Neoadjuvant Chemoimmunotherapy in Resectable Stage IIIA/IIIB Non-Small Cell Lung Cancer

Yulong Chen; Bo Yan; Feng Xu; Zhenzhen Hui; Gang Zhao; Jie Liu; Huan Zhang; Ziqing Zeng; Ran Zhang; Mariano Provencio; Xiubao Ren; Jian You


Transl Lung Cancer Res. 2021;10(5):2193-2204. 

In This Article


As we all knows that single chemotherapy or immune therapy in NSCLC is with lower effective rate and low survival rate; the pCR rate and MPR rate are very low.[1–3] The combination of checkpoint blockade and chemotherapy explores the potential for synergistic immune activation and was found to be impressive in the present study. And several clinical studies have reported that neoadjuvant anti-PD-1 immunotherapy achieves an MPR in 46–83% and a pCR in 38–56% of patients who undergo tumor resection.[3–8] Due to these impressive results, the number of stage IIIA or IIIB NSCLC patients in China receiving neoadjuvant chemoimmunotherapy before surgery. According to the related reports and our own experience, patients with squamous carcinoma appear to show a better pathological response than adenocarcinoma or other kind of NSCLC. Therefore, there are many more patients with squamous carcinoma than with adenocarcinoma.

Neoadjuvant therapy allows for earlier treatment of micrometastatic disease, reductions in surgical risk, improved tolerability and compliance with the therapy. In our study, we observed that neoadjuvant administration of 2 doses of pembrolizumab plus paclitaxel liposome or pemetrexed combined with cisplatin in patients with stage IIIA–IIIB resectable stage NSCLC was associated with few immediate adverse events. NCIO did not delay the planned surgery and led to a pCR in 51.43% of patients and an MPR in 74.29% of patients for the primary tumor. Interestingly, 2 patients had no residual tumor in the primary tumor but had residual tumor in hilar lymph nodes. Moreover, the treatment was not associated with any previously unreported toxic effects.[1–4,12] The NADIM study reported that 13% of patients encountered grade 3–5 treatment-related adverse events, with the most common postsurgical complication being respiratory infection.[12] In the current study, only 1 patient encountered an adverse event of grade 3–5 in the form of grade 3 rash, and none of the patients experienced postsurgical complications such as respiratory infections.

Immune-checkpoint blockade can yield long-term survival benefits for a subset of cancer patients.[12,13] Specifically, only patients with advanced solid tumors show a response to this treatment. Therefore, developing a method to identify the patients who are most likely to respond to immunotherapy is essential. Several predictors, such as PD-L1,[14–16] tumor mutational burden,[17] and radiomics,[18] have been explored to help in the prediction of clinical outcomes. However, currently, there is no reliable predictor to aid in clinical decision-making. In the present study, no significant correlation could be established between PD-L1 expression and pathological response n. Also, pathological regression did not differ significantly between patients with TPS scores ≥50% and <50% (Pearson's r=−0.071 and P=0.685), with cases of pCR and MPR occurring in patients with high and low TPS. PD-L1 expression is not a good predictor of pathological response. Hence, we studied the dynamic changes in squamous cell carcinoma, including changes in tumor size before and after NCIO, original tumor volume, carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) in response to NCIO. These factors did not show any significant difference between patients with and without pCR. Surprisingly, intracavitary and extracavitary tumors type T was associated with pathological response. Of the patients in the invasion group, 76.47% showed pCR and 100% exhibited MPR, compared to only 31.58% and 50% of patients, respectively, in the non-invasion group (P<0.001). Furthermore, the Pearson's rho was 0.7280, which indicated that intracavitary and extracavitary tumors types might be a valuable parameter for the prediction of the pathological response to NCIO.

It is thought that PD-1 blockade has the highest likelihood of success in tumors microenvironment with functional CD8+ TILs, functional antigen presentation machinery proteins, and T-helper type 1 cytokines and chemokines such as IFN-γ and IL-2.[19–21] The PD-1 blockade is difficult to play a role if the tumor is completely deprived of immune cells (immune desert), or the immune cells are unable to infiltrate the tumor properly (immune-excluded tumors). Combination therapy with immunotherapy and chemotherapy may solve the problem. Recent data show that chemotherapy is also possess immunostimulatory properties. It has the potential to induce favorable immunogenic conditions within the tumor microenvironment, which may be difficult to achieve by just targeting immune cells.[22,23] Furthermore, we also studied the immune proofing of T cells to the NCIO and identified CD4+ and CD8+ T cells and Tregs. Goldberg et al. demonstrated that PD-1 blockade enhances early-stage T-cell activation in lymph nodes.[24] Liu et al. reported that neoadjuvant PD-1 blockade enhances the systemic priming of antitumor T cells, thereby potentially eliminating micrometastatic cancer cells that might otherwise cause postsurgical relapse.[25] Our findings did not reveal any significant differences in CD4+ and CD8+ T cells and Tregs between the pCR and non-pCR groups or the MPR and non-MPR groups. The number of CD4+ and CD8+ T cells and Tregs was m the same between the pCR and non-pCR groups. Although no difference in the number of these T cells, the function of these cells might be different. Salmon et al. described the importance of dendritic cells to the antitumor effects of PD-1 pathway blockade and suggested that PD-1 blockade not only works to directly unleash intratumoral T-cell killing but also enhances the tumor antigen-driven priming of T cells.[26] In the present study, changes in TPS before and after treatment were also analyzed. In the pCR group, the TPS increased and decreased in 64.28% and 27.27% of patients, respectively, while in the non-pCR group, 2 and 3 out of 11 patients showed an increase and decrease in TPS, respectively. Strikingly, in the pCR group, no residual tumor was left but a large number of PD-L1-positive immune cells were detected. Further investigation of the influence of anti-PD-1 drugs on cells with PD-L1 antigen might be the key to understanding the antitumor mechanism.

The present study has some limitations that need to be discussed. First, there was a small sample size and short postoperative follow-up. However, for the first time, this report has demonstrated the safety of surgical resection after treatment with pembrolizumab plus paclitaxel liposome or pemetrexed combined with cisplatin for patients with stage IIIA–IIIB NSCLC. This study is also the first to confirm the intracavitary and extracavitary tumors type as a predictor of the pathological response to NCIO, which will be critical and of tremendous assistance to avoiding non-essential surgery. Long-term follow-up study will be necessary to establish whether or not MPR and pCR translate to prolonged OS and PFS.