Neoadjuvant Immunotherapy or Chemoimmunotherapy in Non-Small Cell Lung Cancer

A Systematic Review and Meta-Analysis

Juan Jiang; Yuling Wang; Yang Gao; Haruhiko Sugimura; Fabrizio Minervini; Junji Uchino; Balazs Halmos; Sai Yendamuri; Jeffrey B. Velotta; Min Li


Transl Lung Cancer Res. 2022;11(2):277-294. 

In This Article

Abstract and Introduction


Background: In recent years, a series of clinical trials have explored the application of neoadjuvant immunotherapy or chemoimmunotherapy in non-small cell lung cancer (NSCLC). However, no randomized control trials comparing neoadjuvant immunotherapy with chemoimmunotherapy have yet been reported. This study aimed to summarize and compare the efficacy and safety of neoadjuvant immunotherapy and chemoimmunotherapy in NSCLC.

Methods: Literature focusing on the efficacy and safety of neoadjuvant immunotherapy or chemoimmunotherapy in NSCLC published before June 2021 was retrieved from PubMed, Embase, and the Cochrane Library. Study endpoints included major pathological response (MPR), complete pathological response (pCR), treatment-related adverse events (TRAEs), severe adverse events (SAEs), resection rate, surgical delay rate, and conversion to thoracotomy. The risk of bias was assessed using the Cochrane bias risk assessment tool. Subgroup and sensitivity analyses were further performed.

Results: A total of 988 patients from 16 studies were included in this meta-analysis. For patients who received neoadjuvant immunotherapy with single/combined ICIs or chemoimmunotherapy, the pooled MPR rate was 43.5% and the pooled pCR rate was 21.9%. The pooled incidence of TRAEs and SAEs were 54.8% and 15.3%, respectively. The pooled resection rate was 85.8%, the surgical delay rate was 7.4%, and the conversion rate was 17.4%. Patients who received neoadjuvant chemoimmunotherapy had remarkably improved pathological response (MPR rate: 53.3% vs. 28.6%; pCR rate: 28.6% vs. 9.9%) compared with those receiving neoadjuvant single-agent immunotherapy, while the incidence of SAEs (18.0% vs. 12.3%) and surgical delay rate (3.8% vs. 7.4%) did not significantly increase. Neoadjuvant nivolumab combined with ipilimumab also achieved a high pCR rate (28.6%) with tolerable toxicity. Nivolumab- and pembrolizumab-based neoadjuvant therapy showed a higher MPR rate (nivolumab 51.5%, pembrolizumab 46.8%) and pCR rate (nivolumab 29.1%, pembrolizumab 31.5%). Besides, patients with positive programmed death-ligand 1 (PD-L1) expression [tumor proportion score (TPS) ≥1%] exhibited favorable pathological responses than PD-L1 negative patients.

Discussion: Overall, neoadjuvant immunotherapy or chemoimmunotherapy is effective and safe in NSCLC. Compared with single-agent immunotherapy, neoadjuvant chemoimmunotherapy provides a significant improvement in pathological response without increasing the incidence of SAEs or surgical delay. These results need further confirmation by more large-scale randomized controlled trials.


According to the 2020 global cancer statistics, non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers worldwide and remains the leading cause of cancer deaths.[1] Approximately 70% of NSCLC patients are diagnosed at an advanced stage, leading to a 5-year survival rate less than 18% even after comprehensive treatment.[2] Over the past decades, the early detection of NSCLC has gradually increased with the wider adoption of chest low-dose CT as a screening modality.[3] For patients diagnosed with stages I, II, and selected stage III NSCLC, surgical resection with curative intent is considered to be the best treatment option. However, only 20–25% of tumors overall are suitable for potential curative resection. Moreover, these patients have a high risk of postoperative recurrence, ranging from 25% to 70% based on the disease stage.[4]

Neoadjuvant therapy, defined as systemic anticancer treatment given before surgery, is an accepted practice in NSCLC.[5] Compared with adjuvant therapy, neoadjuvant therapy has potential advantages including early treatment of micrometastasis, reducing tumor burden before surgery, and better tolerability.[6,7] Pathological remission, including major pathological response (MPR) and complete pathological response (pCR), is currently used as a surrogate endpoint to predict survival benefit in clinical trials focusing on neoadjuvant chemotherapy.[8] A meta-analysis conducted by the NSCLC Meta-analysis Collaborative Group involving 15 randomized clinical trials in patients with stages IB–IIIA disease has demonstrated that compared with surgery alone, preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC.[9] However, the median rate of pCR from 15 trials of neoadjuvant chemotherapy was only 4% (range, 0–16%), which suggests that more effective neoadjuvant therapy modalities are required to further improve prognosis.[10]

Immunotherapy with immune checkpoint inhibitors (ICIs), which boost antitumor immunity by blocking inhibitory signaling through checkpoint receptors expressed on T lymphocytes and their ligands expressed in tumor cells, has revolutionized the treatment of various cancers, including NSCLC.[4,11] In recent years, the use of ICIs for the treatment of NSCLC has considerably increased. Monoclonal antibodies that target the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis have been approved as first- and second-line treatments for advanced NSCLC worldwide.[12] So far, several clinical trials have reported the efficacy and safety of neoadjuvant immunotherapy[13–18] or chemoimmunotherapy[19–28] in stages I–III NSCLC. Investigational ICIs included PD-1/PD-L1 inhibitors such as nivolumab,[13,18,25,27,28] pembrolizumab,[16,20] sintilimab,[15] durvalumab,[26] atezolizumab,[14,19] avelumab,[23] and a CTLA-4 inhibitor ipilimumab.[24] In NSCLC patients who receive preoperative immunotherapy, the naive tumor can serve as a "vaccine" boosting the activation of T lymphocytes.[29] Based on available research data from previous studies, patients who received neoadjuvant immunotherapy or chemoimmunotherapy before surgery had improved pathological response and downstaging of the tumor compared to those who received neoadjuvant chemotherapy. However, most of these studies are single-armed trials with small sample sizes. On the other hand, while neoadjuvant immunotherapy or chemoimmunotherapy offers numerous advantages, immune-related adverse events (irAEs) have attracted significant attention.[30,31] The occurrence of severe irAEs can lead to delayed surgical resection or even death. Moreover, increasing complexity of the surgical field in the chest, which is caused by fibrosis and nodal flares, has been observed in patients receiving neoadjuvant immunotherapy, even with tumor downstaging.[13] So far, no data from randomized controlled trials on neoadjuvant immunotherapy and chemoimmunotherapy have been reported. Therefore, in order to improve the knowledge of and compare the clinical benefits between neoadjuvant immunotherapy and chemoimmunotherapy in NSCLC, a meta-analysis on their efficacy and safety, based on current data from clinical trials, is necessary.

Herein, we conducted a systematic review and meta-analysis of clinical trials focusing on neoadjuvant immunotherapy or chemoimmunotherapy in NSCLC. We analyzed efficacy- and safety-related endpoints including MPR, pCR, incidence of treatment-related adverse events (TRAEs) and severe adverse events (SAEs), resection rate, surgical delay rate, and conversion rate in resectable stages I–III NSCLC patients who received neoadjuvant immunotherapy or chemoimmunotherapy. We further compared these endpoints among different treatment modes and ICI types, and summarized the profiles of TRAEs and SAEs. This meta-analysis was conducted and reported in accordance with the PRISMA reporting checklist[32] (available at