Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II-III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study.

This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II-III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2-4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3-48.1) in arm A and were 55.6% (95% CI 21.2-86.3) and 11.1% (95% CI 0.3-48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8-61.6) and 55.6% (95% CI 21.2-86.3). With a median follow-up of 22.4 months (95% CI 19.0-26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II-III NSCLC.

Pulmonary Function Recovery and Displacement Patterns After Anatomic Segmentectomy vs Lobectomy.

BACKGROUND: The functional benefit of segmentectomy compared with lobectomy remains controversial. This ambispective study characterizes the changes in pulmonary function as correlated to displacement patterns of residual lung after segmentectomies vs lobectomies. METHODS: Patients with normal preoperative pulmonary function and undergoing segmentectomy or lobectomy between 2017 and 2021 were considered. Pulmonary function testing was scheduled preoperatively and at least 3 months postoperatively. Differences in the proportions of the median forced expiratory volume in 1 second (FEV1) reduction between segmentectomy and lobectomy were calculated. Covariance analysis was used to estimate the adjusted postoperative FEV1 (apoFEV1) and compare the difference value (DV) in apoFEV1 between segmentectomy and lobectomy. RESULTS: The study enrolled 634 patients (334 lobectomies and 300 segmentectomies). Median difference in the proportions of the FEV1 reduction between segmentectomy and lobectomy was 4.58%, with maximal difference observed in right S6 (9.08%) and minimal difference in left S1+2+3 (2.80%). For resections involving the upper lobe, apoFEV1 was significantly higher after segmentectomy than after lobectomy (DV, 0.15-0.22 L), except for left S3 and S1+2+3 segmentectomies (DV, 0.08 L and 0.06 L, respectively). Compared with a lower lobe lobectomy, S6 segmentectomy conferred a higher apoFEV1, whereas S7+8 and S9+10 had a similar apoFEV1 (DV, 0.16-0.18 L, 0.07 L, and 0.00-0.06 L, respectively). Functional recovery after segmentectomy was associated with the number of intersegment planes (P < .01) and the presence of an adjacent nonoperated on lobe (P = .03). CONCLUSIONS: Basilar and left S3 segmentectomies did not preserve more pulmonary function compared with their corresponding lobectomies, possibly due to the presence of multiple intersegmental resection planes.

Neoadjuvant Afatinib for stage III EGFR-mutant non-small cell lung cancer: a phase II study.

Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.

Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing.

BACKGROUND: Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored. METHODS: We characterized the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8). RESULTS: Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response. CONCLUSIONS: Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.

Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.

BACKGROUND: This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC). METHODS: Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. RESULTS: In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). CONCLUSIONS: Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. TRIAL REGISTRATION: ChiCTR1900024014, June 22, 2019.

Neoadjuvant Sintilimab and Chemotherapy for Resectable Stage IIIA Non-Small Cell Lung Cancer.

BACKGROUND: Evidence of neoadjuvant chemoimmunotherapy for locally advanced non-small cell lung cancer remains investigational and requires prospective validation. This phase II trial (https://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR1900023758) aimed to investigate the safety and effectiveness of neoadjuvant PD-1 inhibitor sintilimab in addition to chemotherapy in the management of resectable stage IIIA non-small cell lung cancer. METHODS: Eligible patients received two to four 21-day cycles of neoadjuvant therapy: sintilimab (200 mg) and carboplatin (area under the curve 5) on day 1, gemcitabine (1000 mg/m2) on day 1 and day 8 for squamous cell carcinoma, or pemetrexed (500 mg/m2) on day 1 for adenocarcinoma and non-small cell lung cancer not otherwise specified. The primary endpoints were adverse events and major pathological response. The secondary endpoint was disease-free survival at 1 year. RESULTS: Fifty patients were enrolled, and 23 (46%) achieved partial response after neoadjuvant chemoimmunotherapy. Four (8%) patients experienced grade 3 to 5 adverse events. Thirty patients received surgery, none of whom experienced treatment-related surgery delays, and 13 (43.3%) of 30 patients achieved major pathological response (viable tumor ≤10%). With a median follow-up of 13.6 months, 85.3% of patients were disease-free at 1 year (N = 50). CONCLUSIONS: Neoadjuvant sintilimab with platinum-containing dual-agent chemotherapy was feasible and safe for patients with resectable stage IIIA non-small cell lung cancer.

Neoadjuvant immunotherapy combined with chemotherapy for local advanced non-small cell lung cancer: a case report.

Immunotherapy has revolutionized lung cancer management and revitalized the field of tumor immunology. Anti-programmed death 1 (anti-PD-1) immunotherapy can significantly improve the survival of patients with advanced non-small cell lung cancer (NSCLC), but its role in neoadjuvant therapy of local advanced NSCLC remains uncertain. Herein, we reported a case from a clinical trial of our department, a patient who achieved excellent outcome after neoadjuvant immunotherapy and chemotherapy for local advanced NSCLC. A 70 years old male patient with stage IIIA squamous cell carcinoma was admitted in our hospital, who initially needed to undergo pneumonectomy. After two cycles of neoadjuvant immunotherapy combined with chemotherapy, the tumor significantly shrank and the patient underwent left upper lobectomy finally. The patient had grade 2 myelosuppression and recovered after injection with recombinant human granulocyte colony stimulating factor. There was no operation-related complication the patient was discharged uneventfully. The patient received two cycles adjuvant chemotherapy combined with immunotherapy, then immunotherapy alone monthly. The patient was well during the 4-month follow-up after surgery and would receive immunotherapy till one year after surgery. Our case added evidence of the feasibility and efficacy of neoadjuvant immunotherapy combined with chemotherapy in local advanced NSCLC. Randomized, controlled, multi-center studies are needed to confirm these findings.

Outcomes of sleeve lobectomy versus pneumonectomy: A propensity score-matched study.

OBJECTIVES: To compare short- and long-term outcomes between sleeve lobectomy and pneumonectomy for lung cancer in a single center during a 15-year period. METHODS: One thousand nine hundred eighty-one patients who underwent either a sleeve lobectomy (n = 964; 48.7%) or a pneumonectomy (n = 1017; 51.3%) from January 2003 to December 2017 at the Shanghai Pulmonary Hospital, were matched according to a propensity score to produce 2 groups of 665 patients each. The study period was divided into 3 5-year subperiods. RESULTS: Sleeve lobectomy was associated with a lower 30- and 90-day mortality (0.60% and 0.90% vs 1.5% and 3.91%; P = .177 and P = .001, respectively, after matching), lower morbidity (4.36% vs 8.16%; P = .005 before matching, 3.61% vs 8.72%; P < .001 after matching), improved 5-year survival (62.7% vs 43.1%; P < .001 before matching and 61% vs 44.7%; P < .001 after matching), and 5-year disease-free survival after matching (56.6% vs 46.2%; P < .001). The sleeve lobectomy to pneumonectomy ratio increased by 78%, whereas 90-day mortality decreased by 66.81% between the first and the last subperiods. CONCLUSIONS: Sleeve lobectomy is associated with improved short- and long-term outcomes and should be the resection of choice for centrally located lung cancers, when feasible.

Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer.

BACKGROUND: Malignant transformation and progression of cancer are driven by the co-evolution of cancer cells and their dysregulated tumor microenvironment (TME). Recent studies on immunotherapy demonstrate the efficacy in reverting the anti-tumoral function of T cells, highlighting the therapeutic potential in targeting certain cell types in TME. However, the functions of other immune cell types remain largely unexplored. RESULTS: We conduct a single-cell RNA-seq analysis of cells isolated from tumor tissue samples of non-small cell lung cancer (NSCLC) patients, and identify subtypes of tumor-infiltrated B cells and their diverse functions in the progression of NSCLC. Flow cytometry and immunohistochemistry experiments on two independent cohorts confirm the co-existence of the two major subtypes of B cells, namely the naïve-like and plasma-like B cells. The naïve-like B cells are decreased in advanced NSCLC, and their lower level is associated with poor prognosis. Co-culture of isolated naïve-like B cells from NSCLC patients with two lung cancer cell lines demonstrate that the naïve-like B cells suppress the growth of lung cancer cells by secreting four factors negatively regulating the cell growth. We also demonstrate that the plasma-like B cells inhibit cancer cell growth in the early stage of NSCLC, but promote cell growth in the advanced stage of NSCLC. The roles of the plasma-like B cell produced immunoglobulins, and their interacting proteins in the progression of NSCLC are further validated by proteomics data. CONCLUSION: Our analysis reveals versatile functions of tumor-infiltrating B cells and their potential clinical implications in NSCLC.