Preoperative Immunochemotherapy for Locally Advanced Non-Small Cell Lung Cancer

An Analysis of the Clinical Outcomes, Optimal Number of Cycles, and Peripheral Immune Markers

Hongsheng Deng; Hengrui Liang; Jiawei Chen; Wei Wang; Jianfu Li; Shan Xiong; Bo Cheng; Caichen Li; Zhuxing Chen; Haixuan Wang; Jianqi Zheng; Zhuoxuan Guo; Jianxing He; Wenhua Liang


Transl Lung Cancer Res. 2022;11(12):2364-2381. 

In This Article

Abstract and Introduction


Background: This retrospective study aimed to evaluate the real-world efficacy of neoadjuvant immunochemotherapy in locally advanced stage III non-small cell lung cancer (NSCLC), with a particular focus on analyzing the optimal treatment cycle and peripheral immune markers.

Methods: Eligible patients with biopsy-confirmed stage III NSCLC who underwent neoadjuvant immunochemotherapy between January 1st, 2018 and March 30th, 2021 were identified, and their oncological outcomes were collected.

Results: A total of 115 patients were identified, among whom 61, 51, and three cases were classified as clinical stage IIIA, IIIB, and IIIC at presentation, respectively. The objective response rate was 61.7% (71/115) after immunochemotherapy. The most frequent surgical procedure was lobectomy, performed in 91 (79.1%) cases, and all patients had microscopic-free margins. Major pathological response (MPR) was observed in 64 (55.7%) patients, among whom 44 (38.3%) achieved a complete pathological response; pathological-confirmed lymph node downstage (cN2–3 to ypN0–1) was described in 73.6% (67/91) of patients with cN2–3 diseases. The median disease-free survival (DFS) of all enrolled patients was 23.6 [95% confidence interval (CI): 15.9–31.3] months, while for patients with residual tumors of more than 10%, the median DFS was 18.1 (95% CI: 12.5–23.8) months. The post-hoc multivariable analysis showed that three [odds ratio (OR), 4.78; 95% CI: 1.17–19.55] and four (OR: 6.50; 95% CI: 1.12–37.54) cycles of neoadjuvant immunochemotherapy were prone to higher MPR rates compared to two cycles in patients that were classified as complete/partial response (CR/PR). However, adding over five cycles was not associated with a higher MPR rate (OR, 0.91; 95% CI: 0.15–5.47). The pretreatment lymphocyte count level (1.89±0.68 vs. 1.59±0.63, P=0.019) and monocyte count level (0.71±0.32 vs. 0.59, P=0.020) were significantly higher in MPR patients compared to non-MPR patients.

Conclusions: The present study confirmed a favorable real-world tumor downstage efficacy of neoadjuvant immunochemotherapy in locally advanced NSCLC. Even though CR/PR was achieved, it is still beneficial when extended into 3–4 cycles of neoadjuvant immunochemotherapy.


Lung cancer remains the leading cause of cancer-associated deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of newly diagnosed cases,[1] about one-third of which are locally advanced diseases at diagnosis.[1,2] Multimodality therapies are currently considered the standard treatment[3] for stage III NSCLC; however, the therapeutic outcomes remain poor despite definitive concurrent chemoradiotherapy,[4] with a median progression-free survival (PFS) of 13 months and a 3-year overall survival of just 30%. Furthermore, a significant number of locally advanced NSCLC cases eventually develop disease progression or locoregional relapse.[5]

The emergence of immune checkpoint blockades (ICBs), which block the binding of the programmed cell death protein 1 (PD-1) receptor and its ligands (PD-L1/2) and subsequently reinvigorate an antitumor response due to T-cell activation, have already changed the treatment strategy[6] of advanced NSCLC in recent years. Long-term outcomes from phase III clinical trials of PD-1/PD-L1 inhibitors in previously treated patients with advanced NSCLC demonstrated a 2-year overall survival of 23–29% and 5-year overall survival of 16%.[7,8] The subsequent PACIFIC[9] trials confirmed the survival benefit of the consolidation ICB strategy after concurrent chemoradiotherapy in locally advanced unresectable NSCLC and reported a 3-year overall survival (OS) of 57.0% in the durvalumab group versus 43.5% in the placebo group. Recently, more publications have focused on the role of immunotherapy plus chemotherapy[10–12] or dual checkpoint inhibition[13] in the neoadjuvant setting for resectable NSCLC. The NADIM trial[14] accessed the efficacy of neoadjuvant nivolumab combined with chemotherapy in stage IIIA NSCLC, and the major pathologic response (MPR) rate reached 85%, with a remarkable PFS rate of 95.7% at 12 months and 77.1% at 24 months. Unpublished results from the LCMC3 trial showed an MPR rate of 21% and pathologic complete response (pCR) rate of 7%, and about 43% of stage IIB-IIIB NSCLCs had a pathological downstage after neoadjuvant atezolizumab.[15] The SAKK 16/14 trial[16] employing three cycles of neoadjuvant durvalumab combined with chemotherapy revealed an MPR rate of 62%. In the Checkmate816 trial,[17] nivolumab plus platinum-based chemotherapy resulted in a significantly improved median event-free survival (31.6 vs. 20.8 months; P=0.005) and pCR rate (24.0% vs. 2.2%; P<0.001) compared with platin-chemotherapy alone. Theoretically, preoperative immunotherapy has the potential advantages of increasing operability and eradicating micrometastases,[18,19] and may be able to induce long-term tumor regression and potentially cure locally advanced NSCLC. Despite the clinically established efficacy and safety of neoadjuvant immunochemotherapy, little is known about its long-term efficacy in a real-world setting.

Notably, two to four treatment cycles were administrated in most of the relevant phase II/III trials on neoadjuvant immunotherapy.[15–17,20,21] Extended treatment cycles might result in the postponement of surgery, while a short course of treatment may not be sufficient for ICB to induce its effect. Nevertheless, the optimal cycle number of neoadjuvant immunotherapy could not be explored in the aforementioned trials because there were no head-to-head comparisons in the different cycle groups. Thus, further exploration of the correlation between the treatment cycle and treatment-induced pathological response is needed.

Herein, we assess the real-world efficacy of neoadjuvant immunochemotherapy for locally advanced stage III NSCLC, with a particular focus on analyzing the optimal treatment cycle and peripheral immune markers. We present the following article in accordance with the STROBE reporting checklist (available at