Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment Po-Lan Su (Conceptualization) (Data curation) (Investigation) (Methodology) (Writing -review and editing), Jeng-Shiuan Tsai (Conceptualization) (Data curation) (Investigation) (Methodology) (Writing -review and editing), Szu-Chun Yang (Data curation) (Writing -review and editing), Yi-Lin Wu (Data curation) (Writingreview and editing), Yau-Lin Tseng (Data curation) (Writing -review and editing), Chao-Chun Chang (Data curation) (Writing -review and editing), Yi-Ting Yen (Data curation) (Writing -review and editing), Chia-Ying Lin (Data curation) (Writing -review and editing), Chien-Chung Lin (Conceptualization) (Data curation) (Investigation) (Methodology) (Writing -review and editing), Chin-Chou Wang (Conceptualization) (Data curation) (Investigation) (Methodology) (Writing -review and editing), Meng-Chih Lin (Data curation) (Writing -review and editing), Wu-Chou Su (Conceptualization) (Data curation) (Investigation) (Methodology) (Writing -review and editing)
Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician’s discretion based on patient’s request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy.
The use of immune checkpoint inhibitors (ICIs) has provided overall survival (OS) benefits in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, studies comparing ICIs monotherapy with combination therapy either with chemotherapy or radiotherapy in programmed death-ligand 1 high expressors remain limited. This study aimed to retrospectively compare the treatment efficacy of the therapies by studying 47 patients with treatment-naïve advanced NSCLC who received ICI monotherapy (n = 28) or combination therapy either with chemotherapy or radiotherapy (n = 19). Progression-free survival (PFS) and OS were estimated using the Kaplan–Meier method and compared using log–rank tests. It was observed that patients who received combination therapy had a better PFS than monotherapy, but no such significant benefit was observed in OS. The difference in PFS was higher in the subgroup of patients with low neutrophil-to-lymphocyte ratio (NLR) than in the high-NLR patient subgroup. This study suggests that pembrolizumab in combination with chemotherapy or radiotherapy could provide a significant benefit in PFS, especially in patients with treatment-naïve advanced NSCLC with low NLR. Furthermore, our study also demonstrates the potential use of NLR as a biomarker for prediction of treatment outcomes in patients with advanced NSCLC receiving combination therapy.
12510 Background: Safety and efficacy of malignant glioma treatment with carmustine-containing biodegradable implants (Gliadel® Wafers) followed by conventional radiotherapy (RT) and treatment with RT and concomitant temozolomide have both been well established. Multimodal therapy combining Gliadel® Wafers, RT, and temozolomide has recently demonstrated significant improvements in clinical outcomes of newly-diagnosed glioblastoma multiforme (GBM) patients. However, Gliadel® Wafer implantation in newly-diagnosed GBM patients is limited by the suspected risk of toxicities associated with multimodal therapy. Thus, the safety of multimodal therapy with Gliadel® Wafers, RT, and temozolomide needs to be determined. Methods: We conducted a retrospective analysis of medical records of 21 Florida Hospital Neuro- Oncology Center patients who were newly diagnosed with GBM from January 2003 to December 2005 and initially received multimodal therapy. All systemic and local toxicities were graded according to CTC AE v.3.0. Results were compared to historical data. Results: Our study population did not differ significantly from prior study populations with regard to patient demographics. 4 of 21 (19%) patients had grade 3 toxicities, which may have been related to multimodal therapy. None of the 21 patients had grade 4 toxicities. Median time to progression from initial surgery was 12.8 months (range 2–24 months). Median overall survival was 17 months (95% CI of 15–25 months). Conclusion: The addition of Gliadel® Wafers to concurrent RT and temozolomide did not result in a notable increase in grade 3 and 4 toxicities but did produce clinical outcomes comparable with those found in prior studies. The small sample size does not allow for definitive conclusions regarding efficacy. However, the addition of Gliadel® Wafers to concurrent RT and temozolomide appears to be safe in newly-diagnosed GBM patients. [Table: see text] No significant financial relationships to disclose.
Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical–regulatory factors for the entrance protein of SARS-CoV-2, angiotensin–converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman’s r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019–1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb–/– mice; however, exogenous ROS increased the ACE2 in Cybb–/– AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS–induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.
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