical baseline characteristics of patients in both groups before and after PSM.
| Characteristic | Before PSM (N=334) | After PSM (N=274) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| CIT (n=252) | CT (n=82) | P value | SMD | CIT (n=196) | CT (n=78) | P value | SMD | ||
| Age, years | 0.19 | −0.168 | 0.91 | −0.015 | |||||
| <65 | 138 (54.8) | 38 (46.3) | 97 (49.5) | 38 (48.7) | |||||
| ≥65 | 114 (45.2) | 44 (53.7) | 99 (50.5) | 40 (51.3) | |||||
| Sex | 0.11 | 0.192 | 0.58 | 0.072 | |||||
| Male | 233 (92.5) | 71 (86.6) | 180 (91.8) | 70 (89.7) | |||||
| Female | 19 (7.5) | 11 (13.4) | 16 (8.2) | 8 (10.3) | |||||
| Smoking history | 0.25 | 0.145 | 0.33 | 0.130 | |||||
| Yes | 177 (70.2) | 52 (63.4) | 140 (71.4) | 51 (65.4) | |||||
| No | 75 (29.8) | 30 (36.6) | 56 (28.6) | 27 (34.6) | |||||
| ECOG performance status | 0.42 | 0.126 | – | 0.000 | |||||
| 1 | 250 (99.2) | 82 (100.0) | 196 (100.0) | 78 (100.0) | |||||
| 2 | 2 (0.8) | 0 | 0 | 0 | |||||
| KRAS gene | 0.26 | 0.194 | 0.55 | 0.133 | |||||
| Positive | 10 (4.0) | 5 (6.1) | 8 (4.1) | 4 (5.1) | |||||
| Negative | 39 (15.5) | 18 (22.0) | 35 (17.9) | 18 (23.1) | |||||
| Unknown | 203 (80.6) | 59 (72.0) | 153 (78.1) | 56 (71.8) | |||||
| TP53 gene | 0.40 | 0.129 | 0.56 | 0.131 | |||||
| Positive | 9 (3.6) | 3 (3.7) | 6 (3.1) | 3 (3.8) | |||||
| Negative | 39 (15.5) | 18 (22.0) | 35 (17.9) | 18 (23.1) | |||||
| Unknown | 204 (81.0) | 61 (74.4) | 155 (79.1) | 57 (73.1) | |||||
| PD-L1 expression rate | 0.81 | 0.021 | 0.99 | −0.008 | |||||
| <1% | 23 (9.1) | 8 (9.8) | 19 (9.7) | 7 (9.0) | |||||
| 1–49% | 22 (8.7) | 6 (7.3) | 15 (7.7) | 6 (7.7) | |||||
| ≥50% | 17 (6.7) | 8 (9.8) | 15 (7.7) | 7 (9.0) | |||||
| Unknown | 190 (75.4) | 60 (73.2) | 147 (75.0) | 58 (74.4) | |||||
| Clinical stages | 0.37 | 0.107 | 0.67 | 0.056 | |||||
| II | 12 (4.8) | 6 (7.3) | 10 (5.1) | 5 (6.4) | |||||
| III | 240 (95.2) | 76 (92.7) | 186 (94.9) | 73 (93.6) | |||||
| Histological type | 0.002 | 0.225 | 0.051 | 0.108 | |||||
| Adenocarcinoma | 48 (19.0) | 29 (35.4) | 45 (23.0) | 26 (33.3) | |||||
| Squamous carcinoma | 193 (76.6) | 46 (56.1) | 142 (72.4) | 45 (57.7) | |||||
| Other | 11 (4.4) | 7 (8.5) | 9 (4.6) | 7 (9.0) | |||||
Data are presented as n (%). CIT, chemoimmunotherapy; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death-ligand 1; PSM, propensity score matching; SMD, standardized mean difference.
Surgical conversion rate and R0 resection rate
Following conversion therapy, 184 patients in the CIT group underwent surgery compared with 50 in the CT group, yielding surgical conversion rates of 73.0% and 61.0%, respectively (P=0.04). In the matched cohort after PSM, 144 patients in the CIT group and 47 in the CT group underwent surgical resection, with conversion rates of 73.5% [144/196, 95% confidence interval (CI): 67.2–79.7%] vs. 60.3% (47/78, 95% CI: 49.2–71.4%; P=0.03). Furthermore, before and after PSM, all patients who ultimately underwent surgical resection achieved R0 resection in both treatment groups (Table 2).
Table 2. Comparison of surgical conversion and R0 resection rates in matched cohorts.
| Outcome | Before PSM (N=334) | After PSM (N=274) | |||||
|---|---|---|---|---|---|---|---|
| CIT (n=252) | CT (n=82) | P value | CIT (n=196) | CT (n=78) | P value | ||
| Surgical resection | |||||||
| Surgery | 184 (73.0, 67.5–78.5) | 50 (61.0, 50.2–71.8) | 0.04 | 144 (73.5, 67.2–79.7) | 47 (60.3, 49.2–71.4) | 0.03 | |
| Non-surgery | 68 (27.0, 21.5–32.5) | 32 (39.0, 28.2–49.8) | 0.04 | 52 (26.5, 20.3–32.8) | 31 (39.7, 28.6–50.8) | 0.03 | |
Data are presented as n (%, 95% CI). CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; PSM, propensity score matching.
Postoperative pathologic remission and long-term survival
To evaluate pathological response and long-term survival outcomes following conversion therapy, we identified 234 patients who underwent R0 resection, comprising 184 recipients of CIT and 50 of CT. After PSM in this surgical cohort, all covariates had SMDs below 0.2 (Table 3).
Table 3. Clinical baseline characteristics of the two groups of surgical patients before and after PSM.
| Characteristic | Before PSM (N=234) | After PSM (N=180) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| CIT (n=184) | CT (n=50) | P value | SMD | CIT (n=131) | CT (n=49) | P value | SMD | ||
| Age, years | 0.71 | 0.059 | 0.61 | 0.085 | |||||
| <65 | 105 (57.1) | 30 (60.0) | 72 (55.0) | 29 (59.2)) | |||||
| ≥65 | 79 (42.9) | 20 (40.0) | 59 (45.0) | 20 (40.8) | |||||
| Sex | 0.02 | 0.324 | 0.12 | 0.182 | |||||
| Male | 168 (91.3) | 40 (80.0) | 118 (90.1) | 40 (81.6) | |||||
| Female | 16 (8.7) | 10 (20.0) | 13 (9.9) | 9 (18.4) | |||||
| Smoking history | 0.26 | 0.176 | 0.72 | 0.060 | |||||
| Yes | 126 (68.5) | 30 (60.0) | 84 (64.1) | 30 (61.2) | |||||
| No | 58 (31.5) | 20 (40.0) | 47 (35.9) | 19 (38.8) | |||||
| Clinical stages | 0.07 | 0.256 | 0.17 | 0.169 | |||||
| II | 9 (4.9) | 6 (12.0) | 8 (6.1) | 6 (12.2) | |||||
| III | 175 (95.1) | 44 (88.0) | 123 (93.9) | 43 (87.8) | |||||
| Histological type | 0.07 | −0.076 | 0.052 | 0.024 | |||||
| Adenocarcinoma | 40 (21.7) | 13 (26.0) | 23 (17.6) | 13 (26.5) | |||||
| Squamous carcinoma | 134 (72.8) | 30 (60.0) | 102 (77.9) | 30 (61.2) | |||||
| Other | 10 (5.4) | 7 (14.0) | 6 (4.6) | 6 (12.2) | |||||
| KRAS gene | 0.99 | 0.018 | 0.55 | 0.165 | |||||
| Positive | 10 (5.4) | 3 (6.0) | 4 (3.1) | 3 (6.1) | |||||
| Negative | 37 (20.1) | 10 (20.0) | 23 (17.6) | 10 (20.4) | |||||
| Unknown | 137 (74.5) | 37 (74.0) | 104 (79.4) | 36 (73.5) | |||||
| TP53 gene | 0.28 | −0.160 | 0.58 | 0.025 | |||||
| Positive | 9 (4.9) | 0 | 2 (1.5) | 0 | |||||
| Negative | 37 (20.1) | 11 (22.0) | 24 (28.3) | 11 (22.4) | |||||
| Unknown | 138 (75.0) | 39 (78.0) | 105 (80.2) | 38 (77.6) | |||||
| PD-L1 expression rate | 0.61 | −0.100 | 0.22 | 0.027 | |||||
| <1% | 14 (7.6) | 3 (6.0) | 10 (7.6) | 3 (6.1) | |||||
| 1–49% | 19 (10.3) | 3 (6.0) | 9 (6.9) | 3 (6.1) | |||||
| ≥50% | 14 (7.6) | 6 (12.0) | 5 (3.8) | 6 (12.2) | |||||
| Unknown | 137 (74.5) | 38 (76.0) | 107 (81.7) | 37 (75.5) | |||||
| Treatment cycle | 0.01 | 0.512 | 0.04 | 0.034 | |||||
| 1 period | 2 (1.1) | 1 (2.0) | 2 (1.5) | 0 | |||||
| 2 period | 94 (51.1) | 38 (76.0) | 90 (68.7) | 38 (77.6) | |||||
| 3 period | 72 (39.1) | 9 (18.0) | 39 (29.8) | 9 (18.4) | |||||
| 4–5 period | 16 (8.7) | 2 (4.0) | 0 | 2 (4.1) | |||||
Data are presented as n (%). CIT, chemoimmunotherapy; CT, chemotherapy; PD-L1, programmed death-ligand 1; PSM, propensity score matching; SMD, standardized mean difference.
Replace this paragraph with: Before PSM, the MPR rates were 57.1% in the CIT group versus 30.0% in the CT group (P<0.001), and the pCR rates were 39.1% versus 24.0% (P=0.048); no statistically significant difference was observed in pathological downstaging (Table 4; Figure 2A,2B).
Table 4. Comparison of response and surgical resection after PSM.
| Outcomes | Before PSM (N=234) | After PSM (N=180) | |||||
|---|---|---|---|---|---|---|---|
| CIT (n=184) | CT (n=50) | P value | CIT (n=131) | CT (n=49) | P value | ||
| Pathological remission | |||||||
| MPR | 105 (57.1, 49.8–64.3) | 15 (30.0, 16.8–43.2) | <0.001 | 79 (60.3, 51.8–68.8) | 10 (20.4, 8.7–32.1) | <0.001 | |
| pCR | 72 (39.1, 32.0–46.2) | 12 (24.0, 11.7–36.3) | 0.048 | 52 (39.7, 31.2–48.2) | 6 (12.2, 2.7–21.8) | <0.001 | |
| Surgical resection | |||||||
| R0 | 184 (100, 98.0–100) | 50 (100, 92.9–100) | 131 (100, 97.2–100) | 49 (100, 92.7–100) | |||
| Downstaging rate | |||||||
| Pathologic | 146 (79.3, 73.4–85.3) | 39 (78.0, 66.1–89.9) | 0.84 | 106 (80.9, 74.1–87.7) | 38 (77.6, 65.4–89.7) | 0.62 | |
Data are presented as n (%, 95% CI). CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; MPR, major pathological response; pCR, pathological complete response; PSM, propensity score matching.
Figure 2.
Comparison of MPR and pCR rates between the CIT and CT groups. (A) MPR before PSM. (B) pCR before PSM. (C) MPR after PSM. (D) pCR after PSM. P values were derived from Chi-squared tests. CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; MPR, major pathological response; pCR, pathological complete response; PSM, propensity score matching.
After 1:2.67 PSM, 180 patients were retained (131 CIT vs. 49 CT) (Table 3). In this matched cohort, the CIT group continued to demonstrate significantly higher MPR rates (60.3% vs. 20.4%; P<0.001) and pCR rates (39.7% vs. 12.2%; P<0.001) compared with the CT group (Table 4; Figure 2C,2D). For long‑term survival, the CIT group was associated with significantly improved EFS compared with the CT group (HR =0.29; 95% CI: 0.15–0.57; P<0.001; median EFS: not reached vs. 34.0 months) (Figure 3A). Long‑term analysis further revealed that CIT was associated with significantly prolonged EFS (HR =0.28; 95% CI: 0.14–0.55; P<0.001; median EFS: not reached vs. 33.9 months). The 2‑year and 3‑year EFS rates in the matched cohort were 60.3% and 30.5% for the CIT group, compared with 48.9% and 14.3% for the CT group, respectively (Figure 3B). However, given the immature survival data, these EFS results should be considered preliminary and warrant prolonged follow-up. These findings collectively confirm that CIT treatment generated superior survival outcomes compared with CT in patients with potentially resectable NSCLC.
Figure 3.
Kaplan-Meier EFS in patients receiving CIT vs. CT, before (A) and after (B) PSM. CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; EFS, estimates of event-free survival; HR, hazard ratio; NR, not reached; PSM, propensity score matching.
Subgroup analysis of EFS
To better identify optimal candidates for CIT, we performed a subgroup analysis. As shown in Figure 4, EFS was significantly superior after CIT among patients with ages <65 years (HR =0.172; 95% CI: 0.081–0.364; P=0.001), SCC (HR =0.197; 95% CI: 0.094–0.411; P=0.001), N2–3 (HR =0.279; 95% CI: 0.136–0.571; P=0.001), and stage III diseases (HR =0.347; 95% CI: 0.187–0.644; P=0.001), compared with their counterparts, respectively. Furthermore, patients with different smoking statuses and clinical T stages displayed consistent benefit from CIT (Figure 4).
Figure 4.
The forest plot of EFS in subgroups. CI, confidence interval; CIT, chemoimmunotherapy; CT, chemotherapy; EFS, event-free survival; ICI + Chemo, immune checkpoint inhibitor + chemotherapy; TNM, tumor-node-metastasis.
Safety
During conversion therapy, both groups of patients experienced TRAEs of varying severity, but no treatment-related deaths occurred. Analysis of the PSM cohorts demonstrated comparable incidences of TRAEs, with nausea (27.5% vs. 22.4%), neutropenia (22.1% vs. 12.2%), and anorexia (17.6% vs. 14.3%) being the most common in both groups. Grade 3 or higher TRAEs were reported in 21 patients (16.0%) in the CIT group and 8 patients (16.3%) in the CT group. In the CIT group, the most frequent grade ≥3 TRAE was nausea (n=7, 5.3%). In the CT group, the most common grade ≥3 TRAEs were neutropenia (n=2, 4.1%), anorexia (n=2, 4.1%), and platelet count decrease (n=2, 4.1%). Regarding surgery-related adverse events, three grade ≥3 events occurred in the CIT group, comprising pleural effusion (n=2, 1.5%) and chylothorax (n=1, 0.8%). One grade ≥3 surgery-related adverse event, postoperative pneumonia (n=1, 2.0%), was recorded in the CT group. In the CIT group, grade ≥3 immune-related adverse events (irAEs) included pneumonia (n=1, 0.8%) and rash (n=2, 1.5%), with no other clinically significant irAEs observed (Table 5).
Table 5. Comparison of safety between groups.
| Event | CIT (n=131) | CT (n=49) | |||
|---|---|---|---|---|---|
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | ||
| Treatment-related AEs | |||||
| Nausea | 36 (27.5) | 7 (5.3) | 11 (22.4) | 1 (2.0) | |
| Neutropenia | 29 (22.1) | 5 (3.8) | 6 (12.2) | 2 (4.1) | |
| Anorexia | 23 (17.6) | 3 (2.3) | 7 (14.3) | 2 (4.1) | |
| Anemia | 13 (9.9) | 3 (2.3) | 5 (10.2) | 0 | |
| Platelet count decreased | 10 (7.6) | 0 | 4 (8.2) | 2 (4.1) | |
| Vomiting | 10 (7.6) | 3 (2.3) | 3 (6.1) | 0 | |
| Fatigue | 8 (6.1) | 0 | 6 (12.2) | 1 (2.0) | |
| Blood creatinine increased | 3 (2.3) | 0 | 0 | 0 | |
| Surgery-related AEs | |||||
| Postoperative pneumonia | 2 (1.5) | 0 | 3 (6.1) | 1 (2.0) | |
| Pleural effusion | 5 (3.8) | 2 (1.5) | 2 (4.1) | 0 | |
| Chylothorax | 3 (2.3) | 1 (0.8) | 0 | 0 | |
| Immune-related AEs | |||||
| Rash | 8 (6.1) | 2 (1.5) | 0 | 0 | |
| Pneumonitis | 3 (2.3) | 1 (0.8) | 0 | 0 | |
| Immune hepatitis | 2 (1.5) | 0 | 0 | 0 | |
Data are presented as n (%). AE, adverse event; CIT, chemoimmunotherapy; CT, chemotherapy.
Predictors for EFS upon conversion CIT
We conducted univariate and multivariate Cox regression analyses in 184 patients who underwent R0 resection following CIT. The univariate analysis showed that pathological stages ypT3 or T4, ypN2-3, ypTNM stage III, and postoperative adjuvant immunotherapy or radiotherapy were associated with worse EFS. Conversely, squamous histology, pCR, and MPR were correlated with longer EFS (Table 6). Subsequent multivariate analysis (Table 7) identified MPR as an independent predictor for improved EFS (HR =0.305; 95% CI: 0.086–0.978; P=0.04), while postoperative radiotherapy was associated with worse EFS (HR =4.523; 95% CI: 1.504–13.603; P=0.007), this observation may be attributable to the fact that postoperative radiotherapy is typically reserved for patients with adverse surgical-pathological risk factors.
Table 6. One-way COX regression analysis of EFS in patients receiving CIT.
| Variable | N | HR (95% CI) | P value |
|---|---|---|---|
| Age, years | |||
| <65 | 105 | 1 | |
| ≥65 | 79 | 1.141 (0.587–2.220) | 0.70 |
| Sex | |||
| Female | 16 | 1 | |
| Male | 168 | 1.498 (0.358–6.260) | 0.58 |
| Smoking history | |||
| No | 58 | 1 | |
| Yes | 126 | 1.122 (0.538–2.343) | 0.76 |
| ypT stage | |||
| T0 | 74 | 1 | |
| T1 | 46 | 1.002 (0.364–2.759) | >0.99 |
| T2 | 49 | 1.999 (0.841–4.752) | 0.12 |
| T3 | 8 | 8.181 (2.766–24.197) | <0.001 |
| T4 | 7 | 4.434 (1.208–16.282) | 0.03 |
| ypN stage | |||
| N0 | 128 | 1 | |
| N1 | 18 | 1.252 (0.368–4.257) | 0.72 |
| N2–N3 | 38 | 3.276 (1.621–6.618) | <0.001 |
| ypTNM stage | |||
| 0 | 73 | 1 | |
| I | 42 | 0.371 (0.081–1.693) | 0.20 |
| II | 27 | 2.464 (0.925–6.565) | 0.07 |
| III | 42 | 3.052 (1.348–6.911) | <0.001 |
| PD-L1 | |||
| <1% | 14 | 1 | |
| 1–49% | 19 | 0.327 (0.082–1.311) | 0.12 |
| ≥50% | 14 | 0.255 (0.051–1.266) | 0.10 |
| Unknown | 137 | 0.295 (0.119–0.732) | 0.008 |
| Histologic type | |||
| ADC | 40 | 1 | |
| SCC | 134 | 0.405 (0.200–0.821) | 0.01 |
| Other | 10 | 0.838 (0.238–2.946) | 0.78 |
| KRAS | |||
| Positive | 10 | 1 | |
| Negative | 37 | 1.378 (0.302–6.300) | 0.68 |
| Unknown | 137 | 0.782 (0.184–3.317) | 0.74 |
| TP53 | |||
| Positive | 9 | 1 | |
| Negative | 37 | 1.403 (0.311–6.337) | 0.66 |
| Unknown | 138 | 0.672 (0.157–2.873) | 0.59 |
| Therapy cycles | |||
| ≤2 | 96 | 1 | |
| 3 | 72 | 0.951 (0.446–2.028) | 0.90 |
| ≥4 | 16 | 1.738 (0.647–4.666) | 0.27 |
| Adjuvant therapy | |||
| No | 76 | 1 | |
| Yes | 108 | 1.491 (0.729–3.048) | 0.27 |
| Adjuvant immunotherapy | |||
| No | 101 | 1 | |
| Yes | 83 | 2.128 (1.072–4.226) | 0.03 |
| Postoperative radiotherapy | |||
| No | 168 | 1 | |
| Yes | 16 | 6.331 (2.965–13.517) | <0.001 |
| pCR | |||
| Non-pCR | 112 | 1 | |
| pCR | 72 | 0.444 (0.207–0.954) | 0.04 |
| MPR | |||
| Non-MPR | 79 | 1 | |
| MPR | 105 | 0.319 (0.158–0.644) | <0.001 |
ADC, adenocarcinoma; CI, confidence interval; CIT, chemoimmunotherapy; EFS, estimates of event-free survival; HR, hazard ratio; MPR, major pathological response; pCR, pathological complete response; PD-L1, programmed death-ligand 1; SCC, squamous cell carcinoma; TNM, tumor-node-metastasis.
Table 7. Multifactorial COX regression analysis of EFS among patients receiving CIT.
| Variable | N | HR (95% CI) | P value |
|---|---|---|---|
| Postoperative radiotherapy | 0.007 | ||
| No | 168 | 1 | |
| Yes | 16 | 4.523 (1.504–13.603) | |
| MPR | 0.04 | ||
| Non-MPR | 79 | 1 | |
| MPR | 105 | 0.305 (0.086–0.978) |
CI, confidence interval; CIT, chemoimmunotherapy; EFS, estimates of event-free survival; HR, hazard ratio; MPR, major pathological response.
Discussion
Potentially resectable NSCLC accounts for approximately 20% of locally advanced NSCLC. It represents a clinically heterogeneous entity spanning from definitively resectable to unresectable diseases, which poses great challenges for clinical management. Currently, there is no universally accepted definition for potentially resectable NSCLC, nor do international clinical guidelines offer standardized treatment recommendations. Conversion CT using platinum-based doublets is frequently used for pursuing curative resection. Nevertheless, the benefit of CT remains limited (8-11). The benefit of immunotherapy in neoadjuvant settings has raised the question of whether adding PD-1/PD-L1 inhibitors to CT further improves the efficacy in potentially resectable NSCLC. Our current study demonstrates that for patients with potentially resectable NSCLC, CIT as a conversion strategy yields superior surgical conversion rates, higher pathological response rates, and improved long-term survival compared to chemotherapy alone, while exhibiting a comparable safety profile. These findings suggest that CIT is associated with higher surgical conversion rates and improved survival outcomes compared with CT alone.
Although several single-arm studies have reported the potential of CIT in the conversion therapy of potentially resectable NSCLC, there is no matched comparative study between CT and CIT. A prospective single-arm phase II trial enrolled 41 NSCLC patients with potentially resectable stage IIIB, and demonstrated a R0 resection rate of 63%, along with MPR and pCR of 44.4% and 22.2%, respectively (21). In some small-sample retrospective studies, preoperative CIT demonstrated a surgical conversion rate of 68.9% in potentially resectable stage IIIA/IIIB diseases. The pCR and MPR are around 65% and 40%, respectively, which are consistent with our findings (7,11). Our current study is the largest comparative study to date, demonstrating that CIT was associated with a significantly higher R0 resection rate compared with CT. More importantly, the increased opportunity for definitive surgery translated into improved patient EFS. We also employed PSM in both the pre-treatment and surgical populations to mitigate confounding and selection bias, providing more robust data. Taken together, these findings suggest that CIT may represent a promising conversion strategy for potentially resectable NSCLC, warranting further evaluation in randomized trials. Phase III randomized controlled trials are required to further validate our findings.
Exploratory subgroup analyses, although underpowered, suggested that patients with younger age (<65 years), squamous histology, and N2–3 stage derived greater benefit from CIT, a trend consistent with larger phase III trials of nCIT, including the CheckMate 816, Keynote 671, AEGEAN, Neotorch, and CheckMate 77T studies (16-19). The enhanced benefit in younger patients may be attributed to more robust immune function (29-32). It has been demonstrated that compared with older patients, younger ones maintain a more abundant pool of CD8+ TCF-1+ stem-like T cells and demonstrate an enhanced capacity to expand CD8+ effector memory T cell populations (33-35). Furthermore, T-cell receptor diversity in younger patients is generally greater, suggesting that their immune systems can recognize a wider array of tumor-associated antigens and mount a more robust anti-tumor response (33-35). It is reported that compared with adenocarcinoma, SCC harbors a higher tumor mutational burden and a more active immune microenvironment (36,37), which facilitates the activation and effector function of T cells upon immune checkpoint inhibitors. These observations may partly explain the greater benefit of CIT observed in SCC. For patients with N2–3 and stage III diseases, higher tumor burden and intratumoral heterogeneity lead to more prevalent immunogenic subclones, thus increasing susceptibility to immune checkpoint inhibition (20,38-41). This phenomenon was also observed in the InTRist study, where the addition of immunotherapy led to significantly improved ORR and PFS in patients with stage III unresectable NSCLC (42).
Notably, this investigation emphasizes that MPR, rather than pCR, serves as an independent predictor of EFS. Although numerous studies demonstrated pCR as the most robust surrogate endpoint for long-term survival, the present study, together with recent evidence like the LCMC3 and CheckMate-816 trials (16,43), suggests that MPR may carry prognostic value comparable to that of pCR in the immunotherapy era. Indeed, data from the CheckMate-816 trial indicate that patients who achieve MPR, irrespective of whether they also attain pCR, show significantly improved survival outcomes compared to those without MPR (16). In a recent large-scale meta-analysis on nCIT for early-stage NSCLC, MPR demonstrated a stronger association with EFS (R2=0.54), compared to PCR (44). These results suggest that MPR represents a clinically meaningful prognostic marker in its own right. Our current study did not confirm the independent predictive value of pCR, likely owing to the limited incidence of pCR, which resulted in insufficient statistical power. Together, these findings highlight that MPR represents a clinically meaningful and potentially applicable endpoint for assessing treatment efficacy and prognosis in the context of conversion CIT for NSCLC.
This study has several limitations. First, owing to a limited follow-up period, the median EFS in the CIT group was not reached. Longer observation is therefore required for assessing definitive long-term outcomes. Second, biomarker data—including PD-L1 expression and KRAS/TP53 mutation status—were not comprehensively collected, which precluded a robust evaluation of their impact on patient outcome. Third, as a retrospective analysis, this study is inherently subject to methodological constraints, including potential confounding factors, selection bias, and information bias. Finally, the assessment of surgical resectability may be partly influenced by the clinician’s judgment, and such subjectivity may introduce detection bias into study endpoints related to surgical outcomes. Future prospective studies should adopt standardized, protocol-defined criteria to determine resectability, so as to minimize this potential source of bias.
Conclusions
In this retrospective study, CIT was associated with higher surgical conversion rates, higher rates of MPR and pCR, and improved EFS compared with CT alone, while demonstrating a comparable safety profile. Subgroup analysis indicated that patients aged <65 years, those with SCC, and those with N2–3 disease derived greater benefit from CIT. In addition, achieving MPR was associated with prolonged EFS.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors thank the patients and the study staff at each center for their contributions to research.
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 was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (No. SDTHEC202411001) and was approved by all participating institutions. Due to the retrospective nature of the study, the ethics committee granted an exemption from the requirement for informed consent.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0561/rc
Funding: This work was supported by China Postdoctoral Science Foundation (No. 2025M782125), Shandong Provincial Natural Science Foundation (No. ZR2025LH162), Wu Jieping Medical Foundation (Nos. 320.6750.2025-17-8 and 320.6750.2024-6-132), Beijing Science and Technology Innovation Medical Development Foundation (No. KC2023-JX-0288-PQ88), Mount Taishan Scholar Program Special Fund (Nos. tstp20221162 and tsqn202312369), and China Health & Medical Development Foundation (No. chmdf2025-xrky02-16).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0561/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0561/dss
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