Survival benefit of neoadjuvant therapies in patients with surgically resected non-small cell lung cancer with pathologic complete response

Introduction

Background

Lung cancer is the leading cause of cancer deaths in the US (1). Treatment strategies including neoadjuvant chemotherapy or chemoradiotherapy have been shown to improve survival in patients with locally advanced non-small cell lung cancer (NSCLC) (2-5). There has been a paradigm shift in the treatment of advanced NSCLC with the advent of immunotherapy. Several trials have shown improved outcomes with the addition of neoadjuvant immunotherapy to the current standard of care. The Checkmate 816 trial showed neoadjuvant immunotherapy plus chemotherapy had a survival benefit over chemotherapy alone in patients with resectable NSCLC (6). Following this, chemoimmunotherapy was approved for use for early-stage, resectable NSCLC in the neoadjuvant setting in 2022. Prior to its approval for early-stage NSCLC, chemoimmunotherapy had been approved and offered to patients with advanced stage NSCLC (7).

Rationale

Pathological complete response (pCR) and major pathologic response (MPR) have been shown to serve as surrogate markers for improved overall survival (OS) after the receipt of neoadjuvant therapy followed by surgical resection (8-10). However, the prognostic value of pCR status has varied based on neoadjuvant strategy for operable, advanced NSCLC. Studies have shown variable pCR rates between 4% and 34% (10-12). This may be due to differences in choice of neoadjuvant treatment strategy. Current literature has shown pCR rates are higher in patients who receive neoadjuvant chemoradiotherapy, compared to chemotherapy alone but has also shown that pCR obtained from neoadjuvant chemoradiotherapy is less likely to result in sustained long-term survival than PCR obtained from neoadjuvant chemotherapy alone (10,13). Currently, the value of pCR after neoadjuvant chemoimmunotherapy as compared to other neoadjuvant therapies is unknown. We hypothesize that the associated survival benefit from pCR status from neoadjuvant chemotherapy and chemoimmunotherapy will be comparable and both superior to that of chemoradiotherapy.

Objective

The purpose of this study is to utilize a current representative national sample to investigate the long-term survival benefits in patients receiving neoadjuvant chemoimmunotherapy versus other neoadjuvant strategies for surgically resected NSCLC with pCR. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0172/rc).

Methods

A retrospective cohort review was completed utilizing the 2021 National Cancer Database (NCDB). The NCDB is a joint project of the Commission on Cancer (CoC) of the American Cancer Society and the American College of Surgeons (ACS) that captures 70% of all diagnosed cancers in the United States yearly. Approximately 1,500 hospitals with CoC-accredited cancer programs are included in the NCDB. The ACS-CoC have not verified nor are responsible for the analysis or conclusions of this review. The institutional review board at Thomas Jefferson University deemed this study exempt (IRB#2020-117A). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Patients with clinical stage IB through IIIA NSCLC with pCR between 2017–2020 who underwent surgical resection and received neoadjuvant chemotherapy, chemoradiation, or chemoimmunotherapy met inclusion. Exclusion criteria included patients with an unknown survival status. Pathologic complete response (pCR) was defined as the absence of residual invasive carcinoma in the resected lung specimen [ypT0, pT0, or carcinoma in situ only (ypTis or pTis)] and the absence of tumor involvement in all examined regional lymph nodes (ypN0 or pN0, including cases with isolated tumor cells only). This review compared patients who received the neoadjuvant therapies of chemotherapy only, chemotherapy and radiation therapy, and chemotherapy and immunotherapy.

Patient clinical characteristics [tumor size, clinical stage, Charlson-Deyo Comorbidity Index (CCI), year of diagnosis], and demographics (age, sex, race, insurance, income) were recorded. Operative variables analyzed included surgical margins, procedure type, and characteristics of lymph node sampling (number of lymph nodes and lymph nodes examined). We also included the time from neoadjuvant therapy to surgery. The postoperative outcomes included 30- and 90-day survival, and 30-day readmission rate.

Statistical analysis

Analysis of variance, Pearson Chi-squared, and student t-tests were utilized for statistical analysis when appropriate. Multivariable Cox regression analysis was conducted to evaluate the association between neoadjuvant therapy types and survival using neoadjuvant chemoimmunotherapy as the reference group. Kaplan-Meier survival analysis with log-rank tests assessing for 5-year OS between the neoadjuvant therapies was performed. A P value less than 0.05 was considered statistically significant. Stata/SE 15.1 statistical software (StataCorp LLC) was used for analysis.

Results

Demographics and patient characteristics

From 2017–2020, 584 patients underwent surgical resection for NSCLC with pCR, and received neoadjuvant chemotherapy, chemoradiation, or immunotherapy. Of this cohort, 15.2% (n=89) received neoadjuvant chemoimmunotherapy, 25% received chemotherapy only (n=146), and 59.8% (n=349) received chemoradiation. Median age at NSCLC diagnosis was 63 years [interquartile range (IQR), 58–70 years], with a majority of patients identifying as White (88.4%, n=516). Median tumor size was 3.6 cm (IQR, 2.5–6 cm). The predominant histologic subtypes were squamous cell carcinoma (45.5%, n=266) and adenocarcinoma (41.4%, n=242). A majority of patients underwent lobectomy (86.8%, n=505), followed by pneumonectomy (8.9%, n=52), wedge resection (2.7%, n=16), segmentectomy (1%, n=6), and unknown (0.5%, n=3).

There was an increase in the proportion of patients who underwent neoadjuvant chemoimmunotherapy, increasing from 7.9% (n=7) of patients in 2017 to 29.2% (n=26) of patients in 2020. In comparison, the proportion of patients who underwent neoadjuvant chemoradiation [33.5% (n=117) vs. 19.2% (n=67)] and chemotherapy [29.5% (n=43) vs. 20.5% (n=30)] decreased from 2017 to 2020. Patients who underwent chemoradiation more often had a CCI score ≥1 when compared to chemotherapy and chemoimmunotherapy [46.7% (n=163) vs. 32.9% (n=48) vs. 34.8% (n=31), P=0.007]. There were no differences in tumor size, sex, race, or income (Table 1).

The majority of the cohort was clinical stage IIIA (64.4%, n=376), followed by clinical stage IIB (26.2%, n=153). When evaluating pathological stage, the vast majority were unknown (93.5%, n=546). All patients in the chemoimmunotherapy group had an unknown pathological stage (Table 2).

Short-term clinical outcomes

Patients who underwent neoadjuvant chemoradiation were found to have a lower 90-day survival rate than those who underwent neoadjuvant chemotherapy and chemoimmunotherapy (94% vs. 99.3% vs. 97.8%, P=0.02). There were no significant differences in 30-day survival rates or 30-day readmission rates among patients who underwent neoadjuvant chemotherapy, chemoradiation, and chemoimmunotherapy (Table 3). Patients who underwent neoadjuvant chemotherapy had a significantly higher median number of lymph nodes resected when compared to those who underwent chemoradiation and chemoimmunotherapy (15.5 vs. 11 vs. 14 nodes, P=0.01). There were no differences in positive resection margins or surgical resection type among neoadjuvant therapy types. Patients undergoing neoadjuvant chemotherapy received surgery within 3 months after the start of neoadjuvant therapy less often than patients who underwent chemoradiation and chemoimmunotherapy [19.9% (n=29) vs. 33.3% (n=116) vs. 33.7% (n=30), P<0.001].

OS

There was a significant difference in 5-year OS when comparing patients who underwent chemoimmunotherapy (84.43%) versus chemoradiation (70.11%) (P=0.01) and chemotherapy only (82.04%) versus chemoradiation therapy (70.11%) (P<0.001) (Figure 1). There was no significant difference in 5-year OS between patients who underwent chemotherapy only versus chemoimmunotherapy. Multivariable Cox regression analysis was conducted to evaluate the association between neoadjuvant therapy types and survival using neoadjuvant chemoimmunotherapy as the reference group (Table 4). Age was not significantly associated with survival [hazard ratio (HR) =1.03, 95% confidence interval (CI): 0.947–1.121, P=0.48]. Neoadjuvant chemotherapy alone had a lower HR compared to the chemoimmunotherapy group (HR =0.85, 95% CI: 0.372–1.951, P=0.75). However, the effect was small and not statistically significant. Comparatively, neoadjuvant chemotherapy and radiation had a significantly higher HR compared to the chemoimmunotherapy group (HR =2.38, 95% CI: 1.197–4.739, P=0.01).

Figure 1 Kaplan-Meier 5-year overall survival curve by neoadjuvant therapy type. Shaded regions represent 95% confidence intervals. Chemo, chemotherapy; IO, immunotherapy; RT, radiation therapy.

Discussion

In this study, we utilized a current representative national sample to find a significantly greater association of OS in patients with pCR after resection who received neoadjuvant chemoimmunotherapy compared to those who received chemoradiation. This suggests using pCR remains a useful endpoint in evaluating the success of a novel treatment, specifically for neoadjuvant chemoimmunotherapy.

We found a majority of our cohort between 2017–2020 underwent neoadjuvant chemoradiation, with neoadjuvant chemoimmunotherapy offered the least amongst all therapy types. However, chemoimmunotherapy use increased from 2017 to 2020, whereas chemoradiation and chemotherapy decreased. This increase in neoadjuvant chemotherapy use is similar to the increase seen in Pilon et al., in which authors studied trends and surgical outcomes in NSCLC patients treated with chemoimmunotherapy (14). This may also be affected by the enrollment of randomized clinical trials CheckMate 816 and KEYNOTE-671, which began in 2017 and 2018, respectively.

Current literature shows the addition of neoadjuvant radiotherapy to chemotherapy has an effect on local control, tumor downstaging, and nodal sterilization. However, this does not translate to an improvement in OS when compared to chemotherapy (15). One likely explanation to this finding is that radiation causes local tumor destruction and does not effectively eradicate systemic micro metastasis. More recently, landmark randomized control trial CheckMate 816 showed improvement in event-free survival and pCR with the addition of nivolumab to neoadjuvant chemotherapy regimens. Although pCR has been used as a surrogate marker for OS, its value has not been evaluated with regard to various neoadjuvant therapies; our study fills a gap in current literature by showing an improved survival in patients with pCR after receipt of neoadjuvant chemoimmunotherapy versus chemoradiation.

While data is still scarce, studies have shown patients who received neoadjuvant chemoimmunotherapy can safely undergo resection with adequate lymph node sampling and a sound oncological resection, which corroborates with our data (16). We found patients who received chemoimmunotherapy had a median of 14 lymph nodes resected, which is well above the recommended guidelines (17). Although this is lower compared to patients who underwent neoadjuvant chemotherapy (15.5 lymph nodes), it is significantly higher compared to patients who underwent chemoradiation (11 lymph nodes). The lower lymph node harvest in patients who underwent chemoradiation may be related to treatment-induced fibrosis. Delay to surgery or surgical complexity due to tissue scarring necessitating a more high-risk surgical resection (i.e., pneumonectomy) are often cited by those who do not consider neoadjuvant therapies, despite current literature refuting these concerns. In a 3-year follow-up of CheckMate 816, patients who received immunotherapy were more likely to undergo definitive surgery and had lower rates of high-risk surgeries. We found no significant difference in surgical resection type, including pneumonectomy, among patients who underwent different neoadjuvant therapies; however, this may be due to our small sample size of patients receiving chemoimmunotherapy. Patients who underwent chemoimmunotherapy (33.7%) and chemoradiation (33.7%) were more likely to receive definitive surgery within 3 months after the start of neoadjuvant therapy than those who underwent chemotherapy, in line with the findings of CheckMate 816. While we found no significant differences in 30-day survival or readmission, patients who underwent surgical resection after receipt of neoadjuvant chemoimmunotherapy had a 90-day survival rate of 97.8%, which was slightly lower than those who underwent chemotherapy (99.3%), but significantly higher than patients who underwent chemoradiation (94%), indicating it remains a safe treatment regimen. We also found that patients who underwent chemoimmunotherapy had significantly fewer patients with CCI scores ≥1, compared to chemoradiation. It is likely that there is a component of selection bias in the chemoimmunotherapy group, with a tendency to favor healthier and younger patients. Therefore, additional studies are needed to verify these findings. Overall, this data suggests that tumor biology and susceptibility to systemic therapy is more valuable than the ability to locally ablate a tumor in the setting of advanced disease.

This study poses some limitations. Our sample size in the chemoimmunotherapy group that achieved pCR was small, which affected the power of the study. This also affected the number of variables that were included in our multivariable regression analysis. Some patients were not included in the final analysis as they lacked long-term survival data. Additionally, during the study period, the determination of pCR was not standardized. In 2020, the International Association for the Study of Lung Cancer (IASLC) published formal recommendations for pathologic assessment of NSCLC after neoadjuvant therapy; previously, methodologies for assessing pCR in NSCLC were limited and varying (18). Furthermore, our study period from 2017-2020 likely includes patients who were enrolled in clinical trials, as CheckMate 816 KEYNOTE-671 started enrolling patients in 2017 and 2018, respectively. This may bias OS data as these patients are generally healthier. Due to limitations of the database, we were unable to quantify how many patients in our cohort were enrolled in a clinical trial during our study period. Although the NCDB indicates if patients participated in a clinical trial, the data is not well elucidated. Nearly all patients are recorded as not receiving cancer treatment under that variable. However, the majority of patients treated with chemoimmunotherapy in our study cohort had stage III disease, which indicates they were treated according to the standard of care paradigm for advanced stage NSCLC. Furthermore, if enrolled, the database does not include if they received immunotherapy or placebo, which would introduce additional uncertainty and potential misclassification bias. Additionally, our multivariable regression model only included age and treatment group, as inclusion of other variables (CCI, clinical stage, tumor size, year of diagnosis, surgical type, lymph node yield, etc.) introduced unexpected and inconsistent hazard estimates that were difficult to interpret and often suggested paradoxical associations, likely due to multicollinearity or residual confounding. As a result, we chose to present a more parsimonious model focused on age and treatment group to highlight the primary effect of the treatment strategy, while minimizing distortion from model instability. However, the NCDB does not provide data on recurrence and cancer-related mortality; therefore, further studies are needed to confirm if the survival differences found in our study are undoubtedly attributed to treatment strategy alone.

Moreover, the NCDB is a retrospective database and may introduce biases such as selection bias. We are limited by the variables captured by the NCDB and are thus unable to comment on additional aspects related to chemotherapy regimen, pCR and survival. For example, the NCDB does not include programmed death-ligand 1 (PD-L1) expression or other molecular markers as well as drug-specific data, treatment completion rates, or day therapy was finalized. This prevented us from calculating time from treatment completion to surgery as an analysis parameter. Lastly, the NCDB draws data only from hospitals with CoC accreditation, thereby limiting the generalizability of findings.

Conclusions

Our study demonstrated an increased survival benefit in patients with pCR who received neoadjuvant chemoimmunotherapy compared to those who received chemoradiation. This study highlights the safety and efficacy of chemoimmunotherapy, as well as continued use of pCR as a surrogate for OS in patients who receive neoadjuvant chemoimmunotherapy.

Acknowledgments

This abstract was presented at the General Thoracic Surgical Club 2025 Meeting; February 6–9, 2025; Bonita Springs, Florida.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0172/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0172/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0172/coif). N.R.E. III and O.T.O. received research funding from the Bristol Myers Squibb Foundation, paid to their institution. Additionally, N.R.E. III received speaker and consultant honoraria from Intuitive, Merck, Bristol Myers Squibb, and AstraZeneca. O.T.O. received speaker honoraria from Intuitive Surgical, AstraZeneca, Atricure, and Johnson & Johnson. The other 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. The data for this research was acquired through the National Cancer Database. Data analysis was performed at the investigator’s institution. This research was deemed exempt from Institutional Review Board approval at Thomas Jefferson University (IRB#2020-117A, 9/7/21). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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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