Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Progression inevitably happens after 10–14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of EGFR T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of EGFR-mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with EGFR-addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.

Purpose: Considering the limited data, we aimed to identify the greatest immune activation irradiated site of common metastases and response to immune checkpoint inhibitors simultaneously in non-small cell lung cancer (NSCLC).Methods: A total of 136 patients with advanced NSCLC who had received radiation to a primary or metastatic solid tumor were enrolled. We recorded blood cell counts in three time periods, before, during, and after radiotherapy (RT), and derived some blood index ratios including monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The delta-IBs were calculated as medio-IBs ÷ pre-IBs − 1. We analyzed the changes before and during RT using Spearman rank correlation test, Kruskal–Wallis rank sum test, and logistic regression analyzing their correlation with efficacy.Results: The medians of delta-MLR and delta-PLR were both the lowest while the median of delta-L was the highest in brain. Therapeutic effect evaluation showed that the objective response rate (ORR) of 48.65% (18/37) in the brain irradiation group was the highest, compared with 17.07% (7/41) in bone and 41.94% (13/31) in lung.Conclusions: In this study, results suggested that irradiation to brain has the best immune activation effect and patient outcome compared with other organs in NSCLC, and when the earlier-line ICIs were combined with RT, a better patient outcome was reached. Prospective studies are also necessary to provide more convincing evidence and standards for clinical irradiation metastases selection.

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7–78.9%) and the DCR was 76% (95% CI: 54.9–90.6%). The mPFS was 6.0 months (95% CI: 5.4–9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

Since there is high local failure and poor survival for unresectable esophageal squamous cell carcinoma (ESCC), the necessity of elective node irradiation is controversial. The purpose of this study was to investigate the failure patterns and survival in patients with locally advanced ESCC receiving involved-field irradiation (IFI).