Background:Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). Methods:Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. Results:The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. Conclusions:Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

IntroductionPlatinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of immuno checkpoint inhibitor (ICI) based treatments for EGFR mutated NSCLC patients who carried programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50% progressed after EGFR-TKI therapy. In this study, we retrospectively investigated the outcomes of ICI-based treatments for EGFR mutated NSCLC patients carried PD-L1 TPS≥50% after developing EGFR-TKI resistance and to explore the population that may benefited from ICI-based treatment.MethodsWe retrospectively collected data of advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation at Shanghai Chest Hospital between January 2018 and June 2021. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of this study.ResultsA total of 146 patients were included. Up to June 20th, 2022, median follow-up was 36.7 months (IQR, 12.5-44.2 months). Among the population, 66 patients (45.2%) received chemotherapy, the remaning (54.8%) received ICI-based treatment, including 56 patients(70.0%) received ICI combined with chemotherapy (IC) and 24 patients (30.0%) received ICI monotherapy (IM). In IC group,31 patients received ICI combined with chemotherapy,19 patients received ICI combined with antiangiogenic therapy and remaing received ICI combined with chemotherapy and antiangiogenic therapy. Survival analysis shown that patients who received ICI-based treatment had better progress-free survival (PFS) and overall survival (OS) compared with those treated with other therapy (median PFS, 10.0 vs. 4.0 months, P<0.001; median OS, 39.5 vs. 24.2 months, P<0.001). What’s more, patients who treated with IC treatment had a superior survival time than those received IM treatment (median PFS, 10.3 vs. 7.0 months, P<0.001; median OS, 41.6 vs. 32.4 months, P<0.001). Subgroup analysis found that the PFS and OS benefit of IC was evident in all subgroups.ConclusionsFor advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation, ICI-based treatment could provide a more favorable survival than classical chemotherapy. What’ s more, compared with ICI monotherapy, ICI combined with chemotherapy seems to be the preferred treatment.

Acquired resistance represents a bottleneck to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. Our study aimed to explore the efficacy of antiangiogenic‐based therapy in osimertinib‐resistant NSCLC patients and assess the efficacy of anlotinib in vitro study.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Introduction: Extensive stage small cell lung cancer (ES-SCLC) is associated with poor prognosis. Recently, anlotinib has demonstrated significant clinical activity as a third-line or further on treatment. This study aimed to evaluate the safety and efficacy of a combination of anlotinib and platinum-etoposide as first-line treatment in patients with ES-SCLC.Methods: The present multi-center, single-arm, prospective study (NCT04684017) was conducted at three Chi-nese sites, and included patients with asymptomatic metastasis in the central nervous system. Patients were treated with up to six cycles of chemotherapy comprising etoposide with either carboplatin or cisplatin on day 1 of each cycle. Anlotinib was administered orally once daily on days 1-14 per cycle. The primary end points of the study were safety and investigator assessed objective response rate (ORR).Results: A total of 101 patients were screened from August 2018 to September 2021, of which 86 who had received at least one dose of the treatment were included in the formal analysis. The median follow-up duration was 27.9 months. Complete response and partial response were observed in 2 and 73 patients, respectively, with an ORR of 87.2 % and a disease control rate of 97.7 %. Progression-free survival (PFS) and overall survival (OS) events occurred in 78 and 47 patients, respectively. The median PFS and OS were 9.0 (95 % confidence interval [CI]: 7.5-10.5) and 19 (95 % CI: 16.7-21.3) months, respectively. The incidence of grade 3 or higher adverse events (AEs) was 58.1 % and 24 patients (27.9 %) experienced serious treatment-related AEs. No fatalities consequent to AEs were recorded. Conclusion: Given its promising efficacy, safety profile and durability, anlotinib combined with chemotherapy deserves further investigation as first-line anticancer therapy in ES-SCLC (NCT: 04684017).

Background Large cell neuroendocrine carcinoma (LCNEC) is a rare high-grade neuroendocrine carcinoma of the lung. Little is known about the differences between the pure and combined LCNEC subtypes, and thus we conducted this study to provide more comprehensive insight into LCNEC. Methods We reviewed 221 patients with pure LCNEC (P-LCNEC) and 120 patients with combined LCNEC (C-LCNEC) who underwent pulmonary surgery in our hospital to compare their clinical features, driven genes’ status ( EGFR/ALK/ROS1/KRAS/BRA F), and adjuvant chemotherapy regimens. Propensity score matching (PSM) was applied to reduce selection bias. Results The P-LCNEC group included a higher proportion of males and smokers than the C-LCNEC group. Furthermore, the C-LCNEC group had higher incidences of visceral pleural invasion (VPI), EGFR mutation and ALK rearrangement compared with the P-LCNEC group. Expression of neuroendocrine markers (CD56, CGA, and SYN) and recurrence patterns were not significantly different between the two groups. The P-LCNEC group had better disease-free survival (DFS) and overall survival (OS) compared with the C-LCNEC group (median DFS: 67.0 vs. 28.1 months, p = 0.021; median OS: 72.0 vs. 45.0 months, p = 0.001), which was further confirmed by the PSM method ( p = 0.004 and p < 0.001, respectively). Adjuvant chemotherapy was also an independent factor for DFS and OS. Subgroup analysis found that regardless of whether it was for the entire LCNEC group or the P- and C-LCNEC subtypes, the small cell lung cancer (SCLC) regimens presented with superior survival compared with the non-small cell lung cancer (NSCLC) regimens. Conclusion P-LCNEC was associated with more favorable prognosis compared with C-LCNEC. SCLC-based adjuvant chemotherapy was more appropriate for LCNEC patients than NSCLC-based regimens, regardless of whether they were the pure or combined LCNEC subtypes. C-LCNEC patients may be the potential beneficiary of targeted therapy.

AbstractBackgroundLocal consolidative therapy (LCT) has emerged as a treatment option in patients with oligometastatic non‐small cell lung cancer (NSCLC) undergoing chemotherapy or targeted therapy. However, the current literature lacks evidence as to whether LCT improves survival in NSCLC patients receiving immunotherapy. Our study aimed to assess whether LCT combined with pembrolizumab ± chemotherapy could improve the survival of patients with synchronous oligometastatic NSCLC.MethodsPatients with NSCLC, without EGFR or ALK genetic aberrations, who were treated with first‐line pembrolizumab ± chemotherapy, were included in the study. Survival analysis of the LCT and non‐LCT groups was compared.ResultsA total of 231 patients were included in the study. The median follow‐up time was 15.24 months. Median progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 12.00 and 23.43 months, respectively. Of the 231 patients included, 76 patients received LCT combined with pembrolizumab ± chemotherapy (LCT group) while 155 patients received pembrolizumab ± chemotherapy alone (non‐LCT group). Of note, the PFS of the LCT and non‐LCT groups was 13.97 and 10.08 months (p = 0.016), respectively. The OS were 30.67 and 21.97 months (p = 0.011), respectively. The PFS and OS were significantly improved with LCT for patients with brain or lung metastases but not bone metastases. No significant increase in treatment‐related toxicity was observed in the LCT group.ConclusionsThe present study shows that LCT to metastatic sites is an option for consideration in patients with synchronous oligometastatic NSCLC during first‐line pembrolizumab treatment, with significantly improved PFS and OS compared with systemic treatment alone.

Abstract Background Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR‐mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. Methods From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture‐based targeted next‐generation sequencing (NGS) with a panel of 68 lung cancer‐related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence‐free survival (RFS) were analyzed. Results A total of 637 patients were enrolled in this study. The top three frequent co‐mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07–4.00, p = 0.030; HR 3.09, 95% CI 1.49–6.40, p = 0.002, respectively]. Conclusions Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR‐mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.

Objective Several trials have shown that pembrolizumab plus chemotherapy was more effective in patients with advanced non-small-cell lung cancer (NSCLC) than chemotherapy monotherapy. However, whether pembrolizumab plus chemotherapy is still a better choice for first-line treatment in elderly patients (≥75 years old) remain unknown. We retrospectively compared the efficacy and safety of these two treatments in elderly patients. Patients and Methods We collected data of 136 elderly patients with advanced NSCLC who were treated with pembrolizumab plus chemotherapy or chemotherapy monotherapy in our hospital from 2018 to 2020. We compared the progression-free survival (PFS) and overall survival (OS) of patients and analyzed which subgroups might benefit more significantly from pembrolizumab plus chemotherapy. Results In total population, pembrolizumab plus chemotherapy showed superior PFS and OS than chemotherapy monotherapy (PFS: 12.50 months vs. 5.30 months, P<0.001; OS: unreached vs. 21.27 months, P=0.037). Subgroup analysis showed patients with positive PD-L1 expression, stage IV, good performance score (ECOG-PS <2), fewer comorbidities (simplified comorbidity score <9) or female patients had demonstrated a more evident OS benefit in pembrolizumab plus chemotherapy. In terms of safety, the pembrolizumab plus chemotherapy group had higher treatment discontinuation (26% vs. 5%). Conclusions Elderly patients using pembrolizumab plus chemotherapy achieved longer PFS and OS, but were more likely to discontinue due to adverse effects, so disease stage, PD-L1 expression, ECOG-PS and comorbidities should be considered when selecting first-line treatment.

AbstractBackgroundSmall cell lung cancer (SCLC) is the most malignant and common form of neuroendocrine lung cancer with pure (P‐SCLC) and combined subtypes (C‐SCLC). However, little is known about the differences between these two groups and in this study we aimed to provide a more comprehensive insight into SCLC.MethodsData from 580 postoperative patients with pathologically confirmed SCLC in Shanghai Chest Hospital from January 2010 to December 2020 were collected retrospectively. The clinical characteristics and prognosis were analyzed.ResultsA total of 357 P‐SCLC patients and 223 C‐SCLC patients were included. The results indicated that P‐SCLC appeared to have a higher proportion of being located in the middle lobe than C‐SCLC. The incidences of P‐SCLC in patients with visceral pleural invasion (VPI) and in stage II were higher than C‐SCLC, while C‐SCLC was more likely to be accompanied by higher incidences of epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and higher levels of CEA, SCCA and CYFRA21‐1 than P‐SCLC. The most common were SCLC combined with large cell neuroendocrine components among 223 C‐SCLCs. Survival analysis confirmed a more favorable disease‐free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.024) in patients with P‐SCLCs compared with C‐SCLCs. Histological type, tumor location, pN stage, adjuvant chemotherapy, serum NSE and CA125 levels were independent risk factors for survival rate in SCLC. In addition, adjuvant chemotherapy was beneficial in improving stage I P‐SCLC and C‐SCLC DFS and OS rates, and similar results were not seen in adjuvant radiation therapy.ConclusionsPatients with C‐SCLC have a poorer prognosis than P‐SCLC patients. We determined that large cell neuroendocrine carcinoma was the most common additional component of C‐SCLC, and patients with this component appeared to have a longer DFS and OS than other combined components.

OBJECTIVES:Combined large cell neuroendocrine carcinoma (C-LCNEC) is pulmonary large cell neuroendocrine carcinoma (LCNEC) mixed with other components, such as adenocarcinoma (AD) and squamous cell carcinoma (SCC). This study aimed to describe the distinct features between C-LCNEC with different components and explore the treatment strategy.METHODS:We retrospectively collected data of 96 C-LCNEC patients who underwent surgical resection. Propensity score matching was used to balance baseline characteristics of LCNEC combined with AD (LCNEC/AD) and LCNEC combined with SCC (LCNEC/SCC).RESULTS:In our final cohort, 71 (74%) were LCNEC/AD, while 25 (26%) were LCNEC/SCC. LCNEC/AD was more likely to occur in female, younger adults, with visceral pleural invasion and with driver gene expression. However, there was no significant difference in disease-free survival and overall survival between the 2 groups (before matching: P = 0.79 and P = 0.85; after matching: P = 0.87 and P = 0.48), while adjuvant chemotherapy (P = 0.019 and P = 0.043) was an independent predictor. C-LCNEC patients of stage II or III receiving adjuvant chemotherapy had longer disease-free survival and overall survival (P = 0.054 and P = 0.025), and the benefit of etoposide-based chemotherapy was greater than the other regimens (P = 0.010 and P = 0.030). EGFR and ALK mutations were present in 28% (17/60) and 7% (4/60) of C-LCNEC patients, respectively, and they responded well to targeted therapy.CONCLUSIONS:LCNEC/AD was the most common type of C-LCNEC, and there were many differences between different combined components. Adjuvant chemotherapy, especially etoposide-based chemotherapy, was a beneficial option for resected C-LCNEC.Subj collection: 152.

Introduction: Although the interaction between tumor immune microenvironment and angiogenesis has been well established, evidence supporting the chemo-free combination of immune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors in treatment-naive patients with advanced NSCLC is insufficient. This report provides the efficacy and safety of sintilimab combined with anlotinib as first-line therapy for advanced NSCLC from a phase 1b trial (NCT03628521). Methods: Eligible patients who were treatment-naive and had unresectable stage IIIB/C or IV NSCLC without EGFR/ ALK/ROS1 mutations received sintilimab (200 mg, day 1) and anlotinib (12 mg, day 1-14) every 3 weeks till disease progression or unacceptable toxicity. Baseline programmed death-ligand 1 expression and tumor mutation burden status was assessed in all patients. The primary end points were objective response rate and safety. Results: A total of 22 patients received sintilimab and anlotinib. Median follow-up was 15.8 months (range: 8.3- 19.3). Sixteen patients achieved confirmed partial response with an objective response rate of 72.7% (95% confidence interval [CI]: 49.8%-89.3%) and disease control rate of 100% (95% CI: 84.6%-100%). Median progression-free survival was 15 months (95% CI: 8.3 m, not reached), and the 12-month progression-free survival rate was 71.4% (95% CI: 47.2%-86.0%). The incidence rate of grade 3 or higher treatment-related adverse events was 54.5%, and grade 3 hypertension was predominant (two of 22, 9.1%). No grade 4 treatment-related adverse events were observed, and one case of grade 5 immune-related pneumonitis occurred. Conclusions: To the best of our knowledge, this is the first study that assessed an anti-programmed cell death protein 1 antibody combined with a multitarget antiangiogenic tyrosine kinase inhibitor in the frontline setting for patients with NSCLC. In view of its encouraging efficacy, durability, and safety profile, sintilimab plus anlotinib represents a novel chemotherapy-free regimen in this patient population. (c) 2020 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.

OBJECTIVES:More and more encouraging evidence revealed that immunotherapy could improve clinical outcomes in patients with previously treated non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) variations. However, immunotherapy is still a controversy for NSCLC patients with EGFR mutation.METHOD:In this retrospective analysis, we compared the clinical efficacy of pembrolizumab monotherapy (PM), pembrolizumab combined with chemotherapy (P+C) and pembrolizumab combined with anlotinib (P+A) in NSCLC patients with EGFR mutation who had failed on EGFR-TKI and platinum-based chemotherapy.RESULT:Eighty-six patients were included in this study. The overall median progression free survival (PFS) was 3.24 months. Multivariate analysis suggested that EGFR L858R and combined therapy were positive prognostic factors of PFS. The overall median OS was 12.28 months. Multivariate analysis found that high PD-L1 expression (≥50%) and combined therapy seemed to be positive prognostic factors of OS. Among the population, 32 patients received PM, 26 patients received P+C and 28 patients received P+A. Up to Jan 30, 2021, the median progression-free survival was 1.5 months in the PM group, 4.30 months in the P+C group and 3.24 months in the P+A group. The median OS were 7.41, 14.92 and 15.97 months, respectively. The ORR were 3.1%, 23.1% and 21.4%.CONCLUSION:The addition of chemotherapy or antiangiogenic therapy to pembrolizumab resulted in significantly longer PFS, OS and ORR than pembrolizumab alone in our study. EGFR L858R might be a positive prognostic factor of PFS and high PD-L1 expression might be a positive prognostic factor of OS.

OBJECTIVES:Pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy (PM) both become standard of care in patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50%. This study aimed to figure out the better treatment choice.METHOD:In this retrospective analysis, we compared the clinical efficacy of PM and PC as first-line treatment in NSCLC patients with a PD-L1 ≥50% and negative for genomic alterations in the EGFR and ALK genes.RESULT:Among the population, 115 patients received PC, and 91 patients received PM. Up to Dec 30, 2020, median follow-up was 17.13 months. The median progression-free survival (PFS) rates of PC and PM were 12.37 and 9.60 months (HR: 0.44, p < 0.001), respectively. The median overall survival (OS) rates were NE and 28.91 months (HR: 0.40, p = 0.005), respectively. Subgroup analysis found that the PFS benefit of PC was evident in most subgroups excepting patients with brain metastasis. The 1-year overall survival rates of PC and PM were 89.3% and 76.1%, respectively. The ORR was 61.7 and 46.9% (p = 0.004), respectively.CONCLUSION:In patients with previously untreated, PD-L1 ≥50%, advanced NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard platinum-based chemotherapy seems to be the preferred treatment, which needs to be validated by further prospective trials.

Background Angiogenic placental growth factor (PlGF) plays a role in hypoxia-induced angiogenesis. Here, we aimed to investigate the biological roles of PlGF in cell proliferation and glycolysis of lung adenocarcinoma (LUAD) and the underlying molecular mechanisms. Methods PlGF was knocked down in H358 and H1975 cells by lentiviruses, which were then cultured under hypoxia (90% N 2 , 5%CO 2 and 5%O 2 ) for 24 h. PlGF was overexpressed in PC9 cells treated with XAV939, inhibitor of Wnt/β-catenin signaling pathway. PlGF-silencing H1975 cells were implanted into mice, and tumor xenografts were harvested and analyzed. Results Hypoxia treatment led to up-regulation of PlGF, C-myc, lactate dehydrogenase A (LDHA), and β-catenin, promotion of cell proliferation and glycolysis in H358 and H1975 cells, which were obviously reversed by knocking down PlGF. In tumors, PlGF knockdown significantly prohibited cell proliferation and glycolysis, and decreased expression of C-myc, LDHA, and β-catenin. PlGF overexpression markedly strengthened cell proliferation, which was inhibited by β-catenin knockdown. Consistently, XAV939, inhibitor of Wnt/β-catenin pathway, also inhibited PlGF-induced cell proliferation, glycolysis, and β-catenin expression in PC9 cells. Conclusion PlGF knockdown inhibited the stimulatory effect of hypoxia on cell proliferation and glycolysis of LUAD through deactivating Wnt/β-catenin pathway.

Atezolizumab, an immune checkpoint inhibitor, has been approved for use in clinical practice in non-small cell lung cancer (NSCLC) patients, but potential biomarkers for response stratification still need further screening. In the present study, a total of 399 patients with high-quality ctDNA profiling results were included. The mutation status of ubiquitin-like conjugation (UBL) biological process genes (including ABL1 , APC , LRP6 , FUBP1 , KEAP1 , and TOP2A ) and clinical information were further integrated. The results suggested that the patients with the clinical characteristics of male or history of smoking had a higher frequency of UBL mutation positivity [UBL (+)]; the patients who were UBL (+) had shorter progression-free survival (PFS) (1.69 vs. 3.22 months, p = 0.0007) and overall survival (8.61 vs. 16.10 months, p < 0.0001) than those patients with UBL mutation negativity [UBL (–)]; and more promising predictive values were shown in the smoker subgroup and ≤ 3 metastasis subgroup. More interestingly, we found the predictor has more performance in TP53 -negative cohorts [training in an independent POPLAR and OAK cohorts ( n = 200), and validation in an independent MSKCC cohort ( n = 127)]. Overall, this study provides a predictor, UBL biological process gene mutation status, not only for identifying NSCLC patients who may respond to atezolizumab therapy but also for screening out the potential NSCLC responders who received other immune checkpoint inhibitors.

Objectives Pulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis. Materials and Methods We compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis. Results We included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis. Conclusions The mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

Background Co-mutations was associated with poor response to EGFR-TKIs. First-generation EGFR-TKIs combined with chemotherapy was reported to be more effective than TKIs alone in advanced lung adenocarcinoma patients. Objective This retrospective study aimed to explore whether EGFR-mutant patients with co-mutations can benefit from EGFR-TKIs plus chemotherapy. Patients and Methods We retrospectively collected data of 137 EGFR-mutant patients with advanced lung adenocarcinoma who underwent next-generation sequencing in our hospital in 2018. Among them, 96 were treated with EGFR–TKIs alone and 41 received EGFR–TKIs plus chemotherapy. We analyzed the progression-free survival (PFS) of patients with co-mutations using different treatments. Results Concurrent TP53 mutations, especially exon 4 and 6, were associated with a markedly shorter time to progression on EGFR-TKI monotherapy (11.4 months vs. 16.6 months, P=0.003), while EGFR–TKIs plus chemotherapy would benefit those patients more (with TP53: 11.4 months vs. 19.1 months, P=0.001, HR=0.407; without TP53: 16.6 months vs. 18.9 months, P=0.379, HR=0.706). The incidence of T790M after resistance was equal in patients treated with different treatments (53% vs. 53%, P=0.985). Conclusions In our study, concurrent TP53 mutations were found to be risk factors for EGFR-TKI monotherapy, but TKI combined with chemotherapy could eliminate this heterogeneity.

Immunotherapy, a chemotherapy-free process, has emerged as a promising therapeutic strategy to prolong the overall survival (OS) of patients with non-small-cell lung cancer (NSCLC). However, effective stratification factors for immunotherapy remain unclear. The purpose of this study was to discuss the potential stratification factors of NSCLC immunotherapy using immune checkpoint inhibitors (ICIs) by integrating genomic profiling and tumor lesion–type information. In this study, 344 patients with NSCLC, whose clinical and tissue (including metastatic and primary lesions) mutation information was available, were included. The potential gene mutation status for predicting the outcomes of immunotherapy was screened by comparing the difference in mutation frequency between responders and non-responders. Our results indicated that the potential predictors of immunotherapy were significantly different, especially between patients with TP53 (+) (including metastatic and primary lesions) and TP53 (−) (including metastatic and primary lesions). According to this classification, patients with NSCLC who suggested immunotherapy had a higher OS than those who did not (25 months vs. 7 months, P < 0.0001, hazard ratio = 0.39). Collectively, this study provides a new perspective for screening immunotherapy predictors in NSCLC, suggesting that the TP53 mutation status and source of biopsy tissue should be considered during the development of immunotherapy biomarkers.

Background Osimertinib is a standard therapy for advanced non-small cell lung cancer (NSCLC) patients with an acquired epidermal growth factor receptor (EGFR) T790M mutation; however, the exploration of clinical characteristics that may affect prognosis and long-term survival is still lacking. Objective This retrospective study aimed to provide long-term survival data and explore meaningful prognostic factors in patients treated with osimertinib. Patients and Methods A total of 246 patients with acquired EGFR T790M mutation who were treated with osimertinib were included in this study. Progression-free survival (PFS), overall survival from osimertinib initiation (OS1), overall survival from diagnosis of advanced disease (OS), and possible prognostic clinical features were analyzed. Results The median PFS, OS1, and OS values were 12.17, 24.33, and 47.86 months, respectively. The median PFS of patients harboring EGFR exon 19 deletions/T790M (19del/T790M) and those harboring EGFR 21 L858R/T790M were 13.27 and 9.77 months (p = 0.001), respectively, while the median OS1 values were 25.03 and 18.30 months (p = 0.023), respectively; however, no significant difference was found in median OS (p = 0.060). Cox regression analysis revealed that coexisting mutation type and extrathoracic metastasis affected survival (PFS, OS1). In addition, gene biopsy specimen type (tissue or blood sample) was related to PFS (p = 0.032), which implied that liquid biopsy may be an independent poor prognostic factor. Conclusions This is the first reported survival analysis of osimertinib-treated Chinese patients, which indicates a median OS of 47.86 months. The EGFR T790M mutation is likely to coexist with 19del and indicate longer PFS and OS1 than EGFR 21 L858R/T790M. Additionally, the extrathoracic metastasis status and biopsy specimen type might also affect the survival of patients treated with osimertinib.