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


Patient Characteristics

From January 2019 to May 2020, 35 patients with resectable stage IIIA or IIIB non-NSCLC received neoadjuvant chemoimmunotherapy at TJMUCH. The median age of the cohort was 62.17±5.99 (43–72) years. Of the patients, 82.86% were male, 74.28% had squamous carcinoma, 88.57% were stage IIIA, and 57.14% were PD-L1 positive (≥50%). For the clinical TNM stage, 11 patients were T1N2M0, 8 were T2N2M0, 11 were T3N1M0, 4 were T3N2M0, and 1 was T4N1M0. All the patients underwent baseline tumor staging, including pretreatment biopsy, pathological evaluation of mediastinal lymph nodes (if indicated) by bronchoscopy or mediastinoscopy, positron-emission tomography-computed tomography (PET-CT), and contrast-enhanced CT or magnetic resonance imaging of the brain and chest. Patients with squamous carcinoma received 2 courses of pembrolizumab 2 mg/kg intravenous (IV) q3w added to cisplatin 75 mg/m2 IV q3w plus paclitaxel liposome 135 mg/m2 q3w; patients with non-squamous carcinoma received pemetrexed 500 mg/m2 IV q3w instead of paclitaxel liposome (Table 1).

Safety and Feasibility

Neither neoadjuvant pembrolizumab plus paclitaxel liposome nor pemetrexed combined with cisplatin resulted in any previously unreported toxic effects. Before surgery, 1 patient developed a grade 3 toxicity (rash). All 35 eligible patients (100%) underwent complete tumor resection. The median interval between the administration of the second dose of NICO O and surgery was 33.4 (range, 28–35) days. No treatment-related surgical delays occurred as defined in the protocol. Of the 35 patients enrolled, 18 (51.43%) patients achieved pCR, and 26/35 (74.29%) patients exhibited MPR. Also, 1 patient had no residual tumor in the primary tumor but had residual tumor in hilar lymph nodes, which we considered as 0% pathological regression. According to their pathological responses, the patients were divided into a pCR group and a non-pCR group. In the pCR group, the median age was 61.5±6.88 years. Of the 18 pCR patients, 88.89% were male, 83.33% had squamous carcinoma, 94.4% were stage IIIA, and 61.10% had a PD-L1 TPS >50%. The non-pCR group had a median age of 62.88±5.01 years. Of the 17 non-PCR patients, 76.47% were male, 64.71% had squamous carcinoma, 82.35% were stage IIIA, and 52.94% had a PD-L1 TPS >50% (Table 1 and Figure 1).

Figure 1.

Pathological assessment of response to NCIO. Pathological response in the resected primary lung tumor after NCIO in each of the 35 patients who underwent surgical resection, according to the percentage of remaining viable tumor cells. The gray horizontal line indicates the threshold for a major pathological response (90% regression). Clinical and pathological features including histology, preoperative radiologic response (according to RECIST), sex, smoking status, PD-L1 expression in the pretreatment biopsy sample, and TNM stage are annotated for each patient. PR, partial response; SD, stable disease, PD-L1, programmed death-ligand 1.

After a median of 13.29 (range, 3–24) months of postoperative follow-up, 94.29% (33/35) of patients who had undergone surgical resection were alive and recurrence-free. One patient died 3 months after surgery because of cerebral ischemic stroke (patient 3), and another died 10 months after surgery due to mass N2 lymph node metastasis (patient 1). One patient was diagnosed with brain metastasis (patient 25) 12 months after the surgery. The median duration of recurrence-free survival had not been reached at the time of data analysis. Hence, based on the available data, no significant differences were detected in PFS and OS between the pCR and non-pCR groups (Figure 2).

Figure 2.

Kaplan-Meier curves of PFS and OS for the pCR and non-pCR groups. PFS curve (A) and OS curve (B) for all patients. OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival.

Pathological Findings After Neoadjuvant PD-1 Blockade

Representative radiological and pathological responses before and after 2 cycles of NCIO are shown in Figure 3A. MPR occurred in 26/35 (74.29%) patients, and 18 patients (51.43%) achieved a pCR in the primary tumor. One patient exhibited pCR despite apparent tumor enlargement on preoperative CT (possibly due to infiltration of immune cells into the tumor), which was defined as pseudoprogression. In primary tumors with MPR, we observed a large number of infiltrating lymphocytes and macrophages. This finding was compatible with an immunological mechanism of response as well as the phenomenon of necrotic tumor being associated with fibrotic tissue repair (Figure 3A).

Figure 3.

Characteristic changes before and after NCIO. (A) Patterns of radiological and pathological response to NCIO. Left: CT imaging of the chest of a 56-year-old male never-smoker (patient 28) with stage IIIA squamous lung cancer before and after the administration of NCIO. In the upper panel, the pretreatment scan shows a primary tumor mass with pulmonary atelectasis in the upper lobe of the right lung. A scan performed before the surgery shows 90% shrinkage with associated tumor cavitation. The lower panel consists of the representative sections of tumor specimens obtained from the patient before the administration of NCIO and after (right) HE staining. This patient had 100% pathological regression of the large primary lung tumor and no lymph-node metastases in the resected specimen. Right: CT of the chest of a 63-year-old male smoker (patient 9) with stage IIIA lung adenocarcinoma. In the upper panel, the tumor appears stable on imaging before and after NCIO. In the lower panel, representative sections of tumor specimens obtained from the patient before (left) and after (right) HE. Neoplastic cells are present throughout the pre-treatment specimen, whereas in the post-treatment specimen, 60% tumor regression was detected. (B) Association between intracavitary and extracavitary tumors type e and pathological response to NCIO. The association between intracavitary and extracavitary tumors type and pathological response to the NCIO was analyzed. Patients with intracavitary type had higher pCR and MPR rates as compared with those with extracavitary type (pCR rate: 76.47% vs. 31.58%; MPR rate: 100% vs. 50.00%). The Pearson's rho is 0.7280, and a significant difference can be seen between the 2 groups (P=0.0009). (C) Association of PD-L1 with pathological response to NCIO. Left: PD-L1 expression changes before and after NCIO. Pretreatment biopsy and post-surgery samples were obtained, and PD-L1 testing was performed using the Monoclonal Mouse Anti-Human PD-L1 clone 22C3. In the upper panel, the pre-NCIO TPS of patient 26, who had 100% pathological regression, was 0%, and the post-NCIO CPS was 60%. In the middle panel, the pre- and post-NCIO TPSs of patient 5, who had 60% pathological regression, were both 100%. In the lower panel, the pre-NCIO TPS of patient 30, who had 100% pathological regression, was 30%, and the post-NCIO CPS was 50%. Right. No association was observed between pre-treatment PD-L1 expression and pathological response to NCIO (Pearson's r=−0.071; P=0.685). The dashed black line indicates the linear regression line, and the dashed gray lines indicate the upper and lower boundaries of the 95% confidence interval. (D) Immune proofing of T cells to NCIO in the post-surgery sample. Left: Gating scheme for CD4+ and CD8+ T-cell and Treg cell intracellular cytokine cytometry. FSC-A, forward scatter A; SS, side scatter. Black polygons indicate gated cell subsets. Right: The proportions of CD4+ cells, CD8+ T-cells, and Treg cells to T cells and all cells in the sample. No significant difference was observed between the pCR group and the non-pCR group (P>0.05).

Correlation of Intracavitary and Extracavitary Tumors Type With Pathological Response

In all the patients, we also analyzed intracavitary and extracavitary tumors type by bronchoscopy based on CT. 17/35 (48.57%) patients were evaluated as intracavitary and 18/35 (51.43%) as extracavitary. Thirteen (76.47%) patients in the invasion group achieved pCR, and all 17 (100%) patients showed an MPR. Meanwhile, in the non-invasion group, only 5 (27.78%) patients showed a pCR, and 9 (50.00%) patients did not obtain an MPR. The Pearson's rho was 0.7280, and there was a significant difference between the 2 groups (P=0.0009; Figure 3B).

Expression of PD-L1 With Pathological Response

The expression of PD-L1 could be evaluated in pretreatment biopsy samples in all patients (Figure 3C). A pCR or MPR was found to have occurred in PD-L1-positive and PD-L1-negative tumors. The correlation between the TPS of pretreatment biopsy samples and pathological regression was analyzed. As shown in Figure 3C, there was no association between PD-L1 expression before treatment and the pathological response to NCIO (Pearson's r=−0.071; P=0.685).

Immune Proofing of T Cells to NCIO

To further explore the T-cell changes before and after NCIO of these patients, flow cytometry analysis was performed. CD4+ and CD8+ T cells and Tregs were evaluated in post-surgical samples available from 17 patients (Figure 3D). The ratios of CD4+ T cells, CD8+ T cells, and Tregs to T cells and all cells in the sample were analyzed in pCR and MPR patients. As shown in Figure 3D, in the pCR group and non-PCR group, the proportion of CD 4+ T cells to T cells was 36.93±12.34 and 43.67±14.61, respectively (P>0.05), and the proportion of CD 4+ T cells to all cells in the sample was 7.42±4.94 and 10.39±11.90, respectively (P>0.05). Furthermore, the proportion of CD8+ T cells to T cells in the pCR and non-PCR groups was 50.74±12.78 and 43.90±19.70, respectively (P>0.05), and that of CD 8+ T cells to all cells in the sample was 10.43±7.97 and 9.71±6.97, respectively (P>0.05). The proportion of Tregs to T cells in the pCR and non-PCR groups was 1.55±1.25 and 3.57±2.69, respectively (P>0.05), and that of Tregs to all cells in the sample was 0.41±0.57 and 1.04±1.27, respectively (P>0.05).