Abstract
Background
Adjuvant targeted therapy represents the standard of care for patients with resectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Neoadjuvant therapy can improve surgical and survival outcomes. This study aimed to compare the effectiveness of neoadjuvant immunochemotherapy (NICT) and neoadjuvant targeted therapy plus chemotherapy (NTCT) for EGFR-mutated NSCLCs.
Methods
In this multi-center retrospective study, we reviewed patients with EGFR-mutated NSCLC who underwent surgery following NICT or NTCT. The primary end point was major pathologic response (MPR), and the secondary end points included pathologic complete response (pCR) and 1-year disease-free survival (DFS).
Results
This study included 89 patients (53 females, 36 males) with a median age of 57 (Interquartile range [IQR], 51–57) years. Of these, there were 44 and 45 patients undergoing surgery following NICT and NTCT respectively. Patients who received NICT had a more advanced clinical T stage (p = 0.018), a higher frequency of harboring EGFR exon 20 insertion (P = 0.035) and a shorter length of hospital stay (p = 0.005), compared with those who received NTCT. The MPR rate was 29.5% (95% confidence interval [CI], 16.8–45.2) in the NICT group, compared with 15.6% (95%CI, 6.5–29.5) in the NTCT group (p = 0.185). The 1-year DFS rates were 0.872 (95%CI, 0.762–0.998) in the NICT group and 0.721 (95%CI, 0.586–0.887) in the NTCT group (p = 0.18).
Conclusions
NICT seemed to be an effective treatment for patients with EGFR-mutated NSCLC, further randomized controlled trials are in need to validate the safety and efficacy of NICT in this setting.
Keywords: EGFR, NSCLC, Neoadjuvant therapy, Immunotherapy, EGFR-TKIs
Introduction
Approximately 30% of patients with non-small cell lung cancer (NSCLC) have epidermal growth factor receptor (EGFR) mutations [1, 2]. For resectable NSCLC with EGFR mutations, adjuvant targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) is the standard of care [3, 4]. Neoadjuvant therapy can improve surgical and long-term outcomes. So far, neoadjuvant chemotherapy remains the standard of care for patients with EGFR-mutated NSCLC, although the pathologic response outcomes are poor [5, 6].
Recently, a pivotal phase III study demonstrated improved MPR rate with osimertinib alone or combined with chemotherapy over chemotherapy in patients with EGFR-mutated NSCLC [7]. Meanwhile, several phase III studies revealed that neoadjuvant immunochemotherapy can statistically improve pathologic and survival outcomes of patients with NSCLC compared with chemotherapy [8–12]. However, these studies often excluded patients with EGFR-mutated NSCLC, because EGFR mutant tumors have generally low response to immunotherapy [5, 13]. On the other hand, several studies with a relatively small sample size shed light on the effectiveness of immunochemotherapy on EGFR mutant tumors [14–16]. Therefore, it is controversial whether EGFR mutant tumors respond better to EGFR-TKIs or to immunochemotherapy. This study aims to compare the effectiveness of neoadjuvant immunochemotherapy (NICT) and neoadjuvant targeted therapy plus chemotherapy (NTCT) in patients with EGFR mutant tumors.
Methods
This is a multi-center retrospective observational study comparing the clinical outcomes of patients with EGFR-mutated NSCLC undergoing surgery followed by NICT or NTCT.
Patients
Patients with EGFR-mutated NSCLC who underwent surgery after neoadjuvant therapy were reviewed in 4 high-volume lung cancer surgery centers in China. The NICT group and NTCT group comprised patients who underwent surgery from November 2020 to May 2025 and from January 2016 to May 2025, respectively. Inclusion criteria included: age over 18 years, known EGFR mutation and receipt of NICT or NTCT before surgery. Exclusion criteria were as follows: component of small cell cancer and other types of neoadjuvant treatment. Data were retrospectively collected from the hospital information system. Lymph node status before surgery was diagnosed by either contrast-enhanced computed tomography, positron emission tomography, or endobronchial ultrasound-guided transbronchial needle aspiration.
Treatment
The treatment regimens, including neoadjuvant treatment, surgery and adjuvant treatment were discussed by a multidisciplinary team. All patients made their own decision on treatment after a comprehensive discussion about the pros and cons of different treatments. The NICT regimen was a PD-1 inhibitor (camrelizumab, sintilimab, tislelizumab, toripalimab, pembrolizumab, nivolumab) or PD-L1 inhibitor (durvalumab) combined with platinum-based chemotherapy. The NTCT regimen included EGFR-TKI (gefitinib, icotinib, almonertinib, befotertinib, osimertinib, furmonertinib, sunvozertinib) combined with platinum-based chemotherapy. More specifically, of 44 patients who received NICT, 13 patients received sintilimab, 9 tislelizumab, 8 pembrolizumab, 7 camrelizumab, 2 nivolumab, 1 toripalimab and 1 durvalumab, leaving 3 patients with missing data on the regimen. Data on chemotherapy regimens are available for 42 patients, all of whom received platinum-based chemotherapy, 25 received pemetrexed, 12 received albumin-bound paclitaxel, 5 received paclitaxel. On the other hand, 19 of 45 patients received first-generation EGFR-TKIs (12 icotinib and 7 gefitinib), 26 patients received third-generation EGFR-TKIs (4 almonertinib, 13 osimertinib, 7 furmonertinib, 1 befotertinib and 1 sunvozertinib). Data on chemotherapy regimens are available for 41 patients in the NTCT group, all of whom received platinum-based chemotherapy, 34 received pemetrexed, 3 albumin-bound paclitaxel, 3 paclitaxel and 1 Gemcitabine.
Pathologic examination, follow-up and outcomes
Clinical TNM staging was performed according to the American Joint Committee on Cancer (8th edition). Pathologic samples were evaluated by 2 independent pathologists according to IASLC multidisciplinary recommendations [17]. R0 resection indicates a both macroscopically and microscopically margin-negative resection. R1 resection indicates microscopic margins are positive for tumor without macroscopic residual tumor. R2 resection indicates a macroscopic residual tumor that was not resected. Major pathologic response (MPR) was defined as less than or equal to 10% residual viable tumor. Pathological complete response (pCR) was defined as no viable residual tumor. Objective response rate (ORR) is the proportion of patients who have partial response (PR) or complete response (CR) after neoadjuvant treatment, disease control rate (DCR) is the percentage of patients who achieved stable disease (SD) or PR or CR. CR is defined as no detectable evidence of tumor, PR is defined as at least a 30% decrease in sum of diameters of tumor from baseline, SD is defined as a < 30% decrease and a < 20% increase in sum of diameters, progressive disease (PD) is defined as a ≥ 20% increase in sum of diameters.
Statistical analysis
Statistical analyses were performed using R statistical software 4.5.0. Continuous variables were summarized as mean and standard deviation (SD) and analyzed by the independent-samples T test if normally distributed, otherwise were summarized as median and interquartile range (IQR) and analyzed by the Mann-Whitney test. Normal distribution of continuous variables was evaluated by the Shapiro-Wilk Normality test. Categorical variables were summarized by number and proportions and analyzed by the Chi-Square test or Fisher’s exact test when the Chi-Square test assumptions were not met. Survival was estimated using the Kaplan-Meier method and comparison was evaluated by the log-rank test. The differences in MPR rates with 95% CIs were analyzed using exact binomial confidence interval method. A multivariable Cox proportional hazard model was performed to evaluate disease-free survival while accounting for other potential variables. Variables with a p-value of < 0.2 at univariable analysis were included for a multivariable analysis. A p-value smaller than 0.05 was considered statistically significant.
Results
Characteristics of the patients
Ninety-one patients with EGFR-mutated NSCLC received surgery following neoadjuvant chemotherapy plus targeted therapy and/or immunotherapy. After excluding one patient with a combination of squamous cell carcinoma and small cell cancer and one patient received neoadjuvant immunochemotherapy plus targeted therapy, 89 patients (53 females and 36 males) were included in the study with a median age of 57 years (Interquartile range, IQR 51–57 years). Of all patients, 6 were in cStage IB, 2 in cStage IIA, 23 in cStage IIB, 40 in cStage IIIA, 14 in cStage IIIB, 4 in cStage IVA. Of these, 44 patients underwent surgery following NICT and 45 patients following NTCT. In terms of baseline characteristics, significant differences between the NICT group and the NTCT group were observed in clinical T stage and EGFR mutation types (Table 1). Patients in the NICT group had more advanced clinical T stages (cT3-4, 19 [43.2%] patients vs. 8 [17.8%] patients, p = 0.018), a higher frequency of harboring EGFR exon 20 insertion (20.5% vs. 2.2%, P = 0.035), compared with those in the NTCT group. The distribution of clinical stages among patients in the NICT group and in the NTCT group were as follows: 3 (6.81%) cStage IB, 13 (9.54%) cStage IIB, 17 (38.63%) cStage IIIA, 11 (25.00%) cStage IIIB and 3 (6.67%) cStage IB, 2 (4.44%) cStage IIA, 10 (22.22%) cStage IIB, 23 (48.89%) cStage IIIA, 3 (6.67%) cStage IIIB, 4 (8.89%) cStage IVA, respectively. More than half of the patients (28 [63.6%] in the NICT group and 31 [68.9%] in the NTCT group) in both groups received 1–2 cycles of chemotherapy in the neoadjuvant setting. Treatment duration of targeted therapy was documented in 40 out of 45 patients in the NTCT group, the median treatment duration was 60 (IQR, 22.75-114.75) days. More specifically, treatment duration of the first-generation of EGFR-TKIs, the third-generation of EGFR-TKIs, and osmertinib were 60 (IQR, 28–178) days, 42 (IQR, 21–108) days and 24 (IQR, 15.5–166) days.
Table 1.
Baseline characteristics stratified by neoadjuvant therapy
| Characteristics | NICT, n = 44 | NTCT, n = 45 | P value |
|---|---|---|---|
| Age, yrs, median (IQR) | 58 (51.00, 62.50) | 56 (51.00, 64.00) | 0.889 |
| Sex, n (%) | 0.462 | ||
| Female | 24 (54.5%) | 29 (64.4%) | |
| Male | 20 (45.5%) | 16 (35.6%) | |
| BMI, kg/m2, mean (SD) | 23.65 (2.72) | 24.18 (3.37) | 0.426 |
| PD-L1 expression, n (%) | 0.445 | ||
| < 1 | 5 (12.5%) | 9 (18.4%) | |
| >=1 | 14(27.5%) | 12 (26.3%) | |
| Unknown | 25 (60%) | 24 (55.3%) | |
| Histology, n (%) | 0.153 | ||
| Adenocarcinoma | 39 (88.6%) | 39 (86.7%) | |
| Adenosquamous carcinoma | 0 (0%) | 3 (6.7%) | |
| Squamous | 5 (11.4%) | 2 (4.4%) | |
| SMARCA4 deficient tumor | 0 (0%) | 1 (2.2%) | |
| cT, n (%) | 0.018 | ||
| T1-2 | 25 (56.8%) | 37 (82.2%) | |
| T3-4 | 19 (43.2%) | 8 (17.8%) | |
| cN, n (%) | 0.389 | ||
| N0 | 8 (18.2%) | 10 (22.2%) | |
| N1 | 12 (27.3%) | 7 (15.6%) | |
| N2 | 23 (52.3%) | 28 (62.2%) | |
| N3 | 1 (2.3%) | 0 (0%) | |
| cStage, n (%) | |||
| IB-IIB | 16 (36.4%) | 15 (33.3%) | 0.938 |
| IIIA-IVA | 28 (64.6%) | 30 (66.7%) | |
| Neoadjuvant chemotherapy cycles, n (%) | 0.539 | ||
| 1–2 | 28 (63.6%) | 31(68.9%) | |
| >=3 | 16 (36.4%) | 12 (26.7%) | |
| unknown | 0 (0%) | 2 (4.4%) | |
| EGFR mutation types, n (%) | 0.035 | ||
| 19del | 13 (29.5%) | 19 (42.2%) | |
| 20ins | 9 (20.5%) | 1 (2.2%) | |
| 21L858R | 16 (36.4%) | 21 (46.7%) | |
| Uncommon | 6 (13.6%) | 4 (8.9%) |
Abbreviations:NICT neoadjuvant immunochemotherapy, NTCT neoadjuvant targeted therapy plus chemotherapy, n number, yrs years, IQR Interquartile range, BMI body mass index, PD-L1 programmed death-ligand 1, T tumor, N lymph node, EGFR epidermal growth factor receptor, 19del exon 19 deletion, 20ins exon 20 insertion, 21L858R exon 21 L858R
Surgical outcomes
Fifty-seven (64.04%) patients documented time from last neoadjuvant treatment to surgery, 33 (IQR, 26–43) days in the NICT group and 28 (IQR, 16-34.5) days in the NTCT group. There was no difference in the operation time between the two groups (Table 2). Patients in the NICT group had a shorter length of hospital stay (median [IQR], 9 [7, 12] vs. 12 [10, 18], P = 0.005) than those in the NTCT group (Table 2). No difference in the surgical margin was found between the two groups. MPR was confirmed in 13 (29.5%, 95% confidence interval [CI], 16.8–45.2) patients in the NICT group, which was in trend higher than that 7 (15.6%, 95% CI, 6.5–29.5) of those in the NTCT group without statistically significant difference (Fig. 1; Table 2, p = 0.185). Regarding patients with sensitizing mutations, 9 (31.03%) patients in the NICT group achieved MPR, and 7 of 40 (17.5%) patients in the NTCT group achieved MPR. Patients who achieved MPR were more likely to receive at least 3 cycles of chemotherapy in the neoadjuvant setting than those who did not (Table 3). A similar result was found for pCR as only 4 of 44 (9.1%) patients and 2 of 45 (2.2%) patients achieved pCR in the NICT group and NTCT group, respectively. The NTCT group demonstrated a higher rate of receiving adjuvant targeted therapy (32 [71.1%] vs. 15 [34/1%], p < 0.001) than the NICT group (Table 2). Eighty-one patients were assessed for ORR, of whom 43 patients in the NICT group achieved an ORR of 83.72% and 33 patients in the NTCT group achieved an ORR of 86.84%. DCR was 100% in the NICT group and 97.37% in the NTCT group. In terms of downstaging, 25 of 41 (60.98%) patients in the NICT group and 19 of 39 (48.72%) patients in the NTCT group achieved T-stage downstaging, and 22 of 41 (53.66%) patients in the NICT group and 11 of 39 (28.21%) patients in the NTCT group achieved N-stage downstaging.
Table 2.
Surgical outcomes and pathologic assessment stratified by neoadjuvant therapy
| Characteristics | NICT, n = 44 | NTCT, n = 45 | P value |
|---|---|---|---|
| OP time, mins, median (IQR) | 145 (113.5, 167.5) | 130 (98, 180) | 0.381 |
| Length of stay, days, median (IQR) | 9 (7, 12) | 12 (10, 18) | 0.005 |
| Surgical margin, n (%) | 0.368 | ||
| R0 | 44 (100%) | 43 (95.6%) | |
| R1 | 0 (0%) | 1 (2.2%) | |
| R2 | 0 (0%) | 1 (2.2%) | |
| pCR, n (%) | 0.523 | ||
| No | 40 (90.9%) | 43 (95.6%) | |
| Yes | 4 (9.1%) | 2 (4.4%) | |
| MPR, n (%) | 0.185 | ||
| No | 31 (70.5%) | 38 (84.4%) | |
| Yes | 13 (29.5%) | 7 (15.6%) | |
| Adjuvant therapy, n (%) | < 0.001 | ||
| Targeted therapy | 15 (34.1%) | 32 (71.1%) | |
| Others | 25 (56.8%) | 8 (17.8%) | |
| Unknown | 4 (9.1%) | 5 (11.1%) |
Abbreviations:NICT neoadjuvant immunochemotherapy, NTCT neoadjuvant targeted therapy plus chemotherapy, n number, OP operation, mins minutes, IQR interquartile range, pCR pathologic complete response, MPR major pathologic response
Fig. 1.
The forest plot shows major pathologic response (MPR) rates in subgroups
Table 3.
Clinical characteristics stratified by MPR
| Characteristics | MPR, n = 20 | nonMPR, n = 69 | P value |
|---|---|---|---|
| Age, yrs, median (IQR) | 55.00 (50.00, 59.50) | 59.00 (54.00, 64.00) | 0.130 |
| Sex, n (%) | 0.411 | ||
| Female | 14 (70%) | 39 (56.5%) | |
| Male | 6 (30%) | 30 (43.5%) | |
| BMI, kg/m2, mean (SD) | 22.97 (2.16) | 24.18 (3.23) | 0.130 |
| PD-L1 expression, n (%) | 1.000 | ||
| < 1 | 4 (20%) | 10 (14.5%) | |
| >=1 | 7 (35%) | 19 (27.5%) | |
| unknown | 9 (45%) | 40 (60.0%) | |
| Histology, n (%) | 0.415 | ||
| Adenocarcinoma | 17 (85%) | 61 (88.4%) | |
| Adenosquamous carcinoma | 0 (0%) | 3 (4.3%) | |
| Squamous | 3 (15%) | 4 (5.8%) | |
| SMARCA4 deficient tumor | 0 (0%) | 1 (1.4%) | |
| cT, n (%) | 1.000 | ||
| T1-2 | 14 (70%) | 48 (69.6%) | |
| T3-4 | 6 (30%) | 21 (30.4%) | |
| cN, n (%) | 0.462 | ||
| N0 | 4 (20%) | 14 (20.3%) | |
| N1 | 2 (10%) | 17 (24.6%) | |
| N2 | 14 (70%) | 37 (53.6%) | |
| N3 | 0 (0%) | 1 (1.4%) | |
| cStage, n (%) | |||
| IB-IIB | 6 (30^) | 25 (36.2%) | 0.804 |
| IIIA-IVA | 14 (70%) | 44 (63.8%) | |
| Neoadjuvant therapy, n (%) | 0.185 | ||
| NICT | 13 (65%) | 31 (44.9%) | |
| NTCT | 7 (35%) | 38 (55.1%) | |
| Neoadjuvant chemotherapy cycles, n (%) | 0.027 | ||
| 1–2 | 9 (45%) | 50(72.5%) | |
| >=3 | 11 (55%) | 17 (24.6%) | |
| unknown | 0 (0%) | 2 (2.9%) | |
| EGFR mutation types, n (%) | 0.591 | ||
| 19del | 6 (30%) | 26(37.7%) | |
| 20ins | 3 (15%) | 7 (10.1%) | |
| 21L858R | 10 (50%) | 27 (39.1%) | |
| Uncommon | 1 (5%) | 9 (13%) |
AbbreviationsNICT neoadjuvant immunochemotherapy, NTCT neoadjuvant targeted therapy plus chemotherapy, n number, yrs years, IQR Interquartile range, BMI body mass index, PD-L1 programmed death-ligand 1, T tumor, N lymph node, EGFR epidermal growth factor receptor, 19del exon 19 deletion, 20ins exon 20 insertion, 21L858R exon 21 L858R
Survival outcomes
Five out of 89 patients were lost to follow-up, leaving 84 patients available for survival analyses. The median follow-up was 15 (IQR, 8.75–29.25) months for the whole cohort, 14 (IQR, 10-23.25) months for the NICT group and 19.5 (IQR, 7.75–23.45) months for the NTCT group. Of these, 26 (30.95%) patients experienced disease recurrence after surgery. Kaplan-Meier curves of DFS in both groups were plotted and no statistical difference was identified by log-rank test (Fig. 2A, p = 0.18). The estimated 1-year DFS rate was 87.2% (95% CI, 76.2%-99.8%) in the NICT group and 72.11% (95% CI, 58.63%-88.7%) in the NTCT group.
Fig. 2.
A Kaplan-Meier curves of disease-free survival (DFS) stratified by neoadjuvant therapy. B The forest plot summarizes multivariable analysis of prognostic variables in DFS
To identify potential risk factors for disease recurrence, univariable and multivariable analyses were conducted using Cox proportional hazards regression model (Table 4; Fig. 2B). Multivariable analysis demonstrated that cT3-4 (p = 0.039), neoadjuvant therapy with NTCT (p = 0.013) and non-sensitizing EGFR mutations (p = 0.026) were statistically associated with worse DFS (Fig. 2B).
Table 4.
Univariable and multivariable Cox proportional hazard regression model analysis evaluating disease-free survival
| Variable | Univariable Analysis | Multivariable Analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P value | |
| Age, > 65 yrs | 1.431 (0.571–3.588) | 0.445 | ||
| Sex, male | 1.067 (0.494–2.305) | 0.869 | ||
| BMI, overweight | 0.838 (0.347-2,024) | 0.695 | ||
| Histopathology, others | 2.481 (0.896–6.87) | 0.080 | 1.713 (0.574–5.118) | 0.335 |
| cT, cT3-4 | 1.802 (0.786–4.133) | 0.164 | 2.857 (1.053–7.750) | 0.039 |
| cN, reference N0 | ||||
| N1 | 0.789 (0.253–2.458) | 0.683 | ||
| N2-3 | 0.765 (0.293–1.997) | 0.584 | ||
| PD-L1, PD-L1 > = 1 | 0.609 (0.175–2.121) | 0.436 | ||
| Neoadjuvant therapy, NTCT | 1.753 (0.777–3.957) | 0.177 | 3.268 (1.285–8.313) | 0.013 |
| Cycles of neoadjuvant chemotherapy, 1–2 cycles | 0.672 (0.293–1.541) | 0.347 | ||
| MPR, nonMPR | 1.714 (0.514–5.717 | 0.381 | ||
| EGFR mutation type, sensitizing mutations | 0.533 (0.226–1.256) | 0.15 | 0.352 (0.140–0.883) | 0.026 |
| Adjuvant therapy, targeted therapy | 0.926 (0.401–2.139) | 0.858 | ||
Abbreviations:HR hazard ratio, CI confidence interval, n number, yrs years, BMI body mass index, PD-L1 programmed death-ligand 1, T tumor, N lymph node, MPR major pathologic response, EGFR epidermal growth factor receptor, NTCT neoadjuvant targeted therapy plus chemotherapy
Comment
This is a large series comparing the effectiveness of NICT and NTCT for patients with EGFR-mutated NSCLC. The MPR rate was found to be 29.5% in the NICT group and 15.6% in the NTCT group. In the neoadjuvant setting, irrespective of NICT and NTCT, patients who achieved MPR had a higher probability of receiving at least 3 cycles of chemotherapy than those who did not. Besides, NICT was associated with better 1-year DFS after adjusting for histopathology, cT and EGFR mutation type.
In the NICT group, 13 (29.5%) patients achieved MPR after surgery, which was similar to that reported in previous studies [14–16, 18]. Most of these studies demonstrated a MPR rate around 40% after NICT [14–16], but another two studies showed a MPR rate lower than 10% [5, 18]. With respect to prospective clinical trials, He et al. reported that neoadjuvant durvalumab plus chemotherapy yields a MPR rate of 2/26 (7.7%) in the phase 3 AEGEAN trial [5], Zhang et al. found a MPR rate of 44.4% after neoadjuvant sintilimab plus chemotherapy in the CTONG 2104 trial [14]. The range of reported MPR rate after NICT was wide, possibly due to small sample sizes and different cycles of neoadjuvant therapy. On the other hand, 7 (15.6%) patients achieved MPR after surgery followed by NTCT, which was comparable to that previously reported [7, 19–21]. Li et al. conducted a multi-center retrospective study and reported a MPR rate of 11/38 (28.9%) after neoadjuvant osimertinib [19]. Two phase II trials demonstrated that neoadjuvant osimertinib for six weeks before surgery results in a MPR rate of 10.7% [20] and neoadjuvant osimertinib for 8 weeks yields a MPR rate of 14.8% [21]. The phase III NeoADAURA trial revealed that neoadjuvant osimertinib for 9 weeks given with or without chemotherapy can result in a MPR rate of 26% or 25% respectively [7]. Taken together, it seems that the longer the neoadjuvant treatment duration, the better the surgical results. A previous study shed light on the point that extended neoadjuvant EGFR TKI treatment duration might result in better MPR rate [22]. In the limited studies that evaluated neoadjuvant therapy for patients with EGFR mutation, immunochemotherapy is likely to confer a higher MPR rate than EGFR-TKIs.
This study showed that patients who achieved MPR were more likely to receive at least 3 cycles of chemotherapy in the neoadjuvant setting than those who did not. A previous phase II trial found that increasing treatment cycles of neoadjuvant immunochemotherapy from 2 to 3 lead to an improvement in MPR rate [23], although several retrospective studies failed to identify a benefit in this setting [24, 25]. When it comes to chemotherapy plus targeted therapy, no data have shown that 3 cycles of chemotherapy can confer more benefits than 2 cycles. In addition, a retrospective study revealed that outcomes with immunotherapy were worse in patients with EGFR 19del mutation than those in patients with wild-type EGFR, but comparable to those in patients with EGFR 21L858R mutation [13]. Our study revealed similar results, identifying a MPR rate of 23.07% in patients with EGFR 19del, 33.33% in patients with EGFR 20ins and 37.5% in patients with EGFR 21L858R after surgery followed by NICT. It is worth mentioning that tumors with EGFR 21L858R mutation have substantially more non-synonymous mutations compared with EGFR 19del tumors [26]. Therefore, it is possible that response to immunotherapy is associated with EGFR mutation types. Besides, as high PD-L1 expression is associated with better response to immunotherapy, we observed these patients (PD-L1 expression > = 50%) in our cohort, identifying 1 of 4 (25%) patients in the NTCT group achieved MPR and 3 of 4 (75%) in the NICT group did so.
Our study indicated that NICT might outperform NTCT in reducing the risk of disease recurrence, although a statistically difference in adjuvant therapy with EGFR-TKIs were found between the two groups. The phase III Adaura trial determined that osimertinib significantly improves DFS and overall survival in patients with resected, EGFR-mutated NSCLC [27]. Moreover, a previous study reported that EGFR TKIs significantly reduce disease recurrence in patients with EGFR-mutated NSCLC, while immunochemotherapy does not [28]. However, data on NICT for patients with EGFR-mutated NSCLC are still limited. Currently, it seems that immunochemotherapy has only received acceptance as second-line treatment in patients with EGFR-mutant-advanced NSCLC [29]. A real-world study indicated that the efficacy of immunotherapy for EGFR-mutated NSCLC is associated with PD-L1 expression [30]. Besides, approximately half of EGFR-mutated NSCLCs are PD-L1 positive (expression > 1%), about 20% of these are PD-L1 high expression (expression > 50%) [31]. Therefore, our study indicated that immunochemotherapy for EGFR-mutated NSCLC in the neoadjuvant setting may not follow the pattern established in the adjuvant and first-line settings.
Limitations
The retrospective nature and small sample size are major limitations of the study. Data were retrospectively collected from 4 centers; missing data were treated with unknown data points. Most of the variables have less than 10% missing data except for adjuvant therapy (9/89, 10.1%) and PD-L1 expression (49/89, 55.1%). Unknown imbalance between the two groups in adjuvant therapy and PD-L1 expression might account for the observed differences in MPR. Besides, patients received different kinds of EGFR-TKIs, PD-1 or PD-L1 inhibitors, and chemotherapy regimens. Moreover, patients in the two groups were from different time frames, which might introduce bias in many ways, such as treatment regimens, supportive medical care and data quality. Nevertheless, this is a large cohort study that directly compared the effectiveness of NICT and NTCT in patients with EGFR-mutated NSCLC.
Conclusions
In summary, NICT seemed to be an effective treatment for patients with EGFR-mutated NSCLC, further randomized controlled trials are needed to establish the safety and efficacy of NICT in this setting.
Acknowledgements
The authors wish to thank all patients for participating in this study.
Abbreviations
- NICT
Neoadjuvant Immunochemotherapy
- NTCT
Neoadjuvant targeted therapy plus chemotherapy
- NSCLC
Non-small cell lung cancer
- EGFR
Epidermal growth factor receptor
- MPR
Major pathologic response
- pCR
Pathological complete response
- DFS
Disease-free survival
- TKIs
Tyrosine kinase inhibitors
- PD-1
Programmed death 1
- PD-L1
Programmed death ligand-1
Authors’ contributions
Conception: FL, YQ, ZYG. Design of the work: FL, CQZ, LYH, ZMW, GCY. The acquisition of data: FL, CQZ, LYH, ZMW, GCY. Analysis of data: FL, CQZ, LYH, ZMW, GCY. Interpretation of data: FL, CQZ, LYH, ZMW, GCY. Drafted the manuscript: FL, CQZ, LYH, ZMW, GCY. Substantively revised the manuscript: YQ, ZYG. All authors have read and agreed to the published version of the manuscript.
Funding
Yu Qi received funding from the National Natural Science Foundation of China (No. 82473289), the Cultivation Project of Henan Health Science and Technology Innovation Talents (No. YXKC2022014) and the Higher Education Key Research Project of Henan Province (No. 25A320038). Feng Li received funding from the Henan Province Medical Science and Technology Key Research and Joint Construction Project (No. LHGJ20220284).
Data availability
Data will be made available upon reasonable request from qualified researchers to Prof. Yu Qi ([qiyu@zzu.edu.cn](mailto:qiyu@zzu.edu.cn)).
Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2024-KY-2261-002) and conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent for neoadjuvant therapy as well as surgery was obtained from each patient, but informed consent for the use of clinical data was waived by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be made available upon reasonable request from qualified researchers to Prof. Yu Qi ([qiyu@zzu.edu.cn](mailto:qiyu@zzu.edu.cn)).