Abstract
Objective
We evaluated the feasibility and long-term outcomes of minimally invasive surgery (MIS) after neoadjuvant immunotherapy in patients with resectable non–small cell lung cancer (NSCLC).
Methods
Patients with stage IB-IIIB NSCLC who underwent induction immunotherapy followed by surgery (2015-2022) were included. Overall and event-free survival were estimated using the Kaplan-Meier approach. Cox regression was used to quantify associations between clinical and pathologic variables and survival outcomes.
Results
In total, 69 patients met the inclusion criteria (MIS, n = 38; open surgery, n = 31). Patients who underwent open surgery had larger tumors (P < .001), more-frequent extended resection (P = .007), more major complications (P = .03), and longer in-hospital stay (P = .002), compared with patients who underwent MIS. The rate of conversion to open surgery in the MIS group was 16% (6/38). Histologic subtype (P = .057), completeness of resection (P > .9), response to treatment (P > .9), and stage (P = .6) were not statistically different between groups. Five-year event-free and overall survival in the MIS patients were 72% and 80%, respectively. Among all patients, pathologic N2 disease (hazard ratio [HR], 3.04; 95% CI, 1.1-8.38; P = .031) and upstaging (HR, 2.57; 95% CI, 1.05-6.34; P = .04) were associated with a greater risk of recurrence. Major pathologic response was associated with longer event-free survival (HR, 0.22; 95% CI, 0.05-0.93; P = .039). Programmed death-ligand 1 level (HR, 1.02; 95% CI, 1.01-1.04; P = .007) and tumor dimensional reduction after treatment (HR, 0.96; 95% CI, 0.93-0.99; P = .016) were associated with major pathologic response.
Conclusions
MIS after induction immunotherapy is feasible and does not compromise long-term oncologic outcomes.
Key Words: minimally invasive surgery, induction therapy, immunotherapy, non–small cell lung cancer
Overall survival (with 95% CIs) after surgery in the treatment groups.
Central Message.
Minimally invasive anatomical lung resection after induction immunotherapy is feasible and does not compromise long-term oncologic outcomes in patients with non–small cell lung cancer.
Perspective.
Concerns remain that the use of induction immunotherapy may increase operative difficulty, compromise the availability of minimally invasive techniques, or reduce the likelihood of a complete oncologic resection. We found, in our cohort of patients with non–small cell lung cancer, that induction immunotherapy alone should not preclude the use of minimally invasive surgery in this setting.
Approximately 20% of patients with newly diagnosed non–small cell lung cancer (NSCLC) have advanced locoregional disease at the time of diagnosis.1 Surgical resection and systemic therapy are key components of multidisciplinary treatment for these patients. Current National Comprehensive Cancer Network guidelines recommend that all patients with NSCLC undergo a preoperative evaluation for induction chemoimmunotherapy, particularly those with tumors >4 cm or with node-positive disease.2 These recommendations are supported by multiple clinical trials that demonstrated better outcomes with induction immunotherapy alone or in combination with chemotherapy, compared with standard chemotherapy regimens.3, 4, 5, 6 Of note, the results of CheckMate 816 led to US Food and Drug Administration approval, in March 2022, of neoadjuvant nivolumab with platinum-doublet chemotherapy for resectable NSCLC.
Despite these advances, concerns remain about the potential impact of immunotherapy-associated inflammatory changes on surgical complexity. Some surgeons may be concerned that induction immunotherapy could increase operative difficulty, compromise the availability of minimally invasive techniques, or reduce the likelihood of a complete oncologic resection.3,7, 8, 9, 10, 11 In addition, data on surgical and long-term oncologic outcomes after induction immunotherapy followed by minimally invasive surgery (MIS) are limited.11,12 We therefore evaluated short- and long-term outcomes in patients with NSCLC who were treated with preoperative immunotherapy followed by open or minimally invasive lung resection.
Methods
We performed a retrospective review of a prospectively maintained database at a single cancer center. This study was approved by our institutional review board (no. 18-391; September 7, 2018), and all patients gave informed consent for the publication of study data. Staging was completed in accordance with the American Joint Committee on Cancer eighth edition staging manual.2 Patients with clinical stage IB-IIIB NSCLC who underwent anatomic lung resection after induction immunotherapy, with or without chemotherapy, from January 2015 to December 2022 were included. Therapeutic regimens are listed in Table E1. Patients were excluded if they had a history of lung cancer or other intrathoracic tumors, preoperative radiotherapy, macroscopically incomplete or aborted resection, or salvage surgery. All patients were included in clinical trials; 7 patients in the study period had their treatment blinded and were therefore excluded. Baseline details were obtained for all patients. The operative approach was selected at the discretion of the surgeon, and patients were grouped retrospectively according to the approach that was performed: open surgery (thoracotomy) or MIS (video-assisted thoracoscopic surgery or robotic-assisted thoracoscopic surgery). Patients who underwent thoracoscopy solely to assess resectability and then underwent conversion to open surgery were included in the open surgery group. Operative reports were reviewed to identify any subjective indicators of difficulty in the resection. Perioperative complications were codified according to the Clavien-Dindo classification.13 Recurrence was determined by imaging and/or pathology via tissue biopsy. Recurrence was differentiated from a second primary lung tumor by use of molecular testing and the criteria from Martini and Melamed.14 The site of recurrence was classified as locoregional (ipsilateral lung or regional lymph node, ipsilateral mediastinum) or distant (pleural effusion, contralateral lung, extrathoracic metastasis) with or without simultaneous locoregional recurrence.15 Event-free survival (EFS) and overall survival were calculated from the date of surgery to the date of biopsy that confirmed recurrence, the date of imaging findings that were consistent with recurrence, or the date of the last follow-up and were estimated using the Kaplan-Meier approach.
Clinicopathologic features were summarized as frequency (percentage) or median (interquartile range [IQR]). Cox models were used to estimate associations between clinicopathologic variables and recurrence and survival. Major pathologic response (mPR) was defined as ≤10% of viable tumor remaining. All statistical tests were 2-sided. Statistical analyses were conducted using R 4.3.1 (R Core Team).
Results
In total, 69 patients met the inclusion criteria: 38 in the MIS group and 31 in the open surgery group (Figure E1). The majority of patients in both groups were women (MIS, 61%; open, 58%; P = .8) and former smokers (MIS, 79%; open, 84%; P > .9). Demographic and functional characteristics were similar between the 2 groups (Table 1). Invasive mediastinal staging was performed in only 55% of patients in the MIS group (P = .01). Patients in the open surgery group had larger tumors (5.90 cm vs 4.35 cm; P < .001) and, thus, a greater clinical tumor stage (P = .002) and a greater proportion of clinical stage III disease (77% vs 50%), although the clinical nodal stage and the stage distribution were not statistically significant (P = .8 and P = .13, respectively). Patients who underwent MIS received immunotherapy alone more often than combination chemoimmunotherapy (P = .029). The interval between completion of induction treatment and surgery was shorter among MIS patients than among open surgery patients (20 days [IQR, 19-26] vs 24 days [IQR, 20-42]; P = .02). Patients in the open surgery group had greater reduction in tumor size on computed tomography scan (median, −8% vs 0%; P = .029) (Table 2).
Figure E1.
Surgical approach by year. VATS, Video-assisted thoracoscopic surgery.
Table 1.
Preoperative characteristics
| Variable | MIS (n = 38) | Open surgery (n = 31) | P value |
|---|---|---|---|
| Female sex | 23 (61) | 18 (58) | .8 |
| Age at surgery, y | 69 (61-74) | 65 (60-68) | .070 |
| Smoking history | >.9 | ||
| Current | 5 (13) | 3 (10) | |
| Former | 30 (79) | 26 (84) | |
| Never | 3 (8) | 2 (6) | |
| Smoking pack-years | 38 (12-49) | 25 (20-40) | .4 |
| Body mass index | 26.8 (24.3-31.3) | 28.1 (25.0-30.0) | .6 |
| Comorbidities | 27 (71) | 24 (77) | .5 |
| COPD | 11 (29) | 11 (35) | .6 |
| CAD | 4 (11) | 4 (13) | >.9 |
| Hypertension | 19 (50) | 12 (39) | .3 |
| Diabetes | 5 (13) | 3 (10) | .7 |
| FEV1, L | 2.37 (1.92-2.83) | 2.41 (1.97-2.95) | .7 |
| FEV1, % | 96 (85-103) | 89 (79-99) | .2 |
| FVC, L | 3.30 (2.64-3.98) | 3.30 (2.87-3.89) | .8 |
| FVC, % | 100 (89-106) | 94 (80-104) | .2 |
| DLCO, % | 80 (72-93) | 81 (73-93) | .9 |
Data are no. (%) or median (interquartile range). MIS, Minimally invasive surgery; COPD, chronic obstructive pulmonary disease; CAD, coronary artery disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide.
Table 2.
Preoperative clinicopathologic data
| Variable | MIS (n = 38) | Open surgery (n = 31) | P value |
|---|---|---|---|
| Tumor size, cm | 4.35 (3.55-5.00) | 5.90 (4.80-7.20) | <.001 |
| SUVmax | 12 (9-16) | 17 (13-22) | .017 |
| Mediastinal staging | 21 (55) | 26 (84) | .01 |
| Histologic subtype | .4 | ||
| Adenocarcinoma | 25 (66) | 16 (52) | |
| Squamous cell carcinoma | 10 (26) | 13 (42) | |
| Clinical tumor stage | .002 | ||
| 1 | 5 (13) | 1 (3) | |
| 2 | 21 (55) | 6 (19) | |
| 3 | 8 (21) | 14 (45) | |
| 4 | 4 (11) | 10 (32) | |
| Clinical nodal stage | .8 | ||
| 0 | 12 (32) | 12 (39) | |
| 1 | 12 (32) | 9 (29) | |
| 2 | 14 (37) | 10 (32) | |
| Clinical stage | .13 | ||
| IB | 3 (8) | 0 (0) | |
| IIA | 3 (8) | 1 (3) | |
| IIB | 13 (34) | 6 (19) | |
| IIIA | 17 (45) | 19 (61) | |
| IIIB | 2 (5) | 5 (16) | |
| PD-L1 positive | 16 (52) | 18 (64) | .3 |
| TPS, % | 1 (0-20) | 5 (0-73) | .3 |
| Induction treatment | .029 | ||
| Chemoimmunotherapy | 5 (13) | 11 (35) | |
| Immunotherapy | 33 (87) | 20 (65) | |
| Complications of induction treatment | 23 (61) | 19 (61) | >.9 |
| Interval between end of induction treatment and surgery, d | 20 (19-26) | 24 (20-42) | .020 |
| Delayed surgery (>6 wk) | 3 (8) | 5 (16) | .4 |
| PET response or stable disease | 29 (76) | 21 (68) | .08 |
| ΔSUV between before and after induction treatment, % | −16 (−47 to −8.5) | −24 (−75 to −1) | .69 |
| Postinduction tumor size on CT, cm | 4 (3.3-5.1) | 5 (3.5-6.8) | .1 |
| ΔCT between before and after induction treatment, % | 0 (−8 to 6) | −8 (−30 to 0) | .029 |
Data are n (%) or median (interquartile range). MIS, Minimally invasive surgery; SUVmax, maximum standardized uptake value; PD-L1, Programmed death-ligand 1; TPS, tumor proportion score; CT, computed tomography; PET, positron emission tomography.
Patients in the open surgery group were more likely to undergo chest wall resection, vascular resection, and extensive parenchymal resection, including bilobectomy (13% vs 0%) and pneumonectomy (16% vs 3%), than patients in the MIS group (P = .007). In addition, patients in the open surgery group had longer operative times (median, 278 minutes [IQR, 215-382] vs 227 minutes [IQR, 205-269]; P = .016) and more intraoperative blood loss (median, 150 mL [IQR, 100-225] vs 50 mL [IQR, 50-100]; P < .001) (Table 3). In the MIS group, 6 patients (16%) required conversion to open surgery. The reasons for conversion were intraoperative bleeding (n = 2), extent of disease (n = 2), and difficult resection because of treatment response (n = 2). Main highlighted difficulties were related to the presence of extensive fibrosis due to treatment response or of adenopathy leading to difficult exposure of the hilar structures. All patients with a mPR at final pathology who underwent MIS did so without conversion (n = 11).
Table 3.
Surgical and postoperative outcomes
| Variable | MIS (n = 38) | Open surgery (n = 31) | P value |
|---|---|---|---|
| Tumor location | .6 | ||
| Right upper lobe | 11 (29) | 6 (19) | |
| Right middle lobe | 2 (5) | 3 (10) | |
| Right lower lobe | 6 (16) | 8 (26) | |
| Left upper lobe | 15 (39) | 9 (29) | |
| Left lower lobe | 4 (11) | 5 (16) | |
| Procedure type | .007 | ||
| Segmentectomy | 1 (3) | 0 (0) | |
| Lobectomy | 36 (95) | 22 (71) | |
| Bilobectomy | 0 (0) | 4 (13) | |
| Pneumonectomy | 1 (2.6) | 5 (16) | |
| Operative time, min | 227 (205-269) | 278 (215-382) | .016 |
| Conversion to open surgery | 6 (16) | – | – |
| Blood loss, mL | 50 (50-100) | 150 (100-225) | <.001 |
| Chest wall resection | 0 (0) | 2 (6) | .2 |
| Vascular resection | 0 (0) | 1 (3) | .4 |
| Postoperative length of stay, d | 3.00 (2.00-4.75) | 5.00 (4.00-6.50) | .002 |
| In-hospital complications | 12 (32) | 13 (42) | .4 |
| Complication grade ≥3∗ | 2 (5) | 7 (23) | .03 |
| In-hospital death | 0 (0) | 1 (3) | .4 |
| Readmission within 30 d | 3 (8) | 6 (19) | .2 |
| Death within 90 d | 0 (0) | 2 (6) | .4 |
Data are n (%) or median (interquartile range). MIS, Minimally invasive surgery.
Clavien-Dindo classification.
MIS was associated with better postoperative outcomes, including a lower rate of major complications (Clavien-Dindo ≥3, 5% vs 24%; P = .03) and shorter length of hospitalization (median, 3.00 days [IQR, 2.00-4.75] vs 5.00 days [IQR, 4.00-6.50]; P = .002). Histologic subtype, rates of major and complete pathologic response, extent of lymphadenectomy, and final pathologic tumor-node-metastasis stage were not statistically different between the 2 groups (Table 4). In the entire population, the rate of mPR was 28.9% (20/69); however, 2 of those patients still had pN1 disease and 1 patient had pN2 disease.
Table 4.
Pathologic and histologic characteristics
| Variable | MIS (n = 38) | Open surgery (n = 31) | P value |
|---|---|---|---|
| Histologic subtype | .057 | ||
| Adenocarcinoma | 25 (66) | 12 (39) | |
| Squamous cell carcinoma | 9 (24) | 12 (39) | |
| No tumor | 4 (11) | 4 (13) | |
| Other | 0 (0) | 3 (10) | |
| Major pathologic response | 11 (29) | 9 (29) | >.9 |
| Complete pathologic response | 4 (11) | 4 (13) | >.9 |
| Viable tumor, % | 50 (10-70) | 48 (10-68) | .7 |
| Tumor size, cm | 2.88 (0.69-4.20) | 2.10 (0.55-4.99) | >.9 |
| Lymphovascular invasion | 19 (50) | 15 (50) | >.9 |
| Perineural invasion | 1 (3) | 3 (12) | .3 |
| Pleural invasion | .3 | ||
| Visceral pleural invasion | 3 (8) | 5 (16) | |
| Parietal pleural invasion | 2 (5) | 4 (13) | |
| Spread through air spaces | 12 (32) | 7 (24) | .5 |
| Grade | .8 | ||
| 1 | 1 (3) | 0 (0) | |
| 2 | 12 (39) | 7 (30) | |
| 3 | 18 (58) | 16 (70) | |
| Total lymph node stations | 6 (6-7) | 6 (5-7) | >.9 |
| Total lymph nodes | 21 (16-30) | 21 (15-31) | >.9 |
| R1 resection | 2 (5) | 2 (6) | >.9 |
| Pathologic tumor stage | .4 | ||
| 0 | 4 (11) | 4 (13) | |
| 1 | 15 (39) | 9 (29) | |
| 2 | 11 (29) | 7 (23) | |
| 3 | 4 (11) | 9 (29) | |
| 4 | 4 (11) | 2 (6) | |
| Pathologic nodal stage | .3 | ||
| 0 | 16 (42) | 16 (52) | |
| 1 | 8 (21) | 9 (29) | |
| 2 | 14 (37) | 6 (19) | |
| Pathologic metastasis stage | >.9 | ||
| 0 | 37 (97) | 31 (100) | |
| 1 | 1 (3) | 0 (0) | |
| Pathologic stage | .6 | ||
| 0 | 4 (11) | 4 (13) | |
| IA | 9 (24) | 5 (16) | |
| IB | 1 (3) | 1 (3) | |
| IIA | 1 (3) | 2 (6) | |
| IIB | 5 (13) | 6 (19) | |
| IIIA | 13 (34) | 13 (42) | |
| IIIB | 4 (11) | 0 (0) | |
| IV | 1 (3) | 0 (0) | |
| Upstaging | 10 (26) | 2 (6) | .03 |
| Nodal upstaging | 8 (21) | 6 (19) | .9 |
| N1 upstaging | 3 (8) | 5 (16) | |
| N2 upstaging | 5 (13) | 1 (3) | |
| Tumor upstaging | 5 (13) | 2 (6) | .3 |
| TMB, muts/MB | 7 (4-10) | 9 (5-14) | .3 |
| Adjuvant treatment | 23 (61) | 17 (55) | .6 |
Data are n (%) or median (interquartile range). MIS, Minimally invasive surgery; TMB, tumor mutational burden.
The median length of follow-up was similar between the MIS group and the open surgery group (58 vs 44 months; P = .1). Patients in the MIS group had longer 5-year EFS than patients in the open surgery group (72% vs 51%; P = .044) (Figure 1). The site of recurrence was not statistically different between the 2 groups; the majority of recurrences in each group were distant (MIS, 67%; open, 91%; P = .5). Five-year overall survival for all patients was 76% (MIS, 80%; open, 72%; P = .2) (Figure 2).
Figure 1.
Event-free survival after surgery in the overall study population (A) and by surgical treatment group (B). Shaded areas represent 95% CIs. MIS, Minimally invasive surgery.
Figure 2.
Overall survival after surgery in the overall study population (A) and by surgical treatment group (B). Shaded areas represent 95% confidence intervals. MIS, Minimally invasive surgery.
EFS was significantly longer in patients with an mPR (P = .024); of note, no patients with an mPR experienced disease recurrence (Figure E2). Patients who had an mPR were more likely to have greater expression of PD-L1 (hazard ratio [HR], 1.02; CI, 1.01-1.04; P = .007) and greater dimensional reduction after induction treatment (HR, 0.96; 95% CI, 0.93-0.99; P = .016) (Figure E2).
Figure E2.
Event-free survival after surgery in patients with and without a major pathologic response. Shaded areas represent 95% CIs. MIS, Minimally invasive surgery.
On univariable analysis for disease recurrence, mPR was identified as a protective factor (HR, 0.22; 95% CI, 0.05-0.93; P = .039). Vascular invasion (HR, 2.92; 95% CI, 1.13-7.54; P = .027), persistent N2 disease (HR, 3.04; 95% CI, 1.10-8.38; P = .031), and pathologic upstaging (HR, 2.57; 95% CI, 1.05-6.34; P = .04) were all associated with recurrence. Surgical approach did not influence the risk of recurrence (open vs MIS: HR, 2.34; 95% CI, 1.00-5.50; P = .051), even after adjustment for disease stage (HR, 2.41; 95% CI, 0.98-5.93; P = .055). Among all variables, only receipt of adjuvant therapy was associated with longer overall survival at univariable analysis (HR, 0.31; 95% CI, 0.10-0.95; P = .04).
Discussion
Our findings demonstrate that MIS after induction immunotherapy is feasible, is associated with relatively low conversion rates and low morbidity, and does not compromise long-term oncologic outcomes. Recent clinical trials have demonstrated the benefits of neoadjuvant immunotherapy alone or combined with chemotherapy for patients with resectable NSCLC.3, 4, 5, 6 As more neoadjuvant therapies are evaluated and show promising results, concerns will remain within the surgical community about the effects of these therapies on the ability to perform MIS, particularly with respect to the safety and feasibility of minimally invasive techniques.5,7, 8, 9, 10, 11 In addition, there is a paucity of data on the association between surgical approach and long-term oncologic outcomes after induction immunotherapy.
In a large study from Mathey-Andrews and colleagues,7 conversion rates between patients who received induction immunotherapy (n = 218) and patients who received chemotherapy alone (n = 4011) were not statistically different. Similarly, Chu and colleagues16 found that only clinical nodal stage was associated with an unsuccessful MIS approach, and the rate of conversion was low (16%). In our cohort, the conversion rate was 16%, which is significantly lower than the initial experience after neoadjuvant nivolumab (54%) reported by Bott and colleagues9 and is comparable with rates in other reports.3,5 Importantly, review of the operative reports for our cohort revealed that conversion was attributed to treatment-related technical difficulty in only 2 cases.
In the NEOSTAR trial, surgeons graded resection difficulty and reported increased complexity in 23% of cases after neoadjuvant therapy.11 In our study, we did not use a standardized assessment or questionnaire; an objective grading of surgical complexity should be considered in a future trial to assess this point.
mPR did not appear to affect the feasibility of MIS; all 11 patients with a mPR who were scheduled to undergo MIS underwent MIS without the need for conversion. Postoperative outcomes were better in the MIS group, with shorter operative times, less blood loss, and lower complication rates. In addition, oncologic quality was maintained in the MIS group: rates of R0 resection, the number of lymph node stations sampled, and the total number of lymph nodes removed were similar between the 2 groups.
The greater rate of upstaging in the MIS group may be reflective of incomplete preoperative staging, as only 55% of the patients in the MIS group underwent invasive mediastinal staging, and this is a notable limitation of our series.3,4,6 Thorough staging of the mediastinum should be considered in every case in accordance with national and international guidelines.2,17
Long-term outcomes were excellent in the MIS group, with a 5-year EFS of 72% and 5-year overall survival of 80%. Our data demonstrate that a high-quality MIS resection after induction immunotherapy was associated with equivalent oncologic outcomes compared with open surgery.
As an exploratory analysis, we evaluated the impact of mPR on oncologic outcomes, as mPR has been proposed as a possible surrogate endpoint of survival.18 Indeed, patients with mPR in our cohort had longer EFS, compared with patients without mPR. We found that programmed death-ligand 1 level was associated with mPR, confirming previous findings.19 Dimensional reduction measured after induction treatment was also associated with mPR in our study; this contrasts with previous reports, which found that dimensional change was not associated with pathologic response.20 Although we did not analyze these 2 parameters with a specific cutoff value, tumor proportion score ≥50% and reduction in tumor size >30%, which is the iRECIST cutoff for partial response,21 were associated with mPR (Figure E3).
Figure E3.
A, Percentage of tumor reduction measured on computed tomography before and after induction treatment in patients without mPR, with mPR, and with cPR. The dotted line indicates 30% dimensional reduction. B, PD-L1 expression in patients without mPR, with mPR, and with cPR. The dotted line indicates 50% tumor proportion score. mPR, Major pathologic response; cPR, complete pathologic response; PD-LI, programmed death-ligand 1.
This study has several limitations. This is a retrospective study from a single high-volume cancer center, which limits the generalizability of our findings. In addition, the surgical approach for each patient was selected on the basis of a single surgeon's evaluation; experience and training background could have a significant effect on choice of approach. Systemic therapy regimens varied by patient, and the study was underpowered to analyze differences on the basis of treatment type or on the type of adjuvant therapies. Finally, there were some baseline differences between the open and MIS groups that were not possible to adjust for, making the two populations unbalanced.
Conclusions
Minimally invasive lung resection in patients with locally advanced NSCLC treated with induction immunotherapy is feasible, effective, and does not compromise oncologic outcomes. Induction immunotherapy alone should not preclude the use of MIS in this setting.
Conflict of Interest Statement
M.J.B. is a consultant for AstraZeneca Pharmaceuticals, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. P.S.A. declares research funding from ATARA Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPactBio, Johnson & Johnson, Orion Pharma, and Outpace Bio; reports patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics; issued a patent method for the detection of cancer cells using virus, and pending patent applications on programmed cell death-1 dominant negative receptor, wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. J.M.I. has served as an advisory board member for AstraZeneca and Merck; as an uncompensated steering board member for Genentech; has received institutional research support from ArcherDx/Invitae, Guardant Health, GRAIL, and Intuitive Surgical and travel support from Intuitive Surgical; and has equity/ownership interest in LumaCyte. B.J.P. serves as a consultant for Intuitive Surgical, CEEVRA, Medtronic, and Becton Dickinson. G.R. has received royalties from Scanlan International, has served as an uncompensated advisor for AstraZeneca, and has served as a consultant for Medtronic. V.W.R. reports unreimbursed participation in Data Safety and Monitoring Committees for Cancer Research UK MARS II and RAMONA trials. S.S. is a member of the AstraZeneca Advisory Board. D.R.J. is a member of the Advisory Council for AstraZeneca and receives research grant support from Merck. D.M. serves on a steering committee for AstraZeneca; as a consultant for Johnson & Johnson, Bristol Myers Squibb, AstraZeneca, and Boston Scientific; and has been an invited speaker for Merck and Genentech.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Footnotes
Supported by the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.
Appendix E1
Table E1.
Chemotherapy and immunotherapy agents used in the study population
| Agent(s) | No. of patients |
|---|---|
| Atezolizumab | 37 |
| Nivolumab | 14 |
| Carboplatin/cisplatin + pemetrexed + nivolumab | 11 |
| Carboplatin + paclitaxel + nivolumab | 2 |
| Nivolumab + ipilimumab | 2 |
| Carboplatin + paclitaxel + pembrolizumab | 1 |
| Other/unknown | 2 |
References
- 1.National Cancer Institute Lung and bronchus stage distribution of SEER incidence cases, 2012-2021. https://seer.cancer.gov/statistics-network/explorer/application.html
- 2.National Comprehensive Cancer Network NCCN clinical practice guidelines in oncology: non-small cell lung cancer, version 3.2025. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450
- 3.Forde P.M., Spicer J., Lu S., et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973–1985. doi: 10.1056/NEJMoa2202170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Heymach J.V., Harpole D., Mitsudomi T., et al. Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med. 2023;389(18):1672–1684. doi: 10.1056/NEJMoa2304875. [DOI] [PubMed] [Google Scholar]
- 5.Provencio M., Nadal E., González-Larriba J.L., et al. Perioperative nivolumab and chemotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2023;389(6):504–513. doi: 10.1056/NEJMoa2215530. [DOI] [PubMed] [Google Scholar]
- 6.Wakelee H., Liberman M., Kato T., et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. 2023;389(6):491–503. doi: 10.1056/NEJMoa2302983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mathey-Andrews C., McCarthy M., Potter A.L., et al. Safety and feasibility of minimally invasive lobectomy after neoadjuvant immunotherapy for non–small cell lung cancer. J Thorac Cardiovasc Surg. 2023;166(2):347–355.e2. doi: 10.1016/j.jtcvs.2022.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Sepesi B., Nicolas Zhou N., William W.N., Jr., et al. Surgical outcomes after neoadjuvant nivolumab or nivolumab with ipilimumab in patients with non–small cell lung cancer. J Thorac Cardiovasc Surg. 2022;164(5):1327–1337. doi: 10.1016/j.jtcvs.2022.01.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bott M.J., Yang S.C., Park B.J., et al. Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non–small cell lung cancer. J Thorac Cardiovasc Surg. 2019;158(1):269–276. doi: 10.1016/j.jtcvs.2018.11.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bott M.J., Cools-Lartigue J., Tan K.S., et al. Safety and feasibility of lung resection after immunotherapy for metastatic or unresectable tumors. Ann Thorac Surg. 2018;106(1):178–183. doi: 10.1016/j.athoracsur.2018.02.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Feldman H., Sepesi B., Leung C.H., et al. Surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non–small cell lung cancer. J Thorac Cardiovasc Surg. 2024;167(4):1444–1453.e4. doi: 10.1016/j.jtcvs.2023.09.073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Rosner S., Reuss J.E., Zahurak M., et al. Five-year clinical outcomes after neoadjuvant nivolumab in resectable non–small cell lung cancer. Clin Cancer Res. 2023;29(4):705–710. doi: 10.1158/1078-0432.CCR-22-2994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Clavien P.A., Barkun J., de Oliveira M.L., et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250(2):187–196. doi: 10.1097/SLA.0b013e3181b13ca2. [DOI] [PubMed] [Google Scholar]
- 14.Martini N., Melamed M.R. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70(4):606–612. [PubMed] [Google Scholar]
- 15.Brandt W.S., Bouabdallah I., Tan K.S., et al. Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma. J Thorac Cardiovasc Surg. 2018;155(3):1212–1224.e3. doi: 10.1016/j.jtcvs.2017.09.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chu N.Q., Tan K.S., Dycoco J., et al. Determinants of successful minimally invasive surgery for resectable non-small cell lung cancer after neoadjuvant therapy. J Thorac Cardiovasc Surg. 2025;169(3):753–762.e6. doi: 10.1016/j.jtcvs.2024.08.012. [DOI] [PubMed] [Google Scholar]
- 17.De Leyn P., Dooms C., Kuzdzal J., et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non–small cell lung cancer. Eur J Cardiothorac Surg. 2014;45(5):787–798. doi: 10.1093/ejcts/ezu028. [DOI] [PubMed] [Google Scholar]
- 18.Chaft J.E., Shyr Y., Sepesi B., Forde P.M. Preoperative and postoperative systemic therapy for operable non–small-cell lung cancer. J Clin Oncol. 2022;40(6):546–555. doi: 10.1200/JCO.21.01589. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Deng H., Zhao Y., Cai X., et al. PD-L1 expression and tumor mutation burden as pathological response biomarkers of neoadjuvant immunotherapy for early-stage non–small cell lung cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2022;170 doi: 10.1016/j.critrevonc.2022.103582. [DOI] [PubMed] [Google Scholar]
- 20.Allaeys T., Berzenji L., Van Schil P.E. Surgery after induction targeted therapy and immunotherapy for lung cancer. Cancers. 2021;13(11):2603. doi: 10.3390/cancers13112603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Seymour L., Bogaerts J., Perrone A., et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–e152. doi: 10.1016/S1470-2045(17)30074-8. [DOI] [PMC free article] [PubMed] [Google Scholar]