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Abstract The incidence rate of pseudoprogression during immune checkpoint inhibitor monotherapy for non‐small cell lung cancer is reportedly 3.6%–6.9%, while pseudoprogression during chemoimmunotherapy is rare. Reports on pseudoprogression during dual immunotherapy combined with chemotherapy are lacking. Herein, a 55‐year‐old male with invasive mucinous adenocarcinoma (cT2aN2M1c [OTH, PUL], stage IVB, and programmed death‐ligand 1 expression

Abstract EGFR‐T790M mutation is a major mechanism underlying acquired resistance to first‐ and second‐generation EGFR tyrosine kinase inhibitors (EGFR‐TKIs) in lung cancer with mutated EGFR. However, differences in the biological characteristics of T790M tumors based on treatment regimens with each generation of EGFR‐TKI are not fully understood. We established cell lines with acquired resistance harboring EGFR‐T790M mutation derived from xenograft tumors treated with each generation of EGFR‐TKI and examined their biological characteristics with respect to third‐generation EGFR‐TKI osimertinib sensitivity. Second‐generation EGFR‐TKI dacomitinib‐resistant cells with T790M‐exhibited higher sensitivity to osimertinib than first‐generation EGFR‐TKI gefitinib‐resistant cells with T790M via inhibition of AKT and ERK signaling and promotion of apoptosis. Furthermore, gefitinib‐resistant cells showed enhanced intratumor heterogeneity accompanied by genomic instability and activation of alternative resistance mechanisms compared with dacomitinib‐resistant cells; this suggests that the maintenance of EGFR dependency after acquiring resistance might depend on the type of EGFR‐TKI. Our results demonstrate that the progression of tumor heterogeneity via both genetic and non‐genetic mechanisms might affect osimertinib sensitivity in tumors with acquired resistance harboring EGFR‐T790M mutation.

Abstract Large‐cell neuroendocrine carcinomas (LCNECs), categorized as high‐grade neuroendocrine carcinomas, account for approximately 3% of resected lung cancers. LCNECs containing other components are called ‘combined LCNECs’ and have no standard treatment. A 73‐year‐old male with a metastatic brain tumour from a combined LCNEC of the lung containing adenocarcinoma and sarcomatoid components was referred to our department. The patient was treated with chemotherapy consisting of carboplatin and nanoparticle albumin‐bound (nab)‐paclitaxel in combination with atezolizumab, which was decided in accordance with the histological evaluation of the components. This treatment resulted in partial response and remained durable for 12 months with an ongoing regimen. The current case suggests that the constituents of chemoimmunotherapy should be selected in accordance with the reported efficacy of relevant regimens for each component of the combined LCNEC.

Abstract Chromosomal rearrangements involving the c‐ros oncogene 1 (ROS1) are identified in approximately 1% of non‐small cell lung cancer (NSCLC) patients. Crizotinib is the first tyrosine kinase inhibitor (TKI) against ROS1‐rearranged NSCLC. G2032R, a secondary resistant mutation, is observed in 41% of patients treated with crizotinib. Entrectinib, a TKI against neurotrophic tropomyosin receptor kinase, is reportedly efficacious against ROS1‐rearranged NSCLC. However, ROS1‐G2032R is resistant to entrectinib both in vitro and in vivo. We report an 85‐year‐old female patient with ROS1‐rearranged NSCLC, who developed drug‐induced interstitial lung disease (DI‐ILD) 2 months after crizotinib treatment, and was treated with prednisolone followed by entrectinib. Entrectinib treatment resulted in stable disease with a marginal response after a partial response to crizotinib. Entrectinib treatment following crizotinib cessation due to DI‐ILD was efficacious, which suggested that ROS1‐G2032R gatekeeper mutation, frequently observed in crizotinib‐resistant disease, was absent.

Abstract Background Treatment with epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR‐mutated non‐small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. Patients and Methods We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR‐TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. Results We enrolled 27 patients who harbored EGFR‐activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P

Background Cancer immunotherapy is under development as a promising alternative strategy for treating advanced non‐small cell lung cancer (NSCLC). However, the development of novel biomarkers to optimize the use of immune checkpoint inhibitors (ICIs) is still ongoing. Gut microbiota are known to regulate a host's immunity and are associated with the response to ICIs in melanoma. Therefore, we analyzed the association between ICI treatment efficacy and bowel movement condition in patients with NSCLC. Methods This retrospective study analyzed patients with advanced NSCLC who were treated with ICIs between December 2015 and March 2018 at University Hospital Kyoto Prefectural University of Medicine in Kyoto, Japan. The association between stool abnormalities and ICI efficacy was investigated. We defined patients with constipation or those who used a laxative as the stool abnormality group. Results We retrospectively enrolled 40 patients with advanced NSCLC who were treated with ICIs. The median age was 69.5 years; 20 patients had a stool abnormality and 20 patients did not. The disease control rates were lower in NSCLC patients with stool abnormalities than in those without stool abnormalities (20% vs. 77.8%, respectively; P = 0.0016). The time to treatment failure with ICI treatment was shorter in NSCLC patients with stool abnormalities compared with those without stool abnormalities (P = 0.003; odds ratio, 3.09; 95% confidence interval 1.41–6.78). Conclusion Stool abnormality might be a predictive biomarker for the clinical benefit of ICI treatment in patients with NSCLC. Further investigations are warranted to validate our findings.