Efficacy and safety analysis of anlotinib combined with PD-1 inhibitors in advanced non-small cell lung cancer: a retrospective cohort study.

Background: Programmed cell death 1 (PD-1) inhibitors are beneficial for patients with advanced lung cancer. However, the population who will benefit from PD-1 inhibitors is limited, and their efficacy needs to be further improved. Antiangiogenic agents may regulate tumor microenvironment to improve immunotherapy efficacy. This real-world study sought to investigate the efficacy and safety of anlotinib combined with PD-1 inhibitors in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: In total, 42 advanced NSCLC patients were included in this retrospective study. All the patients received anlotinib combined with PD-1 inhibitors from May 2020 to November 2022. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) of the patients were evaluated. Results: The patients had an overall median PFS of 5.721 months [95% confidence interval (CI): 1.365-10.076]. The median PFS and ORRs of the male patients compared to the female patients were 10.553 vs. 4.340 months, and 36.4% vs. 0.0%, respectively (P=0.010 and 0.041). The DCRs for the first-, second-, and third-line therapies were 100%, 83.3%, and 64.3%, respectively (P=0.096). In relation to the pathological types, the ORRs of the sarcoma, squamous, and adenocarcinoma patients were 100.0%, 33.3%, and 18.5%, respectively (P=0.025). The DCRs of patients with the tumor protein 53 (TP53) mutation, other status, and epidermal growth factor receptor (EGFR) mutations were 100.0%, 81.5%, and 40.0%, respectively (P=0.020). All-grade AEs occurred in 52.38% of the patients. The grade 3 AEs were hypertension (7.14%), pneumonia (2.38%), and oral mucositis (2.38%). In total, 3 patients discontinued treatment due to anemia, oral mucositis, and pneumonia, respectively. Conclusions: Anlotinib combined with PD-1 inhibitors has potentially good efficacy and a tolerated safety profile in the treatment of advanced NSCLC patients.

Efficacy, safety, and prognostic factors of anlotinib treatment in advanced non-small cell lung cancer patients.

Objective: This study aimed to evaluate the treatment response, survival profiles, prognostic factors and adverse events of anlotinib in treating advanced non-small cell lung cancer (NSCLC) patients. Materials and Methods: Totally, 158 advanced NSCLC patients were included in this retrospective study. All patients received anlotinib treatment until disease progression or intolerance: Administrated orally 12 mg/d for 2 weeks then discontinued for 1 week (3 weeks as a treatment cycle). Furthermore, treatment response, adverse events, and survivals were evaluated. Results: After 2 treatment cycles, no (0%) patients achieved complete response (CR), 7 (5.0%) patients achieved partial response (PR), 112 (80.0%) patients achieved standard deviation (SD), and 21 (15.0%) patients achieved progressive disease (PD), resulting in objective response rate (ORR) of 5.0% and disease control rate (DCR) of 85.0%. After 4 treatment cycles, no (0%) patients achieved CR, 3 (4.3%) patients achieved PR, 51 (74.0%) patients achieved SD, and 15 (21.7%) patients achieved PD, resulting in ORR of 4.3% and DCR of 78.3%. For survivals, the median progression-free (PFS) was 3.7 months (95% confidence interval [CI]: 2.7-4.7 months), and the median overall survival (OS) was 12.4 months (95% CI: 9.4-15.3 months). Subsequently, multivariate Cox's regression analyses illuminate that histological type (adenosquamous carcinoma vs. adenocarcinoma) and other mutation apart from epidermal growth factor receptor independently predicted shorter PFS; meanwhile, history of smoke and brain metastases independently predicted decreased OS. Regarding safety, most of the adverse events were at mild grade. Conclusion: Anlotinib displays good efficacy and well-tolerant safety profiles in the treatment of advanced NSCLC patients.

Afatinib 30 mg in the treatment of common and uncommon EGFR-mutated advanced lung adenocarcinomas: a retrospective, single-center, longitudinal study.

Background: Afatinib 30 mg has been proved to be with comparable efficacy but more tolerable than the dose of 40 mg for Asian patients with non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical outcomes of afatinib at 30 mg/d in the treatment of advanced lung adenocarcinomas (LAD) with common and uncommon epidermal growth factor receptor (EGFR) mutations. Methods: EGFR-mutated advanced LAD patients receiving afatinib (30 mg/d) from January 2017 to November 2021 were retrospectively included. EGFR status was classified into three subtypes, namely common mutations including exon 19 deletions (19del) and exon 21 L858R (21L858R), uncommon mutations including G719X, L861Q, S768I, and complex mutations, and separately exon 20 insertions (20ins). Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs) were analyzed during regular follow-up. Results: The overall median PFS of totally 58 included patients was 9.83 [95% confidence index (CI): 5.76-13.91] months. The number of patients with common, uncommon, and 20ins mutations was 32 (55.2%), 19 (32.8%) and 7 (12.1%), respectively. Baseline characteristics did not differ significantly among the three subtypes. The corresponding median PFS was 13.97 (12.06-15.89), 8.48 (0.32-16.64), and 3.78 (1.93-5.64) months, respectively (P=0.002). In the first-line setting, patients with common and uncommon mutations had a significantly longer PFS compared to those with 20ins [14.53 (13.53-15.53) vs. 10.39 (4.87-15.91) vs. 2.37 (0.00-5.11) months, P<0.001]. The first-line ORR showed significant differences among the three subtypes (60% vs. 80% vs. 0.0%, P=0.023). All-grade AEs occurred in 22 patients (37.9%). AEs ≥ grade 3 mainly included diarrhea (8.6%), and none of the patients discontinued treatment due to severe AEs. Conclusions: Afatinib at 30 mg/d is associated with a favorable efficacy and tolerability in the treatment of advanced LAD with common and major uncommon EGFR mutations except 20ins. Further large-scale prospective studies are warranted to confirm our findings.

Polymeric micellar paclitaxel (Pm-Pac) prolonged overall survival for NSCLC patients without pleural metastasis.

Nanoparticle polymeric micellar paclitaxel (Pm-Pac) has been demonstrated to have a safety profile and efficacy in advanced non-small cell lung cancer (NSCLC) patients. However, whether Pm-Pac could prolong overall survival (OS) for specific advanced NSCLC patients is still unknown. In the present study, a total of 448 patients were randomly assigned (2:1) by the permuted block algorithm to receive Pm-Pac plus cisplatin or solvent-based paclitaxel (Sb-Pac) plus cisplatin (NCT02667743). We performed subgroup analysis based on metastatic status to identify the potential benefit patients. Our results indicated that the metastatic profiles were similar between the Sb-Pac plus cisplatin cohort and the Pm-Pac plus cisplatin cohort. Several subgroups (Metastases = 2, Bone metastasis, No pleural metastasis, etc.) were observed to have increased progression-free survival (PFS) due to Pm-Pac plus cisplatin. Importantly, we found the first evidence that Pm-Pac potentially prolonged OS with a favourable safety profile in NSCLC patients without pleural metastasis. Collectively, this study provides a novel perspective on the development of nanomedicine to investigate chemotherapeutic efficacy and toxicity and provides the first clinical evidence that Pm-Pac administration not only prolongs PFS but also prolongs OS with a favourable safety profile in advanced NSCLC patients without pleural metastasis.

Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer.

Circulating tumor cells (CTCs) have important applications in clinical practice on early tumor diagnosis, prognostic prediction, and treatment evaluation. Platinum-based chemotherapy is a fundamental treatment for non-small cell lung cancer (NSCLC) patients who are not suitable for targeted drug therapies. However, most patients progressed after a period of treatment. Therefore, revealing the genetic information contributing to drug resistance and tumor metastasis in CTCs is valuable for treatment adjustment. In this study, we enrolled nine NSCLC patients with platinum-based chemotherapy resistance. For each patient, 10 CTCs were isolated when progression occurred to perform single cell-level whole-exome sequencing (WES). Meanwhile the patients' paired primary-diagnosed formalin-fixed and paraffin-embedded samples and progressive biopsy specimens were also selected to perform WES. Comparisons of distinct mutation profiles between primary and progressive specimens as well as CTCs reflected different evolutionary mechanisms between CTC and lymph node metastasis, embodied in a higher proportion of mutations in CTCs shared with paired progressive lung tumor and hydrothorax specimens (4.4-33.3%) than with progressive lymphatic node samples (0.6-11.8%). Functional annotation showed that CTCs not only harbored cancer-driver gene mutations, including frequent mutations of EGFR and TP53 shared with primary and/or progressive tumors, but also particularly harbored cell cycle-regulated or stem cell-related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc., most of which derived from primary tumor samples and played crucial roles in chemo-drug resistance and metastasis for NSCLCs. Thus, detection of genetic information in CTCs is a feasible strategy for studying drug resistance and discovering new drug targets when progressive tumor specimens were unavailable.

Analysis of the clinical effect of osimertinib on 90 cases with advanced lung adenocarcinoma.

BACKGROUND: Primary or secondary drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) is a new challenge in the treatment of advanced non-small cell lung cancer (NSCLC). Osimertinib is a third-generation EGFR-TKI, and its efficacy and safety in NSCLC patients with first-generation EGFR-TKI resistance, especially lung adenocarcinoma, are not yet clear. The purpose of this study was to observe the efficacy and adverse reactions of osimertinib in the treatment of patients with advanced lung adenocarcinoma. METHODS: From January 2017 to December 2018, 90 patients with advanced (stage IV) lung adenocarcinoma were diagnosed in Shanghai Chest Hospital. The disease of these patients (94.4%) progressed after first-line EGFR-TKI treatment, and 43.3% of patients received third-line or beyond third-line treatment. The efficacy and adverse reactions of osimertinib treatment were observed. RESULTS: Among 90 patients with advanced lung adenocarcinoma, 57 (63.3%) achieved partial response (PR), 27 (30.0%) had stable disease (SD), and 6 (6.7%) had progressive disease (PD). The objective response rate (ORR) was 63.3%, and the disease control rate (DCR) was 93.3%. The median progression-free time (mPFS) was 10.41 months (95% CI: 8.91-11.91 months), and the median overall survival (mOS) was 31.37 months (95% CI: 26.37-36.37 months). The incidence of adverse events of degree 3 and above was 7.78%. The main adverse events were diarrhea (28.9%) and rash (24.4%). After symptomatic treatment, the incidence of adverse events was significantly reduced. CONCLUSIONS: Osimertinib has a definite curative effect in the treatment of patients with advanced lung adenocarcinoma, and the incidence of adverse reactions is low.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors combined with chemotherapy in first-line treatment in an advanced non-small cell lung cancer patient with EGFR sensitive mutation.

This article demonstrates a case of a lung adenocarcinoma patient in stage IV harboring an epidermal growth factor receptor (EGFR) 19 exon deletion mutation treated with 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin on day 1, sequenced with 250 mg gefitinib on prescription on days 4-28 for six cycles as first-line, then by gefitinib combined with pemetrexed as maintenance therapy. The patient achieved a partial response. Performance status increased from grade 2 to 1. The progression-free survival period was 17 months. Overall survival is now over three years. Side effects of grade two liver dysfunction and dermal toxicity were tolerable. Combined gefitinib with platinum-based chemotherapy as first-line treatment probably benefits non-small cell cancer patients in stage IV harboring sensitive EGFR gene mutations with a better local control rate, longer survival, and tolerable side effects.

[Value of carcinoembryonic antigen levels in predicting the efficacy of EGFR-TKI in advanced non-small cell lung cancer harboring EGFR mutations].

OBJECTIVE: To explore the relevance of carcinoembryonic antigen (CEA) level and efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. METHODS: Between September 2010 and December 2013, 170 NSCLC patients harboring EGFR mutations receiving EGFR-TKI treatment at pulmonary medicine department of Shanghai Chest hospital were retrospectively screened. They were screened for clinical characteristics, efficacy of EGFR-TKI, and tumor markers (CEA/cytokerantin-19-fragment CYFRA21-1) at an initial diagnosis. The cutoff value for CEA was 5 µg/L. RESULTS: The overall objective response rate (ORR) was 37.6% and disease control rate (DCR) 90.0%. Those with high CEA levels (>5 µg/L) had better DCR (94.3% vs 80.4%, P = 0.022). Univariate analysis showed that patients with high CEA levels ( ≥ 20 µg/L) had significantly longer progression-free survival (PFS) than those with low CEA level (HR = 1.444, 95%CI: 1.036-2.014, P = 0.030). HR value increased with rising CEA levels. No significant difference in PFS existed between high-CYFRA21-1 and normal-CYFRA21-1 groups (HR = 1.167, 95%CI: 0.840-1.622, P = 0.357). Close follow-ups were conducted for 51 patients on EGFR-TKI treatment. And their CEA levels was tested within one month after treatment. The patients in descending type group had longer PFS than other two types (HR = 7.344, 95%CI: 2.903-18.578, P < 0.001). CONCLUSIONS: CEA level has a close correlation with the efficacy of EGFR-TKI treatment. And a high CEA level may be a predictive marker for better response and longer PFS in advanced NSCLC.

Monitoring of carcinoembryonic antigen levels is predictive of EGFR mutations and efficacy of EGFR-TKI in patients with lung adenocarcinoma.

For the detection of epidermal growth factor receptor (EGFR) mutations, tumor tissues may not always be available. Not all the patients harboring EGFR mutation have a clinical response after the treatment of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). EGFR mutations were detected in 70 cases of newly diagnosed non-smoking adenocarcinoma, and patients harboring EGFR mutations received EGFR-TKI treatment. The EGFR mutation status of these patients' blood was analyzed by amplification refractory mutation system (ARMS). The patients' carcinoembryonic antigen (CEA) levels were tested on the third, seventh, 15(th), and 30th days after EGFR-TKI treatment. Forty-four cases were found with EGFR mutations. EGFR mutation rate of CEA high-level group was significantly higher than low-level group (70.8% vs. 40.9%, P = 0.017). Multivariate analysis showed that high-level CEA is independently associated with EGFR gene mutation (P = 0.020, OR = 3.508, 95%CI, 1.223-10.059). The sensitivity of high CEA level and ARMS to predict EGFR mutation were 79.1% and 51.2%. We divided the patients who received EGFR-TKI treatment into three groups by the variation types of CEA. Univariate analysis showed that patients in descending type group have longer progression-free survival (P = 0.001, HR 6.981, 95%CI, 2.534-19.237). Multivariate Cox proportional hazards model analyses shows the same result (P = 0.001, HR 9.82, 95%CI, 3.322-26.031). In conditions of the current technique, using high CEA level to predict EGFR mutations seems to be more sensitive than using EGFR mutations in plasma. The variation types of CEA level could help us to predict the efficacy of EGFR-TKI in patients harboring EGFR mutation within only 1 month of tyrosine kinase inhibitor therapy.

[Predictive role of EGFR mutation status on postoperative prognosis in patients with resected lung adenocarcinomas].

BACKGROUND: At present the proportion of lung adenocarcinomas in NSCLC is higher than before. Thus, the study on prognosis of lung adenocarcinoma is extremely important. The predictive value of epidermal growth factor receptor (EGFR) mutations for prognosis in patients with resected lung adenocarcinomas has not be reported in China. The aim of this study is to analyze the association between the EGFR mutations and the outcomes of patients with resected lung adenocarcinomas. METHODS: Total of 301 patients with stage Ia-IIIa resected lung adenocarcinomas whose survival had been identified were retrospectively analyzed. Their EGFR mutations were detected by real-time quantitative PCR and DNA sequencing technology together. RESULTS: The proportion of EGFR mutation was 52.5% (158/301). The 2-year (disease-free survival, DFS) of EGFR-mutant group and wild-type EGFR group was 76.8%, 83.0%; 5-year overall survival (OS) of them was 67.7%, 65.7%. There was no significant difference for two groups (P = 0.252, P = 0.715). Further analysis for subgroups shows that the 2-year DFS, 5-year OS of mutant group and wild-type group in stage I-II was similar. For the patients with stage IIIa, the median DFS, 2-year DFS in mutant group was 12.2 months, 21.1%, lower than the 22.2 months, 42.1% in wild-type group. But there was no significant difference for both groups (P = 0.584, P = 0.295). The median OS, 5-year OS was 34.0 months, 30.8% in mutant group, while 38.7 months, 22.9% in wild-type group. There was no significant difference for both groups (P = 0.907, P = 0.444). CONCLUSIONS: EGFR-mutant group with resected lung adenocarcinomas has a tendency of lower DFS than the wild-type EGFR group only in stage IIIa, but there was no significant difference for both groups. The EGFR mutation status was not associated with disease-free survival or overall survival in resected lung adenocarcinomas.

The value of tumor markers in evaluating chemotherapy response and prognosis in Chinese patients with advanced non-small cell lung cancer.

OBJECTIVE: The aim of this study was to assess the value of tumor markers in monitoring chemotherapy response and predicting prognosis in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We studied carcinoembryonic antigen (CEA), CYFRA21-1 and neuron-specific enolase (NSE) of 111 untreated patients with advanced NSCLC before and after 2 cycles of chemotherapy, meanwhile evaluating the response according to the image, and analyzed the relationship between tumor markers and response rate, time to progression (TTP) and overall survival (OS). RESULTS: The mean percentages of CEA decrease of the 111 patients with advanced NSCLC whose image response was partial response, no response and progressive disease were 22.8, -5.5 and -59.8% (p = 0.002), 28.1, 1.8 and -70.8% for CYFRA21-1 (p = 0.001), and 17.5, -3.1 and -16.9% for NSE, respectively (p = 0.03). The median TTP for all patients was 6.7 months, while the median TTP for CEA decrease and CEA elevated or stable patients was 9.2 and 4.3 months, respectively (p < 0.001). Radiologic and CYFRA21-1 responses were significant predictive factors for TTP on multivariate analysis (p < 0.001 and p = 0.003, respectively). The median OS was 19.2 months for all patients, with a 1-year survival rate of 69.4%. Baseline CEA, baseline CYFRA21-1 and CEA response were significant predictive factors for OS on multivariate analysis (P = 0.004, P = 0.004 AND P < 0.001, respectively). CONCLUSION: CEA, CYFRA21-1 and NSE can be used in evaluating chemotherapy response, and CYFRA21-1 response was a significant predictive factor for TTP, while baseline CEA, baseline CYFRA21-1 and CEA response were significant predictive factors for OS in Chinese patients with advanced NSCLC.

The expression of stem cell-related indicators as a prognostic factor in human lung adenocarcinoma.

INTRODUCTION: The purpose of the present study was to detect the presence of BASC-like stem cell-related indicators, such as clara cell secretory protein (CCSP), Octamer-4 (OCT4) and Bmi-1, and evaluate their implications in the prognosis of patients with lung adenocarcinoma. METHODS: Specimens of 134 cases of lung adenocarcinoma were collected after radical surgery from January 1999 to June 2004. RESULTS: One hundred and twenty-six cases showed cells that were positive for CCSP, 99 cases positive for OCT4, 91 cases simultaneous expression of CCSP and OCT4 and 74 cases positive for Bmi-1. Bmi-1 was significantly higher in patients at stage III compared to patients at stages I and II. The pattern of survival curves showed that Bmi-1 was a significant prognostic factor of poor overall survival in lung adenocarcinoma patients (P = 0.0000), and the patients with OCT4(+) expression showed a greater increase in mortality than OCT4(-) patients (P = 0.0103). The results of univariate and multivariate Cox analysis revealed that the pathological stages of tumor node metastases (P = 0.037), OCT4 (P = 0.046) and Bmi-1 expression (P = 0.001) were independent prognostic factors. CONCLUSIONS: OCT4 and Bmi-1 may be good biomarkers to predict the prognosis of patients with completely resected lung adenocarcinoma.