Search

Background: In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: Patients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression. Results: The incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15–0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18–1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments. Conclusions: First-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient's overall physical health and personal preferences. [ABSTRACT FROM AUTHOR]

Background: Patients with brain oligometastases have better prognosis than those with synchronous extracranial metastases in non‐small cell lung cancer (NSCLC). However, studies focusing on intracranial‐only recurrence after curative surgery remained scarce. This study aimed to explore distinct features of patients with exclusive brain relapse after resection of lung adenocarcinoma. Methods: Records were retrospectively reviewed of 2809 patients who had complete resection and pathologically confirmed stage IB‐IIIA NSCLC in our hospital from October 2012 to September 2019. Patients were enrolled if they were adenocarcinoma and developed intracranial recurrence thereafter. They were divided into two groups depending on whether they had synchronous extracranial metastases. Clinical and pathological features of patients enrolled were collected and compared between groups. Results: Ninety‐seven lung adenocarcinoma patients with intracranial recurrences were enrolled. The median follow‐up time was 40 months. Fifty patients (51.5%) had brain oligometastases and 47 patients had synchronous extracranial metastases (ECM). Multivariate logistic regression suggested EGFR‐sensitive mutation and male sex were positively correlated to brain‐only recurrence (OR = 2.59, 95%CI 1.04–6.84 and OR = 2.58, 95% CI 1.05–6.75), while higher clinical stage was associated with synchronous ECM (stage II (OR = 0.33, 95%CI 0.09–1.14) or stage IIIA (OR = 0.54, 95%CI 0.20–1.38) versus stage I). No other pathological feature (lymphovascular invasion, visceral pleural invasion, low tumor differentiation, etc.) or adjuvant chemotherapy was associated with intracranial‐only relapse after complete resection of primary tumor. Conclusion: Among patients with brain relapse after resection of lung adenocarcinoma, patients with EGFR mutations might have intracranial relapse only without synchronous extracranial metastases. Further prospective studies are warranted to verify this. [ABSTRACT FROM AUTHOR]

Objectives: Central nervous system (CNS) metastases including brain metastases (BM) and leptomeningeal metastases (LM) are frequent in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), and are correlated with poor outcomes. In this study, we evaluated the efficacy of single-agent furmonertinib 160 mg or combining with anti-angiogenic agent in NSCLC patients who had developed BM/LM progression from previous tyrosine kinase inhibior (TKI) treatment. Methods: EGFR-mutated NSCLC patients who developed BM (the BM cohort) or LM progression (the LM cohort) were included, having received furmonertinib 160 mg daily as second-line or later treatment, with or without anti-angiogenic agents. The intracranial efficacy was evaluated by intracranial progression-free survival (iPFS). Results: Totally 12 patients in the BM cohort and 16 patients in the LM cohort were included. Almost one half of patients in the BM cohort and a majority in the LM cohort had a poor physical status, with a Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. The administration of single-agent furmonertinib or combination treatment achieved a median iPFS of 3.6 months (95%CI 1.435–5.705) in the BM cohort, and 4.3 months (95%CI 2.094–6.486) in the LM cohort. Subgroup and univariate analysis has shown that a good ECOG-PS correlated with a favorable efficacy of furmonertinib in the BM cohort (median iPFS = 2.1 with ECOG-PS ≥ 2 vs. 14.6 months with ECOG-PS < 2, P < 0.05). Overall, any grade of adverse events (AEs) occured in 46.4% of patients (13/28). Among them, 14.3% of patients (4 of 28) had grade 3 or higher AEs, and were all under control, led to no dose reductions or suspension. Conclusion: Single-agent furmonertinib 160 mg or in combination of anti-angiogenic agent is an optional salvage therapy for advanced NSCLC patients who developed BM/LM progression from prior EGFR-TKI treatment, with a promising efficacy and an acceptable safety profile, and is worth of further exploration. [ABSTRACT FROM AUTHOR]

Background: Currently, survival benefit of immunotherapy in advanced non‐small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins) is controversial, though it generally indicates poor response and activity. Compared with standard chemotherapy in combination with bevacizumab, first‐line chemotherapy plus immune checkpoint inhibitor (ICI) in advanced NSCLC with EGFR ex20ins remains elusive and lacks real‐world evidence. Patients and Methods: A retrospective real‐world study was conducted to evaluate clinical outcomes of chemotherapy alone (C), chemotherapy plus ICI (C + I), or chemotherapy plus angiogenesis inhibitors (C + A) as first‐line strategies for advanced NSCLC patients with EGFR ex20ins. Investigator‐assessed response and survival outcomes were compared between subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to reveal concomitant alterations and explore the molecular landscape of ex20ins. Results: A total of 164 patients were screened, identifying 35 kinds of ex20ins, and 122 cases treated with C, C + I, and C + A were finally included in the first‐line analysis. C + A achieved much better objective response rate (ORR, 38.1% vs. 18.2%) and significant progression‐free survival (PFS) benefit compared with C (median, 7.73 vs.5.93 months, HR = 0.60, 95% CI: 0.40–0.90, p = 0.014), and it showed similar ORR (38.1% vs. 40.0%), but higher disease control rate (DCR, 96.8% vs. 80.0%) and numerically longer median PFS (7.73 vs. 6.53 months, HR = 0.83, 95% CI: 0.44–1.56, p = 0.30) than C + I. There was no PFS difference between C + I and C, despite of PD‐L1 expression or tumor mutational burden. KEGG analysis revealed concomitant upregulation of PI3K/AKT signaling might mediate intrinsic resistance to ICI in ex20ins. Conclusion: First‐line chemotherapy plus angiogenesis inhibitors might yield more survival benefits than chemotherapy alone for NSCLC with EGFR ex20ins, whereas, it suggests that chemotherapy in combination with ICI might not obtain a better survival benefit for this subset of patients. Activation of PI3K/AKT signaling might mediate intrinsic immunosuppression in NSCLC with EGFR ex20ins. [ABSTRACT FROM AUTHOR]

Purpose: After progression to immunotherapy, the standard of care for non-small cell lung cancer (NSCLC) was limited. Administration of the same or different immune checkpoint inhibitors (i.e., ICI rechallenge) may serve as a novel option. The present study aimed to evaluate the efficacy of ICI rechallenge for NSCLC and explore prognostic factors. Methods: In this retrospective cohort study, data of advanced or metastatic NSCLC patients rechallenged with ICI at the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College between December 2018 and June 2021 were retrieved. Progression-free, overall survivals (PFS; OS), etc. were calculated. Subgroup analyses were conducted according to baseline characteristics, prior treatment results, etc. for prognostic factor exploration using the Cox model. Results: Forty patients were included. Median age was 59 years. Thirty-one (78%) were male. Twenty-seven (68%) were smokers. Adenocarcinoma (28 [70%]) was the major histological subtype. Median PFS of patients receiving initial ICI was 5.7 months. The most common rechallenge regimens were ICI plus chemotherapy and/or angiogenesis inhibitor (93%). Seventeen (43%) were rechallenged with another ICI. Median PFS for ICI rechallenge was 6.8 months (95% CI 5.8–7.8). OS was immature. Tendencies for longer PFS were observed in nonsmoker or patients with adenocarcinoma, response of stable/progressive disease in initial immunotherapy, or whose treatment lines prior to ICI rechallenge were one/two. However, all results of prognostic factors were nonsignificant. Conclusion: ICI rechallenge may be an option for NSCLC after progress to immunotherapy. Further studies to confirm the efficacy and investigate prognostic factors are warranted. [ABSTRACT FROM AUTHOR]

Introduction: EGFR mutations in non-small cell lung cancer (NSCLC) are associated with a poor response to immune checkpoint inhibitors (ICIs), and only 20% of NSCLC patients harboring EGFR mutations benefit from immunotherapy. Novel biomarkers or therapeutics are needed to predict NSCLC prognosis and enhance the efficacy of ICIs in NSCLC patients harboring EGFR mutations, especially lung adenocarcinoma (LUAD) patients, who account for approximately 40–50% of all NSCLC cases. Methods: An ARID1A-knockdown (ARID1A-KD) EGFR-mutant LUAD cell line was constructed using lentivirus. RNA-seq and mass spectrometry were performed. Western blotting and IHC were used for protein expression evaluation. Effects of 3-MA and rapamycin on cells were explored. Immunofluorescence assays were used for immune cell infiltration examination. Results: ARID1A expression was negatively associated with immune cell infiltration and immune scores for ICIs in LUAD with EGFR mutations. In vitro experiments suggested that ARID1A-KD activates the EGFR/PI3K/Akt/mTOR pathway and inhibits autophagy, which attenuates the inhibition of Rig-I-like receptor pathway activity and type I interferon production in EGFR-mutant LUAD cells. In addition, 3-MA upregulated production of type I interferon in EGFR-mutant LUAD cells, with an similar effect to ARID1A-KD. On the other hand, rapamycin attenuated the enhanced production of type I interferon in ARID1A-KD EGFR-mutant LUAD cells. ARID1A function appears to influence the tumor immune microenvironment and response to ICIs. Conclusion: ARID1A deficiency reverses response to ICIs in EGFR-mutant LUAD by enhancing autophagy-inhibited type I interferon production. 4p38v18Tik7_Gskdth_Seh Video Abstract [ABSTRACT FROM AUTHOR]

Objectives: To analyze the clinical relevance of heterogeneous phenotypes of peripheral circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC). Materials and Methods: CTCs in 5 mL venous blood were enriched using the Canpatrol™ CTC technique in 82 NSCLC patients. And then, CTCs were subjected to RNA in situ hybridization with a combination of epithelial (EpCAM and CK8/18/19) and mesenchymal (vimentin and TWIST1) markers. Results: According to the fluorescent dots, CTCs were classified into three groups, including epithelial CTCs (E-CTC), hybrid epithelial/mesenchymal phenotypes (E/M-CTCs) and mesenchymal CTCs (M-CTCs). In 82 NSCLC cohort, only 2 patients didn't detect CTCs, the overall CTCs detection rate was 97.5% (80/82). For 60 treatment naïve NSCLC, only one patient didn't detect CTCs. The median number of total CTCs, hybrid E/M phenotype CTCs, E-CTCs and M-CTCs per 5 mL blood was 22 (range 1–90), 13 (range 0–83), 1 (range 0–17 and 0–47), respectively. Hybrid E/M CTCs, especially the e = m-CTCs, significantly differed between patients with and without distant metastasis. M-CTCs in advanced NSCLC patients were significantly more than the numbers observed in early stage patients. Patients with pure hybrid E/M-CTCs showed a lower proportion in distant metastasis positive cohort compared to negative ones (7% vs 22%), while patients with E + E/M CTCs (20% vs 9%) and E/M + M CTCs (33% vs 20%) showed a higher proportion. CTCs dynamic changes after treatment in 12 advanced NSCLC patients suggested that hybrid E/M-CTCs were related to the primary tumor size at baseline, while M-CTCs may suggest the progression of NSCLC. Conclusion: We concluded that E-CTCs with a hybrid E/M phenotype are associated to metastasis in therapy-naïve NSCLC patients. [ABSTRACT FROM AUTHOR]

Introduction: Leptomeningeal metastasis (LM) commonly occurs in non-small cell lung cancer (NSCLC) patients and has a poor prognosis. Due to limited access to leptomeningeal lesions, the genetic characteristics of LM have not been explored to date. Cerebrospinal fluid (CSF) may be the most representative liquid biopsy medium to obtain genomic information from LM in NSCLC. Methods: CSF biopsies and matched peripheral blood biopsies were collected from 33 NSCLC patients with LM. We profiled genetic alterations from LM by comparing CSF cell-free DNA (cfDNA) with plasma cfDNA. Somatic mutations were examined using targeted sequencing. Genomic instability was analyzed by low-coverage whole-genome sequencing (WGS). Results: Driver mutations were detected in 100% of CSF cfDNA with much higher variant allele frequency than that in matched plasma cfDNA (57.5%). Furthermore, we found that the proportions of CSF cfDNA fragments below 150 bp were significantly higher than those in plasma cfDNA. These findings indicate enrichment of circulating tumor DNA (ctDNA) in CSF and explain the high sensitivity of mutation detection in the CSF. The absence of some mutations in CSF cfDNA—especially the first-/second-generation mutation T790M, which confers resistance to epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs)—that were present in plasma cfDNA samples indicates different mechanisms of cancer evolution between LM and extracranial lesions. In addition, 86.6% of CSF ctDNA samples revealed high levels of genomic instability compared with 2.5% in plasma cfDNA samples. A higher number of large-scale state transitions (LSTs) in CSF cfDNA were associated with a shorter overall survival (OS). Conclusion: Our results suggest that LM and extracranial lesions develop independently. Both CSF cfDNA genetic profiling and plasma cfDNA genetic profiling are necessary for clinical decision-making for NSCLC patients with LM. Through CSF-based low-coverage WGS, a high level of LSTs was identified as a potential biomarker of poor prognosis. [ABSTRACT FROM AUTHOR]

Background: HER2 exon 20 insertions remain a subset heterogeneous alterations in lung cancer, with currently unmet need for precision targeted therapy. G776delinsVC, a typical HER2 exon 20 deletion-insertion at codon Gly776, was reported to respond discrepantly to afatinib compared with the predominant insertion A775_G776insYVMA (YVMA). However, it lacks structural evidence to illustrate the possible mechanism and predict the binding activities of its similar variants over YVMA insertion to HER2 -targered tyrosine kinase inhibitors (TKIs). Methods: Real-world cohort study was performed to investigate clinical outcomes with HER2 -targeted TKI afatinib and pyrotinib, and structural analysis for exon 20 Gly776 deletion-insertions G776delinsVC, G776delinsLC and G776delinsVV, and YVMA by molecular dynamics simulation and cellular kinase inhibition assay were provided for full exploration. Results: Afatinib revealed low objective response rate (ORR) of 0–9.5% and short median progression-free survival (mPFS) of 2.8–3.2 months for YVMA, but with higher ORR of 20–28.6% and longer mPFS of 4.3–7.1 months for G776delinsVC. Pyrotinib presented significantly improved PFS benefit than afatinib for G776delinsVC and YVMA as first-line (median, 6.8 vs. 3.4 months, p = 0.010) or second-line therapy (median, 5.8 vs. 2.8 months, p < 0.001). No significant difference was observed on drug binding pocket and TKI binding activity between G776delinsVC, G776delinsLC and G776delinsVV, and both afatinib and pyrotinib showed favorable binding activity. YVMA insertion significantly affected the loop region with altering HER2 protein secondary structure and forming steric hindrance to binding of afatinib. Pyrotinib showed the best selectivity to HER2 , with more favorable activity to YVMA than afatinib indicated by cellular inhibition assay. Conclusion: Both afatinib and pyrotinib showed favorable activity for NSCLC patients with HER2 exon 20 Gly776 deletion-insertions. Pyrotinib revealed more potent activity to A775_G776insYVMA insertion than afatinib due to the steric binding hindrance induced by YVMA. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings.Methods: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.Results: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone.Conclusions: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size. [ABSTRACT FROM AUTHOR]

Purpose: The high intracranial efficacy of targeted therapeutic agents poses a challenge in determining the optimal sequence of local radiation therapy (RT) and systemic treatment with tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). Therefore, we conducted a cohort study to elucidate the appropriate treatment strategy, either upfront RT or deferred RT including a toxicity assessment, in these patients. Patients and Methods: We retrospectively evaluated patients with gene-driven BMs from a single institution and divided them into deferred and upfront RT groups. Survival was estimated using a log-rank test. Intracranial progression was estimated using Fine-Gray competing risks model. Cox proportional hazards regression was performed for multivariable analysis in the entire group and subgroups. Results: Among the 198 eligible patients, 94 and 104 patients received deferred and upfront RT, respectively. The upfront RT group showed a lower intracranial progression risk with an adjusted sub-distribution hazard ratios of 0.41 (95% CI, 0.30–0.57) than did the deferred RT group (median intracranial progression-free survival [iPFS], 19.9 months vs. 11.1 months; p < 0.001). The median overall survival (OS; 43.2 months vs. 49.1 months, p = 0.377) and BM-specific survival (92.1 months vs. 82.9 months, p = 0.810) after salvage therapy were not significantly different between the upfront and deferred groups. Among patients with progressed extracranial disease, the deferred RT group showed significantly better OS than did the upfront RT group (44.0 vs. 28.1 months, p = 0.022). Grade 3–4 treatment-related adverse events were rare, and similar toxicities were observed between the two groups. Conclusion: Compared to the deferred RT group, the upfront RT group achieved longer iPFS and similar survival outcomes in most patients with gene-driven NSCLC BM, although patients with progression of extracranial disease might benefit from deferred RT. Both groups showed well-tolerated toxicities. Trial registration ID: NCT04832672. [ABSTRACT FROM AUTHOR]

Background: Approximately 3–5% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) harbor exon 18 mutations. The appropriate treatment for such patients has not been clarified. The aim of this study was to investigate the response of patients with NSCLC harboring EGFR exon 18 mutations to different therapeutic options. Methods: Between May 2014 and September 2020, the clinical outcomes of 82 patients harboring EGFR exon 18 mutations who received first-generation (1G) EGFR -tyrosine kinase inhibitor (TKI), second-generation (2G) EGFR -TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed. Results: A total of 82 NSCLC patients harboring EGFR 18 mutations with whose treatment and survival outcomes were available were analyzed. The median age was 59 years, and 47 (57.3%) were female. The most common kind of EGFR exon 18 mutation was G719X (75.6%), followed by E709X (15.9%), E709_T710delinsD (3.6%), and other subtypes (4.9%). There was a significant difference in median progression-free survival (mPFS) by therapeutic strategy (P = 0.017). The mPFS of 1G TKI, 2G TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy were 7.7 (95% CI, 4.2–11.2), 11.3 (95% CI, 5.6–17.0), 5.0 (95% CI, 2.3–17.7), and 11.1 (95% CI, 5.9–16.4) months, respectively. No significant difference in PFS was observed between afatinib and 1G TKI in combination with chemotherapy (P = 0.709). Conclusions: Like afatinib, 1G TKI in combination with chemotherapy might be an effective treatment option for patients harboring EGFR exon 18 mutations. [ABSTRACT FROM AUTHOR]

Background: Clinical evidence has shown that few non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can benefit from immunotherapy. The tumor immune microenvironment (TIME) is a significant factor affecting the efficacy of immunotherapy. However, the TIME transformational process in EGFR -mutation patients is unknown. Methods: The mRNA expression and mutation data and lung adenocarcinoma (LUAD) clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Profiles describing the immune landscape of patients with EGFR mutations were characterized by differences in tumor mutation burden (TMB), ESTIMATE, CIBERSORT, and microenvironment cell populations-counter (MCP-counter). Results: In total, the TCGA data for 585 patients were analyzed. Among these patients, 98 had EGFR mutations. The TMB was lower in the EGFR group (3.94 mut/Mb) than in the KRAS mutation group (6.09 mut/Mb, P < 0.001) and the entire LUAD (6.58 mut/Mb, P < 0.001). The EGFR group had a lower population of activated immune cells and an even higher score of immunosuppressive cells. A further inter-group comparison showed that differences in the TMB and tumor-infiltrating lymphocytes were only found between patients with oncogenic mutations and unknown mutation. Meanwhile, there were more myeloid dendritic cells (DCs) in EGFR 19del than in L858R-mutation patients and in common mutation patents than in uncommon mutation patients (P < 0.05). Additionally, we established a D score, where D = MCP-counter score for cytotoxic T lymphocytes (CTLs)/MCP-counter score for myeloid DCs. Further analysis revealed that lower D scores indicated immune suppression and were negatively related to several immunotherapy biomarkers. Conclusions: The TIME of EGFR mutant NSCLC was immunosuppressive. Myeloid DCs gradually increased in EGFR 19del, L858R, and uncommon mutations. The potential role of CTLs and DCs in the TIME of patients requires further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Osimertinib, a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), has demonstrated substantial clinical benefit in patients with non-small-cell lung cancer (NSCLC) who were resistant to early-generation EGFR-TKIs and had acquired a T790M mutation. The aim of our study was to identify the mechanisms underlying resistance to osimertinib and to correlate them with clinical outcomes. Methods: We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKIs between March 1, 2017 and December 31, 2018. Patients with paired molecular data of pre-osimertinib and after resistance development, which were not confirmed with small-cell lung cancer (SCLC) transformation, were included in the molecular analysis set. Results: Of 49 patients evaluated in the molecular analysis set, 24 patients maintained T790M mutation, while 25 patients exhibited T790M-loss. Molecular modifications were identified in 27 of 49 patients including EGFR acquired mutations (C797S, C796S, G796S, V802I, V834L, E758D and G724S), non-EGFR-dependent mutations (PIK3CA, ALK, BRAF, KRAS and TP53), EGFR amplification and MET amplification. At data cutoff, median progression-free survival (PFS) was 9.3 months in the T790M-retain group compared with 7.8 months in T790M-loss patients (P = 0.053). Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism (13.5 months) than in those with alternative pathway activation (8.2 months; P = 0.012). Conclusions: The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits. [ABSTRACT FROM AUTHOR]

Background: ROS1 gene fusion represents a specific subtype of non‐small cell lung cancer (NSCLC). Crizotinib is recommended for ROS1‐positive NSCLC due to its favorable outcome in published clinical trials. However, due to the low incidence of ROS1‐positive NSCLC, there is limited information on real‐world clinical outcomes in patients treated with either crizotinib or platinum‐based doublet chemotherapy. Methods: Outcomes were recorded in 102 patients with stage Ⅲb or Ⅳ NSCLC who were treated at four Chinese hospitals between April, 2010 and June, 2019. Results: Of the 102 patients followed, 71.6% were females, 81.4% were non‐smokers, and 98.0% had adenocarcinoma. First‐line treatment with crizotinib achieved a significantly longer median progression‐free survival (PFS) compared with platinum‐based chemotherapy (14.9 months vs 8.5 months, respectively; P <.001). Next‐generation sequencing (NGS) identified 61 patients who had ROS1 fusion variants, including CD74 (n = 33) and non‐CD74 (n = 28) variants. In patients harboring CD74 fusion variants, the median PFS with first‐line crizotinib treatment was significantly longer than in those harboring non‐CD74 fusion variants (20.1 months vs 12.0 months, respectively; P =.046). However, in patients treated with platinum‐based chemotherapy, there was no significant difference in PFS between the CD74 and non‐CD74 variant groups (8.6 months vs 4.3 months, respectively; P =.115). Overall survival (OS) was not reached. Conclusions: First‐line therapy with crizotinib is more beneficial than platinum‐based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants. Patients harboring CD74 fusion variants appear to respond better to crizotinib. [ABSTRACT FROM AUTHOR]

BRAF mutation is an oncogenic driver gene in non-small cell lung cancer (NSCLC) with low frequency. The data of patients with NSCLC harboring BRAF mutations is rare. We conducted a retrospective multicenter study in Chinese patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R, and T599dup. Of 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2, 18.7, and 10.1 months of stage I, II, and IIIA patients, respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR), and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0 vs. 70.0%, P = 0.027; median PFS, 9.8 vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8, 5.8, and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, with median PFS of 3.0 months. Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study. [ABSTRACT FROM AUTHOR]

Aim: Valuable and convenient prognostic predictors are essential for targeted therapy of non–small cell lung cancer (NSCLC). Patients with early‐stage cancer and EGFR mutations who's neutrophils‐to‐lymphocytes rate (NLR) could be prognostic factor to evaluate efficacy. However, the prognostic role of NLR in patients receiving ALK inhibitors has not been established. Additionally, the relation between the efficacy of ALK inhibitors and derived NLR (dNLR), platelets‐to‐lymphocytes rate (PLR), white blood cells (WBC) and hemoglobin (HGB) are still unknown. Methods: This is a retrospective single‐center study and enrolled 113 staged IIIB–IV ALK‐positive NSCLC patients who had received crizotinib treatment. Pretreatment NLR, dNLR, PLR, WBC, HGB were collected and calculated. Cox regression analysis were conducted to study the prognostic roles of NLR, dNLR, PLR, WBC, and HGB on progression‐free survival (PFS) and overall survival (OS). Z‐test was utilized to identify the difference among all predictive factors' receiver‐operating characteristics (ROC) curves. Results: The median PFS and OS were 10.1 and 23.4 months. Elevated NLR, dNLR, PLR and decreased HGB were associated with worse PFS (95% confidence interval [CI], 1.078–2.304, P = 0.018; 95% CI, 1.043–2.222, P = 0.028; 95% CI, 1.257–2.757, P = 0.002; 95% CI, 0.368–0.843, P = 0.005, respectively) and OS (95% CI, 1.698–5.721, P < 0.001; 95% CI, 1.273–3.984, P = 0.005; 95% CI, 2.174–6.347, P < 0.001; 95% CI, 0.246–0.710, P = 0.001, respectively). Z‐test revealed there were no significant differences between single factors or combination of them to predict the efficacy. Conclusions: Trend of NLR, dNLR, PLR and WBC could be used to identify patients progress status in ALK‐positive NSCLC patients receiving crizotinib. Combination of all biomarkers is no superior to single biomarker. [ABSTRACT FROM AUTHOR]

Objectives: Crizotinib has demonstrated good efficacy in patients with anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Continuing crizotinib therapy beyond progressive disease (CBPD) can achieve ongoing survival benefit in real‐world clinical practice. In terms of survival, progression‐free survival (PFS), the most commonly used endpoint in efficacy evaluations, may not provide accurate information on the impact of this intervention when crizotinib is administered in sequential therapy. Materials and Methods: A single‐center, retrospective study of 201 ALK‐positive advanced NSCLC patients was conducted to analyze the PFS, overall survival (OS), and treatment duration (TD) of crizotinib. The correlations between the TD of crizotinib and OS in CBPD and non‐CBPD groups of patients were compared. Results: All patients were treated with crizotinib, 150 of whom eventually developed progressive disease (PD). The median PFS1 and PFS2 were 13.2 months and 10.5 months, respectively. The OS of the whole population was 50.5 months. The median TD was 20.7 months, which is shorter than direct PFS1 + PFS2. The TD of crizotinib in CBPD group was significantly longer than that in non‐CBPD group (median 39.7 vs 15.0 months, P < .001). TD correlated better with OS (R = .79) than PFS (R = .64) in the CBPD group. Conclusions: Crizotinib showed good efficacy in patients with ALK‐positive advanced NSCLC. Instead of PFS, treatment duration might be a more reasonable surrogate clinical endpoint in patients who received crizotinib in sequential therapy. [ABSTRACT FROM AUTHOR]

Purpose: Osimertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted for both EGFR sensitizing mutations and T790M resistance mutation in patients with non-small-cell lung cancer (NSCLC). We assessed efficacy and safety of osimertinib in patients with pretreated NSCLC in a real-world setting. Patients and methods: Ninety-four patients with advanced NSCLC who received osimertinib after progression of prior EGFR-TKIs or chemotherapy treatments were retrospectively collected. Results: In patients evaluable for response analysis (n = 91), overall objective response rate (ORR) was 47.3%, and disease control rate (DCR) was 90.1%. Median duration of response (DoR) in responding patients was 12.5 months (95% confidence interval [CI], 10.7 to 14.3). Median progression-free survival (PFS) was 8.5 months (95% CI, 7.4 to 9.6) in 2nd line group, 9.1 months (95% CI, 6.6 to 11.6) in ≥3rd line group, and 8.6 months (95% CI, 7.2 to 10.0) in overall population. For subgroup analysis, DCR and median PFS were 91.9% and 8.6 months (95% CI, 7.2 to 10.0) in patients with detectable T790M mutation, respectively, while 80.0% and 3.2 months (95% CI, 0.5 to 5.9) for those without. Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R (17.9 months vs 7.3 months; P<0.001). Among 45 patients with metastases to the central nervous system (CNS), median systemic PFS was 8.8 months (95% CI, 6.9 to 10.7), while intracranial time to progression (iTTP) was not reached. Safety profile was acceptable, no adverse events (AEs) related deaths was observed. Conclusion: Osimertinib was highly active in patients with pretreated advanced NSCLC who harbored EGFR T790M mutation, with manageable side-effects. [ABSTRACT FROM AUTHOR]

aims to quantify patients' risk-benefit preferences for chemotherapy in the treatment of non-small cell lung cancer (NSCLC), and to elicit their willingness to pay (WTP) for treatment outcomes. Methods: A face-to-face discrete choice experiment (DCE) was conducted on NSCLC patients in four tertiary hospitals each from Beijing, Shanghai, Guangzhou and Chengdu in China. Patients were invited to complete choice questions that constructed by seven attributes: progression-free survival (PFS), disease control rate (DCR), rash, nausea and vomiting, tiredness, mode of administration and out-of-pocket costs. A mixed logit model was used to evaluate the choice model. Estimates of relative preferences and marginal willingness to pay for each attribute were then explored. Results: A total of 361 patients completed the survey. Improvements in PFS (10, 95% CI: 8.4–11.6) were the most important attribute for patients, followed by increase in DCR (4.6, 95% CI: 3.4–5.8). Tiredness (3.9, 95% CI: 2.9–5.1) was judged to be the most important risk. While remaining attributes were ranked in decreasing order of importance: nausea and vomiting (1.9, 95% CI: 0.9–3.0), mode of administration (0.8, 95% CI: 0.2–1.4) and rash (0.5, 95% CI: −0.6–1.5). There was little variation in preferences among patients with different sociodemographic characteristics. Patients were monthly willing to pay $2304 (95% CI, $1916–$2754) that guaranteed 11 months of PFS, followed by $1465 (95% CI, $1163-$1767) per month to improve their disease control rate by 90%. Conclusion: The results suggested that efficacy was the most important attribute for patients. Side effects, mode of administration and treatment cost significantly influenced patient preferences. Patient engagement in prioritizing their treatment preferences should be emphasized during the clinical decision-making process and regimen implementation. [ABSTRACT FROM AUTHOR]

Background: Targeted therapy is an important treatment for advanced non-small cell lung cancer (NSCLC) patients with specific genetic mutations, crizotinib can prolong survival in advanced NSCLC patients with echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) rearrangement. We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with EML4-ALK rearrangement NSCLC receiving treatment with crizotinib. Methods: Advanced (stage IIIb–IV) NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled between January 2007 and January 2016 at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences. Results: Overall, 212 patients were enrolled. Kaplan–Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs 14.1 months, HR =1.251, CI: 1.008–1.553, P=0.004) was significantly associated with shorter PFS, while the post-treatment mean-LDH level (13.3 vs 14.3 months, HR=1.439, 95% CI: 0.994–2.082, P=0.970) was not significantly associated with PFS. Cox proportional hazards model also identified that pre-treatment LDH level (HR=2.085, 95% CI: 1.150–3.781, P=0.016) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase (OR=6.712, 95% CI 3.395–13.273, P<0.01), creatine kinase isoenzyme (OR=6.297, 95% CI 2.953–13.427, P<0.01), and hemoglobin (OR=4.163, 1.741–9.956, P<0.001). Conclusion: An elevated pre-treatment serum LDH level (>250 U/L) was significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level was not significantly associated with PFS, which related to adverse events including muscle damage and anemia. [ABSTRACT FROM AUTHOR]

Objectives: The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) is not clear. Few study explored the trends of the PORT use. In this study, we examine the status of PORT use of completely resected NSCLC in mainland China. Methods: From 2005 to 2014, patients with primary lung cancer from eight hospitals across seven geographic regions of mainland China were selected. Then patients with staged I–IIIA NSCLC receiving radical surgery were enrolled in this study. The chi-square test was used to compare differences in the use of PORT among the groups of different age, regions and stages. The Cochran-Armitage trend test was used to identify the trend in the PORT use from 2005 to 2014. Results: Totally, 2,253 out of 7,184 patients were with staged I–IIIA NSCLC receiving completely resection. Only 122 patients (5.42%) received PORT. During this decade, the use of PORT declined significantly (p = 0.0002). In high socio-economic areas, the percentage of PORT use was 7.43%, which was significantly higher than 1.34% in the low socio-economic areas (p < 0.0001). Age was also associated with PORT use (p = 0.0747). For N0-1 and N2 NSCLC, the proportions of PORT use were 4.01 and 10.22%, respectively (p < 0.0001). And in N0-1 or N2 NSCLC, the proportions both decreased significantly during this decade (p = 0.009 and 0.026, respectively). For stage I, IIA, IIB and IIIA, the proportions who received PORT were 2.59, 4.65, 5.49, and 10.29%, respectively (p < 0.0001). Modern radiation techniques were widely used, but the volumes and doses varied widely. The proportions of using IMRT and EPID/IGRT increased after 2012. Conclusions: In China, the use of PORT was less than developed countries and had a declined trend. The use of PORT was related to disease stages, patients' age and geographic location. Both in N0-1 and N2 diseases, the use of PORT declined. Proper education of radiation doctors was urgently needed. [ABSTRACT FROM AUTHOR]

Aim: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations. Methods: We retrospectively analyzed the EGFR mutation pattern and its association with clinical‐pathological characteristics from 100 cases of nonsmall‐cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients with advanced EGFR‐mutated NSCLC were enrolled and treated with icotinib (oral administration, 125 mg, thrice per day). Results: Among 100 patients, 85 and 15 had common and uncommon mutations, respectively. Four patients had a single mutation in 18 or 20 exon, and 11 had a complex mutation with del‐19 or L858R. There was no significant association between the presence of different mutation type and the type of any clinical and pathological characteristics. Prolonged but not significant progression‐free survival (PFS) was noted in patients with common EGFR mutations (18.07 [14.00–26.23] vs 12.9 [8.43–23.27], P = 0.056). Patients without brain metastases had increased PFS to icotinib than those with brain metastases (18.07 [95% confidence interval, CI 14.77–27.03] vs 13.17 [95% CI 8.63–22.63], P = 0.038). Conclusion: Uncommon EGFR mutations comprised 15% of all mutated patients, in which most were complex mutations. Compared with common EGFR mutation, uncommon EGFR mutations were associated with a modest sensitivity to EGFR TKIs. Our findings will be helpful to make clinical decision and select the appropriate therapy for EGFR‐mutated NSCLC patients. [ABSTRACT FROM AUTHOR]

Poor prognosis of advanced non-small-cell lung cancer ( NSCLC) patients and the promising therapeutic effect of platinum urge the oncologists to evaluate the role of platinum doublet as second-line chemotherapy and establish the definition of platinum sensitivity in NSCLC. We retrospectively analyzed 364 advanced NSCLC patients who received platinum-doublet regimens as second-line chemotherapy after platinum-based first-line treatment. Patients were divided into four groups by their time-to-progression ( TTP) after first-line chemotherapy: 0-3, 4-6, 7-12, and >12-month group, respectively. Treatment efficacy of patients' overall survival ( OS), progression-free survival ( PFS), and response rate ( RR), as well as treatment-related toxicity, were compared among the four groups. A prognosis score system and a nomogram were established by Cox proportional hazard model, and validated by concordance index (c-index). Median OS was 14.0, 16.0, 20.0, 25.0 months for patients in the 0-3, 4-6, 7-12, >12-month group, respectively. Age ≤60 years ( P = 0.002), female ( P = 0.019), and TTP>12 months ( P = 0.003) were independent prognostic factors. Prognostic score was calculated by adding 1 point each for any of the above three indicators, with a c-index of 0.590 (95% confidential interval [ CI], 0.552-0.627). Median OS were equal to 25.0, 16.0, and 11.0 months for best (2-3 points), intermediate (1 point) and worst (0 point) category, respectively ( P < 0.0001). A nomogram that integrated patient's age, gender, and TTP for OS has a c-index of 0.623 (95% CI, 0.603-0.643). Female, younger than 60 years, and TTP greater than 12 months may indicate prolonged survival after platinum-doublet second-line chemotherapy in advanced NSCLCpatients. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged. [ABSTRACT FROM AUTHOR]

ARID1A is a key component of the SWI/SNF chromatin remodeling complexes which is important for the maintaining of biological processes of cells. Recent studies had uncovered the potential role of ARID1A alterations or expression loss in the therapeutic sensitivity of cancers, but the studies in this field requires to be further summarized and discussed. Therefore, we proposed a series of mechanisms related to the resistance to EGFR-TKIs induced by ARID1A alterations or expression loss and the potential therapeutic strategies to overcome the resistance based on published studies. It suggested that ARID1A alterations or expression loss might be the regulators in PI3K/Akt, JAK/STAT and NF-κB signaling pathways which are strongly associated with the resistance to EGFR-TKIs in NSCLC patients harboring sensitive EGFR mutations. Besides, ARID1A alterations or expression loss could lead to the resistance to EGFR-TKIs via a variety of processes during the tumorigenesis and development of cancers, including epithelial to mesenchymal transition, angiogenesis and the inhibition of apoptosis. Based on the potential mechanisms related to ARID1A, we summarized that the small molecular inhibitors targeting ARID1A or PI3K/Akt pathway, the anti-angiogenic therapy and immune checkpoint inhibitors could be used for the supplementary treatment for EGFR-TKIs among NSCLC patients harboring the concomitant alterations of sensitive EGFR mutations and ARID1A. [ABSTRACT FROM AUTHOR]

Introduction Anaplastic lymphoma kinase ( ALK ) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK -rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Methods Among 96 ALK -rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. Results The median Progression-free survival (PFS) of the 96 ALK -rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4 - ALK variants and non EML4 - ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4 - ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4 - ALK variants. Conclusions Our results indicate prolonged PFS in patients with EML4 - ALK variant 2. [ABSTRACT FROM AUTHOR]