The beginning of a new era in induction treatment for operable non-small cell lung cancer: a narrative review
Review Article

The beginning of a new era in induction treatment for operable non-small cell lung cancer: a narrative review

Shuichi Shinohara1,2, Yusuke Takahashi1, Katsuhiro Masago3, Hirokazu Matsushita2, Hiroaki Kuroda1

1Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan; 2Division of Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Japan; 3Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan

Contributions: (I) Conception and design: S Shinohara; (II) Administrative support: H Kuroda, H Matsushita; (III) Provision of study materials or patients: S Shinohara, Y Takahashi, K Masago; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: S Shinohara, H Kuroda; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Hiroaki Kuroda, MD, PhD. Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan. Email:

Background and Objective: The survival benefit of induction therapy for non-small cell lung cancer (NSCLC) remains controversial. Recently, the outcomes of systemic therapy for NSCLC have dramatically changed with the advent of molecular target drugs and immune checkpoint inhibitors (ICIs). The present review was conducted to investigate the outcomes of induction therapy with reference to randomized control trials (RCTs).

Methods: We reviewed RCTs and ongoing clinical trials between 1990 and 2022 using relevant databases: PubMed, Web of Science, and EMBASE database. We investigated the outcomes of induction therapy.

Key Content and Findings: Induction therapy was associated with longer overall survival in comparison to surgery alone in several RCTs for stage III disease. However, its benefit in early-stage (I–II) disease was unclear. Regarding induction chemotherapy and chemoradiotherapy, the safety and survival outcomes did not differ between the two arms. Epidermoid growth factor receptor (EGFR) tyrosine kinase inhibitors as induction therapy in patients with proven EGFR mutations may be a sufficient choice for the improvement of overall survival. In ongoing single arm clinical trials and a randomized control study, the administration of ICIs as induction therapy was associated with a good pathological response and satisfactory safety, which will lead to a better survival outcome. Long-term observation is needed to evaluate the toxicity and survival impact of induction therapy with ICIs.

Conclusions: Induction chemotherapy and EGFR-TKIs for stage IIIA NSCLC may contribute to the improvement of survival outcomes although the effect of systemic therapy on stage I-II remains controversial. ICIs may be considered as a valuable treatment option because of their feasibility and safety for induction therapy.

Keywords: Non-small cell lung cancer (NSCLC); induction; neoadjuvant; immune checkpoint inhibitor (ICI); randomized control study

Submitted Jul 10, 2022. Accepted for publication Nov 25, 2022. Published online Feb 02, 2023.

doi: 10.21037/jtd-22-957


Lung cancer is the leading cause of cancer death worldwide and the most common type of cancer (1). Surgery is one of the curative treatment choices for non-small cell carcinoma (NSCLC), although NSCLC remains associated with poor overall survival (OS) with the exception of stage I disease. This is likely to be explained by the fact that approximately 30% of cases are diagnosed at an advanced stage (2), and a high incidence of local and distant recurrence (21–55%) after surgery (3-5). To prevent local and distant recurrence, it is essential to eliminate circulating tumor cells (6,7) and reduce the cancer volume at the local site before surgery, which helps to facilitate curative resection. Therefore, surgeons and oncologists assume that the combination of surgery and chemo- or chemoradiotherapy are optimal choices for the curative treatment of advanced NSCLC. Induction systemic therapy has therefore been regarded as a key therapeutic strategy for stage IIIA NSCLC. Consequently, several randomized control trials (RCTs) were conducted to elucidate whether induction chemotherapy contributes to the improvement of survival (8-11). Certainly, induction systemic therapy would be a choice for advanced NSCLC with IIIA disease; however, the best regimen for induction therapy remains unclear. We believe that efficacy and tumor volume reduction are the most important to accomplish complete resection for the choices of induction systemic therapy. Molecular target drugs, including epidermoid growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), have dramatically improved survival in advanced NSCLC (12-14). It is necessary to elucidate the possible application of EGFR-TKIs in induction therapy because EGFR-TKIs have relevant effects on the EGFR mutation harboring NSCLC. In addition, the advent of immune checkpoint inhibitors (ICIs) has dramatically changed drug therapy for NSCLC due to its remarkable efficacy in the treatment of tumors with the high expression of programmed death-ligand 1 (PD-L1) (15). A network meta-analysis showed that combination therapy with ICI and platinum doublet is better than monotherapy for inoperable NSCLC (16). Patients with high PD-L1 expression are greatly expected to N2 down staging and tumor shrinking, which leads to resect cancer completely. We would like to elucidate whether ICI therapy for operable NSCLC as induction therapy improves the poor OS. However, the efficacy and safety of ICI therapy before surgery remain unknown.

We consider these new drugs may control the long-term progression and restrain distant metastasis due to the cytotoxicity reaction for the circulating tumor cells and residual lymph node cancer cells. In this manuscript, we review the efficacy of induction systemic therapy for operable NSCLC referring RCTs and investigate the possible application of EGFR-TKI and ICI treatment in NSCLC induction therapy. We present the following article in accordance with the Narrative Review reporting checklist (available at


We reviewed the articles using terms via PubMed, Web of Science, and EMBASE (Table S1). Regarding ICI ongoing studies, we investigated using, and Chinese clinical trial registry. The eligible studies were searched from 1 January 1990 to 1 January 2022. The two reviewers independently screened the manuscripts according to the eligible criteria for the research. When the decision of the two reviewers is not coincided with a discussion, a third reviewer made a final decision (Table 1).

Table 1

The search strategy summary

Items Specification
Date of search From 1st February 2022 to 15 March 2022
Databases and other sources searched PubMed, Web of Science, Embase,, and Chinese clinical trial registry
Search terms used Please see Table S1
Timeframe From 1st January 1990 to 1st January 2022
Inclusion and exclusion criteria Inclusion criteria: randomized trials, induction chemotherapy, induction chemoradiotherapy
Exclusion criteria: the manuscript with the same trial
Selection process The two reviewers (S Shinohara, H Kuroda) independently screened the manuscripts according to the eligible criteria for the research. The articles satisfied with the inclusion criteria were obtained by H Matsushita and K Masago. When the decision of the two reviewers is not agreed with a discussion, a third reviewer (Y Takahashi) makes a final decision
Additional considerations Duplicated articles are excluded by the review authors


The included and excluded process is demonstrated in Figure S1 with regard of the narrative review of RCTs.

Comparison of induction chemotherapy (chemotherapy vs. surgery alone) with platinum doublet

The survival benefit of induction chemotherapy followed by surgery was summarized by several RCTs (9,17-21) (Table 2). Rosell et al. showed that the induction chemotherapy arm, who received mitomycin/ifosfamide/cisplatin, had better OS in comparison to the surgery alone arm among patients with stage IIIA disease (26 vs. 8 months, P<0.001) (20). Similarly, Roth et al. reported that patients treated with perioperative chemotherapy (cisplatin/cyclophosphamide/etoposide) showed better OS in comparison to those who received surgery alone (21 vs. 14 months, P=0.048) (21). However, several reports demonstrated no survival benefit of induction chemotherapy on OS in stage IIIA patients (26,27,29,31). Pass et al. demonstrated no significant difference for OS between their induction chemotherapy group and their surgery alone group. In particular, it should be noted that the studies included patients with multiple positive N2 disease (multiple positive N2: 13/23), which are considered to be inoperable according to the present criteria (31). Nagai et al. reported that induction chemotherapy showed no significant impact (27). Although the study was well designed, the recruitment for the eligible patients was too slow and the number of patients enrolled in the study did not meet the initial expectation (27). In addition, there were no patients with a complete response and the response rate was low (28%) (27).

Table 2

Characteristics of randomized control trial comparing induction therapy vs. non-induction therapy

Author Year Number Excluded Male Female Stage Treatment modality Treatment regimen Control mortality Results Outcome Study Complete resection
Chen et al. (17) 2013 356 19 259 78 I-IIIA CSCRiii MVP SCRiii 57.6 vs. 45.4 months (HR 1.67, P=0.016) Median survival (OS) Positive NR
Scagliotti et al. (9) 2012 270 0 225 45 IB-IIIA CS CDDP + GEM S 7.8 vs. 4.8 years, P=0.04 Median survival (OS) Positive 88% vs. 84%
Felip et al. (22) 2010 413 4 359 50 IA-IIIA CSRiii CBDCA + PTX SRiii 38.3% vs. 34.1% (HR 0.92, P=0.176) 5-year DFS rate Negative NR
Pisters et al. (23) 2010 354 17 222 115 IB-IIIA CS CBDCA + PTX S 62 vs. 40 months (HR 0.79, P=0.11) Median survival (OS) Negative 88% vs. 87%
Gilligan et al. (24) 2007 519 0 374 143 IA-IIIB CS CDDP + GEM or CBDCA + DOC or PTX etc. S 54 vs. 55 months (HR 1.02, P=0.86) Median survival (OS) Negative 81% vs. 79%
Sorensen et al. (25) 2005 90 0 NR NR IB-IIIA CS CDDP + PTX S 34.4 vs. 22.5 months*1 Median survival (OS) Negative 79% vs. 70%
Yao et al. (19) 2004 456 NR 333 123 III CS CDDP + GEM, CDDP + NVB, MVP, EP S 34.2% vs. 23.0% (P<0.001) 5-year OS rate Positive 87.0% vs. 83.7%
Yang et al. (26) 2005 40 0 NR NR IIIA CS CBDCA + GEM S 11/19 vs. 9/21 Total survival number Negative 89.5% vs. 90.5%
Nagai et al. (27) 2003 62 0 41 21 IIIA CS CDDP + VDS S 17 vs. 16 months (P=0.53) Median survival (OS) Negative 65% vs. 77%
Yi et al. (18) 2003 84 0 52 32 I-III CS MVP S no detail, but P=0.047 Total survival rate Positive NR
Depierre et al. (28) 2002 373 18 332 23 I-IIIA CSCRiii MIP SRiii 37 vs. 26 months (P=0.15) Median survival (OS) Negative 42.1% vs. 40.7%
Wu et al. (29) 2002 55 0 NR NR IIIA CS CBDCA + DOC S 36.4% vs. 19.2%*2 Total survival rate Nr 77.3% vs. 80.8%
Splinter et al. (30) 2000 79 0 NR NR IB-II CS CBDCA + PTX or CDDP + teniposide S NR*3 NR Nr NR
Rosell et al. (20) 1994 60 0 59 1 IIIA CSRiii MIP SRiii 26 vs. 8 months (P<0.001) Median survival (OS) Positive 85.1% vs. 90%
Roth et al. (21) 1998 60 0 44 16 IIIA CSC CDDP + CPA + etoposide S 21 vs. 14 months (P=0.048) Median survival (OS) Positive 60.7% vs. 65.6%
Pass et al. (31) 1992 27 0 12 15 IIIA CSC EP SRiii 28.7 vs. 15.6 months (P=0.095) Median survival (OS) Negative 84.6% vs. 85.7%
Dautzenberg et al. (11) 1990 26 0 24 2 II-III CSC CDDP + CPA + VDS S 21 vs. 23 months (P=0.85) Median survival (OS) Negative NR

*1, the difference was not significant although P value was not declared; *2, the present study was available on the conference abstract. *3, the median survival has not yet been reached. NR, not recorded; CSCRiii, induction chemotherapy followed by surgery, and adjuvant chemoradiotherapy for stage III; CS, induction chemotherapy followed by surgery; CSRiii, induction chemotherapy followed by surgery, and adjuvant radiotherapy for stage III; CSC, induction chemotherapy followed by surgery, and adjuvant chemotherapy; MVP, mitomycin + vinblastine + cisplatin; CDDP, cisplatin; GEM, gemcitabine; CBDCA, carboplatin; PTX, paclitaxel; DOC, docetaxel; NVB, vinorelbine; EP, etoposide + cisplatin; VDS, vindesine; MIP, mitomycin + ifosfamide + cisplatin; CPA, cyclophosphamide; SCRiii, surgery and adjuvant chemoradiotherapy for stage III; S, surgery alone; SRiii, surgery followed by adjuvant radiotherapy for stage III; HR, hazard ratio; OS, overall survival.

For patients with stage I-IIIA disease, the benefit of induction chemotherapy is unclear. Eight RCTs for stage I-IIIA NSCLC have been conducted (9,17,22-25,28,30). The Chemotherapy in Early stages NSCLC Trial (ChEST) reported that the induction chemotherapy arm (cisplatin plus gemcitabine) showed better OS in comparison to surgery alone (7.8 vs. 4.8 years, P=0.04) (9). The reason for the positive outcome in the induction chemotherapy arm was explained by the high response rate (35.4%) of this trial, and the statistically significant impact of preoperative chemotherapy on the outcomes in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% vs. 55.4%; P=0.002) (9). Unfortunately, the study was terminated early as the superiority of adjuvant chemotherapy was proven by other clinical trials in that time. Of note, in a subgroup analysis of patients with stage IB/IIA disease, there was no significant difference in OS between the induction chemotherapy arm and the surgery alone arm (HR, 1.02; 95% CI, 0.58–1.19; P=0.94) (9). On the other hand, among patients with stage IIB/IIIA disease, OS was longer in the induction chemotherapy arm than in the surgery alone arm (HR, 0.42; 95% CI, 0.25–0.71; P=0.001) (9). Similarly, the three arms clinical trial [Neoadjuvant/Adjuvant Taxol/Carboplatin Hope (NATCH)], which enrolled patients with IA-IIIA disease (T3N1) and excluded patients with N2 disease, demonstrated that the disease-free survival (DFS) of the induction chemotherapy and surgery alone group did not differ to a statistically significant extent (HR, 0.92; 95% CI, 0.81–1.04; P=0.17) (29). Moreover, a subgroup analysis of patients with stage II-IIIA disease showed that DFS tended to be better in the induction chemotherapy arm than in the surgery alone arm (HR, 0.81; 95% CI, 0.64–1.02; P=0.07) (29). Thus, induction chemotherapy improves the OS of patients with stage II/IIIA disease but not patients with stage I disease. The benefit of induction chemotherapy for I-IIIA disease was also proven by a meta-analysis (32,33). Song et al. reported that induction chemotherapy significantly improves OS in comparison to surgery alone in stage I-III NSCLS (HR, 0.84; 95% CI, 0.77–0.92; P<0.001) (33). The results in patients with stage IIIA disease were similar (HR, 0.84; 95% CI, 0.75–0.95; P=0.005). Thus, induction chemotherapy would significantly improve OS in patients with stage IIIA disease, but the outcome in early-stage disease, particularly stage I disease, is controversial. The best regimen is also unclear; thus, it should be investigated in a large RCT.

Lastly, the safety and feasibility are sufficient for induction therapy, even in the cases in which surgery is postponed. However, the complete resection rate of the induction therapy arm was also the same as that of the surgery alone arm (Table 1). Of note, this did not correspond with the favorable OS of patients who received induction therapy in comparison to those who received surgery alone. This may imply that, systemic intervention (e.g., chemotherapy, which regulates circulating tumor cells) leads to better OS by preventing distant metastasis rather than by providing local disease control.

However, these results should be interpreted carefully because the clinical trials were performed more than 10 years ago. The TNM classification and mediastinal lymph node staging are different in each era.

Comparison of the outcomes of chemotherapy vs. chemoradiotherapy

For stage IIIA (N2) disease, it remains unclear whether chemotherapy or chemoradiotherapy is better for induction therapy. Four RCTs showed no survival difference between induction chemotherapy and chemoradiotherapy arms (8,10,34,35) (Table 3). Thomas et al. conducted the largest RCT comparing induction chemoradiotherapy to chemotherapy followed by surgery among patients with pathologically proven N2 using mediastinoscopy (34). No significant difference in progression-free survival (PFS) was observed between the two groups (5-year PFS 16% vs. 14%; HR, 0.99, 95% CI, 0.81–1.19; P=0.87). The problem of the trial was the high rate of N3 disease (11.4%) and pneumonectomy (35.1%), which resulted in the poor prognosis. In addition, induction chemoradiotherapy followed by pneumonectomy was associated with high mortality in comparison to lobectomy (26% vs. 1%) in the INT0139 trial (36). Therefore, special attention is required when performing induction chemotherapy followed by pneumonectomy. As the same result, Pless et al. showed no survival difference between chemotherapy and chemoradiotherapy while the adverse events in chemotherapy were not increased in chemoradiotherapy (8). Katakami et al. reported that induction chemoradiotherapy did not improve PFS or OS did in comparison to induction chemotherapy (HR, 0.68; 95% CI, 0.38–1.21; P=0.187, HR, 0.77; 95% CI, 0.42–1.41; P=0.397, respectively) (10). While the study was terminated because of a low accrual rate, we the result should be interpreted with care.

Table 3

Characteristics of RCT comparing induction chemotherapy vs. chemoradiotherapy

Characteristics Pless et al. (8) Katakami et al. (10) Thomas et al. (34) Girard et al. (35)
Year 2015 2012 2008 2010
Number 232 60 558 62
Excluded 0 2 34 2
Male 155 40 431 46
Female 77 20 93 14
Treatment modality CRiiiS CRiiiS CRiiiS CRiiiS
Treatment regimen CDDP + DOC CBDCA + DOC CDDP + etoposide CDDP + VNR or CBDNA + PTX
Control mortality CS CS CSRiii CS
Control arm CDDP + DOC CBDCA + DOC CDDP + etoposide CDDP + VNR
Outcome 12.8 vs. 11.6 months (P=0.67) 39.6 vs. 29.9 months (HR 0.77, P=0.397) 32.4 vs. 33.0 months (P=0.54) 13 vs. 24 months (P=0.268)*2
Outcome Median event-free survival Median survival (OS) Median survival (OS) Median survival (OS)
Study Negative Negative Negative Negative
Complete resection 91% vs. 81% (P=0.06) 69.0% vs. 54.5%*1 84% vs. 77% 71.4% vs. 78.1%

*1, complete resection rate was re-calculated in the review as follows: the number of complete resections/that of patients undergone surgery. *2, the study is the three arm RCT. In the review, we declared the result of two arms. RCT, randomized control trial; CRiiiS, induction chemoradiotherapy for stage III followed by surgery; CSRiii, induction chemotherapy followed by surgery, and adjuvant radiotherapy for stage III; CS, induction chemotherapy followed by surgery; CDDP, cisplatin; DOC, docetaxel; CBDCA, carboplatin; VNR, vinorelbine; PTX, paclitaxel; HR, hazard ratio; OS, overall survival.

Tong et al. carried out a systematic review and meta-analysis to elucidate the efficacy and toxicity of induction chemoradiotherapy in comparison to chemotherapy (37). The manuscript indicated that the rates of grade 3–4 adverse events of leukopenia and nausea did not differ between the two groups (RR, 0.84; 95% CI, 0.40–1.77; P=0.65, RR, 1.50; 95% CI, 0.84–2.67; P=0.17, respectively). Unexpectedly, the incidence of grade 3–4 infection in the chemoradiotherapy group was significantly lower than that in the chemotherapy group (RR, 0.38; 95% CI, 0.16–0.94; P=0.04). Thus, chemoradiotherapy would be acceptable with regard to safety and tolerability. Interestingly, chemoradiotherapy has benefits in terms of R0 resection, although there is no survival contribution by a meta-analysis Chen et al. reported (38). The curative resection and pathological response may be surrogate marker, but special attention is needed to consider the results of clinical trials with advanced NSCLC.

Although several RCTs were conducted, whether chemotherapy or chemoradiotherapy is better has been controversial.

Comparison of the outcomes of EGRF TKI vs. platinum-based chemotherapy

Variations in induction therapy regimens have a large influence on OS. Since induction systemic therapy was started, cisplatin-based regimens have been the gold standard. Whereas, the appearance of EGFR-TKIs has dramatically changed the therapeutic strategy for advanced NSCLC. EGFR-TKIs significantly prolong OS and PFS in advanced NSCLC harboring EGFR mutations. Because of the large benefit of EGFR-TKIs in advanced NSCLC, many oncologists and surgeons consider that EGFR-TKIs would be beneficial in neoadjuvant settings. Recently, two RCTs showed that EGFR-TKI induction therapy for patients with adenocarcinoma harboring EGFR mutations tended to improve OS and PFS in comparison to platinum-based regimens (39,40) (Table 4).

Table 4

Characteristics of randomized control trial comparing EGFR-TKI vs. platinum doublet

Characteristics Zhong et al. (39) Chen et al. (40)
Year 2019 2018
Number 72 86
Excluded 0 0
Male 19 26
Female 53 60
Treatment modality CSC CS
Treatment regimen Erlotinib Erlotinib
Control mortality CSC CS
Control arm CDDP + GEM CDDP + PEM
Adjuvant chemotherapy Yes No
Results 21.5 vs. 11.4 months (HR, 0.39, P<0.001) 56 vs. 40 months (P=0.053)
Outcome Median survival (PFS) Median survival (OS)
Study Positive Negative
Complete resection 73.0% vs. 62.9% (P=0.358) 90.7% vs. 83.7%

EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; CSC, induction chemotherapy followed by surgery, and adjuvant chemotherapy; CS, induction chemotherapy followed by surgery; CDDP, cisplatin; GEM, gemcitabine; PEM, pemetrexed; HR, hazard ratio; PFS, progression-free survival; OS, overall survival.

EMERGING-CTONG 1103 is a randomized phase 2 study for stage IIIA-N2 adenocarcinoma harboring EGFR mutations in exons 19 or 21, which was designed to compare the benefit of induction erlotinib vs. gemcitabine plus cisplatin. The median PFS of the erlotinib arm was significantly better than that of the gemcitabine plus cisplatin arm (21.5 vs. 11.4 months; HR, 0.39; 95% CI, 0.23–0.67; P<0.001) (39), although OS was not different between the two arms (45.8 vs. 39.2 months; HR, 0.77; 95% CI, 0.41–1.45; P=0.417). The incidence of adverse events did not differ between the two arms (75.7% and 88.2%, respectively). It should be noted that the contribution of induction therapy in that study is unclear because the study design called for both arms to receive adjuvant treatment after induction treatment.

Chen et al. (40) conducted an RCT for stage IIIA adenocarcinoma harboring EGFR mutations to evaluate the induction of erlotinib versus pemetrexed plus cisplatin followed by surgery. The study showed that the OS of the erlotinib arm tended to be longer in comparison to the pemetrexed plus cisplatin arm, although the difference was not statistically significant (56 vs. 40 months, P=0.053). Currently, the clinical trial of induction Osimertinib for EGFR harboring adenocarcinoma is ongoing (NeoADAURA) (39). The clinical trial is important because Osimertinib is the most effective and harmless EGFR-TKI. We should focus on the result of NeoADAURA in the future (41).

Thus, EGFR-TKIs would be a valuable choice to improve the survival of patients with stage IIIA-N2 lung adenocarcinoma harboring EGFR mutations. However, these results should be interpreted with care due to the very small size of these RCTs. In addition, the timing to use EGFR-TKIs is a crucial matter because early administration of EGFR-TKIs may lead drug-resistant clones. We should investigate the optimal timing to use EGFR-TKIs, whether adjuvant, induction or recurrence is best for NSCLC treatment.

Possible application of ICI as induction systemic therapy

Following the introduction of ICI therapy, there has been a great focus on the tumor immune microenvironment related to the elimination of cancer cells. Certainly, the benefit of adjuvant ICI therapy has been proven in Impower010 (42); however, it is unclear whether ICI induction therapy can contribute to the prognosis of NSCLC. Recently, ICI induction therapy has been applied to stage I-III NSCLC in clinical trials. The efficacy and safety of induction therapy consisting of ICI with PD-1 and PD-L1 drugs is being assessed. There are six RCTs, including ongoing studies (43-48) and six non-randomized trials with available data (49-54) (Table 5). In these reports, the efficacy of induction ICI treatment was relatively satisfied with a high pathological complete response (pCR) rate (range, 5–57.1%) and a high objective response rate (range, 7–86%) (Table 4).

Table 5

Characteristics of clinical studies related to induction immune checkpoint inhibitor

Name/trial number Clinical trial Regimen Cycles Stage Sample size MPR pCR ORR
Checkmate159 (49)/NCT02259621 Open-label phase 2 Nivolumab vs. carboplatin + paclitaxel 2 I-IIIA 22 45.0% 10.0% 10.0%
LCMC3 (50)/NCT02927301 Open-label single arm phase 2 Atezolizumab 2 IB-IIIB 101 18.0% 5.0% 7.0%
NEOSTAR (43)/NCT03158129 Open-label randomized phase 2 Nivolumab vs. nivolumab + ipilimumab 3 IA-IIIA 44*1 25.0% 18.0% 22.0%
ChiCTR-OIC-17013726 (51) Open-label single arm phase 1b Sintilimab 2 IB-IIIA 40 40.5% 8.1% 20.0%
NADIM (54)/NCT03081689 Open-label single arm phase 2 Nivolumab + carboplatin + paclitaxel 3 IIIA 46 83.0% 59.0% 74.0%
NCT02716038 (52) Open-label single arm phase 2 Atezolizumab + carboplatin + nab-paclitaxel 2 IB-IIIA 14 60.0% 27.3% 57.0%
SAKK16/14 (53)/NCT02572843 Open-label single arm phase 2 Cisplatin + docetaxel + durvalumab 2 IIIA 55 60.0% 18.0% 58.0%
Checkmate816 (45)/NCT02998528 Open-label phase 3 randomized control trial Nivolumab + platinum doublet vs. platinum doublet 3 IB-IIIA 358 36% (ITT) 24% (ITT) 54% (ITT)
KEYNOTE-671 (46)/NCT03425643 Open-label phase 3 randomized control trial Pembrolizumab + platinum doublet vs. platinum doublet 4 III 786 Unknown Unknown Unknown
IMpower030 (47)/NCT03456063 Double blind phase 3 randomized control trial Atezolizumab + platinum doublet vs. placebo + platinum doublet 4 II-III 453 Unknown Unknown Unknown
AEGEAN (48)/NCT03800134 Double blind phase 3 randomized control trial Durvalumab + platinum doublet vs. placebo + platinum doublet 4 II-III 800 Unknown Unknown Unknown
NCT04338620 (44) Open-label phase 3 randomized control trial Camrelizumab + nab-paclitaxel vs. platinum doublet 3 III 43*2 65.1% 25.9% 72.1%

*1, MPR, pCR and ORR were calculated by all cases; *2, sample size was calculated based on the intention to treat. MPR, major pathological response; pCR, pathological complete response; ORR, overall response rate; ITT, intention to treat.

NEOSTAR is a phase 2 randomized trial that enrolled 44 patients with operable stage I-IIIA disease to compare nivolumab vs. nivolumab plus ipilimumab combination therapy (43). Overall, the major pathologic response (MPR) rate (defined as <10% residual viable malignant cells) was 25% (4/23 in nivolumab vs. 11/21 in nivolumab plus ipilimumab). The pCR rate reached 15% (2/23 vs. 6/21).

Checkmate 816 is the first phase 3 RCT comparing the efficacy of the combination of ICI and platinum doublet (45). Patients with stage IB-IIIA disease were recruited. The primary endpoint was event-free survival (EFS) and pCR rate. The median EFS was longer in the nivolumab plus platinum doublet arm than in chemotherapy alone (30.2 vs. 20.8 months; HR 0.63: 97.38% CI, 0.43–0.91; P=0.005). The pCR rate of the nivolumab plus platinum doublet arm was significantly higher than that of the platinum doublet arm (24% vs. 2.2%; OR, 13.94; 99% CI, 3.49–55.75; P<0.0001). No significant difference was observed between the two arms with respect to the number of patients who received delayed surgery (21% vs. 24%). Interestingly, the subgroup analysis showed that the pCR rate was not influenced by the stage, histological subtype (squamous cell carcinoma or non-squamous cell carcinoma), or PD-L1 expression rate in either of the arms. Adverse events were equally observed in both arms. Chemotherapy-related deaths were not observed in the nivolumab plus platinum doublet arm, while treatment-related death was observed in the platinum doublet arm. Moreover, grade 3–4 immune-mediated adverse events were observed in only 4 patients (2.3%). However, the grade 5 surgery-related adverse events were only reported in the nivolumab plus platinum doublet arm but not in the platinum doublet arm. Of note, inflammatory response following ICI therapy greatly influenced on the surgical procedure. It makes dissection of the pulmonary artery branches difficult. The influence of ICI on surgical procedures should be taken carefully. Overall, the safety of induction therapy with ICIs may be feasible; however, long-term observation is needed to evaluate its toxicity and impact on survival.

NADIM is a single-arm phase II trial among patients with stage IIIA NSCLC who were administrated with neoadjuvant nivolumab plus paclitaxel and carboplatin (54). The 3-year OS reached 81.9% (95% CI, 66.8–90.6) and showed the possibility of ctDNA clearance as the favorable predictive biomarker for OS in induction ICI therapy. Interestingly, the OS predictivity of pCR was inferior to ctDNA clearance (C-index for OS: 0.72 vs. 0.82). The result implies that ctDNA may be a better predictive biomarker for the response of ICI treatment. Thereby, it is essential to elucidate the most favorable biomarker for the prediction of the benefit of induction ICI therapy.

Thus, ICIs addressed the great effect of cancer cell elimination in several clinical trials, we expect the downstaging of previously unresectable NSCLS and the control of lymph node metastasis when we use ICIs as induction setting. In the future, ICIs may be a standard induction therapy instead of chemotherapy and chemoradiotherapy.


Induction therapy for stage IIIA NSCLC has sufficient value to improve OS and PFS. However, current evidence does not support the application of induction therapy in the treatment of early-stage NSCLC (stage I and II). EGFR-TKIs may be a choice for induction therapy for stage IIIA NSCLC. ICIs may be considered as a valuable treatment option due to their feasibility and safety for induction therapy; however, long-term evaluation is needed.


Funding: This work was supported by the Japanese Respiratory Foundation (2020).


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  1. Barta JA, Powell CA, Wisnivesky JP. Global Epidemiology of Lung Cancer. Ann Glob Health 2019;85:8. [Crossref] [PubMed]
  2. Bade BC, Dela Cruz CS. Lung Cancer 2020: Epidemiology, Etiology, and Prevention. Clin Chest Med 2020;41:1-24. [Crossref] [PubMed]
  3. al-Kattan K, Sepsas E, Fountain SW, et al. Disease recurrence after resection for stage I lung cancer. Eur J Cardiothorac Surg 1997;12:380-4. [Crossref] [PubMed]
  4. Carnio S, Novello S, Papotti M, et al. Prognostic and predictive biomarkers in early stage non-small cell lung cancer: tumor based approaches including gene signatures. Transl Lung Cancer Res 2013;2:372-81. [Crossref] [PubMed]
  5. Torok JA, Gu L, Tandberg DJ, et al. Patterns of Distant Metastases After Surgical Management of Non-Small-cell Lung Cancer. Clin Lung Cancer 2017;18:e57-70. [Crossref] [PubMed]
  6. Naito T, Tanaka F, Ono A, et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol 2012;7:512-9. [Crossref] [PubMed]
  7. Cristofanilli M. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. Semin Oncol 2006;33:S9-14. [Crossref] [PubMed]
  8. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-56. [Crossref] [PubMed]
  9. Scagliotti GV, Pastorino U, Vansteenkiste JF, et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol 2012;30:172-8. [Crossref] [PubMed]
  10. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer 2012;118:6126-35. [Crossref] [PubMed]
  11. Dautzenberg B, Benichou J, Allard P, et al. Failure of the perioperative PCV neoadjuvant polychemotherapy in resectable bronchogenic non-small cell carcinoma. Results from a randomized phase II trial. Cancer 1990;65:2435-41. [Crossref] [PubMed]
  12. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. [Crossref] [PubMed]
  13. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. [Crossref] [PubMed]
  14. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34. [Crossref] [PubMed]
  15. Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 2017;376:2415-26. [Crossref] [PubMed]
  16. Li X, Yan S, Yang J, et al. Efficacy and Safety of PD-1/PD-L1 Inhibitors Plus Chemotherapy Versus PD-1/PD-L1 Inhibitors in Advanced Non-Small Cell Lung Cancer: A Network Analysis of Randomized Controlled Trials. Front Oncol 2020;10:574752. [Crossref] [PubMed]
  17. Chen Z, Luo Q, Jian H, et al. Long-term results of a randomized controlled trial evaluating preoperative chemotherapy in resectable non-small cell lung cancer. Onco Targets Ther 2013;6:645-50. [Crossref] [PubMed]
  18. Yi X, Zhang R, Ding J, et al. A clinicopathologic study on neoadjuvant chemotherapy in the treatment of non-small-cell lung cancer. Zhongguo Fei Ai Za Zhi 2003;6:124-8. [Crossref] [PubMed]
  19. Yao K, Xiang MZ, Min JX, et al. A randomized clinical trial of preoperative neoadjuvant chemotherapy in the treatment of stage III non-small cell lung cancer. J Clin Oncol China 2004;31:611-3.
  20. Rosell R, Gómez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153-8. [Crossref] [PubMed]
  21. Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998;21:1-6. [Crossref] [PubMed]
  22. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010;28:3138-45. [Crossref] [PubMed]
  23. Pisters KM, Vallières E, Crowley JJ, et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol 2010;28:1843-9. [Crossref] [PubMed]
  24. Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 2007;369:1929-37. [Crossref] [PubMed]
  25. Sorensen JB, Riska H, Ravn J, et al. Scandinavian phase III trial of neoadjuvant chemotherapy in NSCLC stages IB-IIIA/T3. J Clin Oncol 2005;23:7146.
  26. Yang X, Wu Y, Gu L, et al. A randomized trial comparing neoadjuvant gemcitabine plus carboplatin or cisplatin followed by surgery with surgery alone in Clinical Stage IIIA non-small-cell lung cancer (NSCLC). Lung Cancer 2005;49:S288.
  27. Nagai K, Tsuchiya R, Mori T, et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage IIIA N2 non-small cell lung cancer (JCOG 9209). J Thorac Cardiovasc Surg 2003;125:254-60. [Crossref] [PubMed]
  28. Depierre A, Milleron B, Moro-Sibilot D, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002;20:247-53. [Crossref] [PubMed]
  29. Wu YL, Gu LJ, Weng YM, et al. Neo-adjuvant chemotherapy with docetaxel plus carboplatin for non-small cell lung cancer. Ann Oncol 2002;13:140.
  30. Splinter TA, van Putten JW, Meuzalaar J, et al. Randomized multicenter phase II study of chemotherapy followed by surgery versus surgery alone in stage I and II non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000;19:495.
  31. Pass HI, Pogrebniak HW, Steinberg SM, et al. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992;53:992-8. [Crossref] [PubMed]
  32. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014;383:1561-71. [Crossref] [PubMed]
  33. Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol 2010;5:510-6. [Crossref] [PubMed]
  34. Thomas M, Rübe C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol 2008;9:636-48. [Crossref] [PubMed]
  35. Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer 2010;69:86-93. [Crossref] [PubMed]
  36. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. [Crossref] [PubMed]
  37. Tong S, Qin Z, Wan M, et al. Induction chemoradiotherapy versus induction chemotherapy for potentially resectable stage IIIA (N2) non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Dis 2018;10:2428-36. [Crossref] [PubMed]
  38. Chen Y, Peng X, Zhou Y, et al. Comparing the benefits of chemoradiotherapy and chemotherapy for resectable stage III A/N2 non-small cell lung cancer: a meta-analysis. World J Surg Oncol 2018;16:8. [Crossref] [PubMed]
  39. Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]
  40. Chen WQ, Li P, Wang Q, et al. A randomized controlled study of erlotinib versus pemetrexed combined with cisplatin in neoadjuvant therapy of stage A EGFR-mutant lung adenocarcinoma. Zhonghua Zhong Liu Za Zhi 2018;40:133-7. [Crossref] [PubMed]
  41. Tsuboi M, Weder W, Escriu C, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for EGFR-mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol 2021;17:4045-55. [Crossref] [PubMed]
  42. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-57. [Crossref] [PubMed]
  43. Cascone T, William WN Jr, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 2021;27:504-14. [Crossref] [PubMed]
  44. Lei J, Yan X, Zhao J, et al. 62MO A randomised, controlled, multicenter phase II trial of camrelizumab combined with albumin-bound paclitaxel and cisplatin as neoadjuvant treatment in locally advanced NSCLC. Ann Oncol 2020;31:S1441-2.
  45. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
  46. Tsuboi M, Luft A, Ursol G, et al. 1235TiP Perioperative pembrolizumab + platinum-based chemotherapy for resectable locally advanced non-small cell lung cancer: The phase III KEYNOTE-671 study. Ann Oncol 2020;31:S801-2.
  47. Peters S, Kim AW, Solomon B, et al. IMpower030: Phase III study evaluating neoadjuvant treatment of resectable stage II-IIIB non-small cell lung cancer (NSCLC) with atezolizumab (atezo) + chemotherapy. Ann Oncol 2019;30:ii30.
  48. Heymach J, Taube J, Mitsudomi T, et al. P1.18-02 The AEGEAN Phase 3 Trial of Neoadjuvant/Adjuvant Durvalumab in Patients with Resectable Stage II/III NSCLC. J Thorac Oncol 2019;14:S625-6.
  49. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378:1976-86. [Crossref] [PubMed]
  50. Lee J, Chaft J, Nicholas A, et al. PS01.05 Surgical and Clinical Outcomes with Neoadjuvant Atezolizumab in Resectable Stage IB–IIIB NSCLC: LCMC3 Trial Primary Analysis. J Thorac Oncol 2021;16:S59-61.
  51. Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. J Thorac Oncol 2020;15:816-26. [Crossref] [PubMed]
  52. Shu CA, Grigg C, Chiuzan C, et al. Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC). J Clin Oncol 2018;36:8532. [Crossref] [PubMed]
  53. Rothschild SI, Zippelius A, Eboulet EI, et al. SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients with Stage IIIA(N2) Non–Small-Cell Lung Cancer—A Multicenter Single-Arm Phase II Trial. J Clin Oncol 2021;39:2872-80. [Crossref] [PubMed]
  54. Provencio M, Serna-Blasco R, Nadal E, et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol 2022;40:2924-33. [Crossref] [PubMed]
Cite this article as: Shinohara S, Takahashi Y, Masago K, Matsushita H, Kuroda H. The beginning of a new era in induction treatment for operable non-small cell lung cancer: a narrative review. J Thorac Dis 2023;15(2):747-758. doi: 10.21037/jtd-22-957

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