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An esophageal stricture is an abnormal esophageal narrowing, usually caused by esophageal diseases and rarely by lung cancer. They cause malnutrition, performance status (PS) deterioration, and difficulty in the oral administration of antitumor drug tablets. A 78-year-old female patient with lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation, experienced dysphagia due to an esophageal stricture caused by retrotracheal lymph node metastases. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor that is efficacious against EGFR-sensitizing mutations. The esophageal stricture hampered food intake and oral administration of osimertinib, causing severe malnutrition and deterioration to PS 3. Esophagogastroduodenoscopy (EGD) revealed severe and entire circumferential stenosis (7 cm in length) of the upper esophagus without mucosal abnormality. A nasogastric tube was inserted under EGD guidance, and an osimertinib suspension was administered accordingly: a tablet containing 80 mg of osimertinib was suspended in 50 mL of sterile hot water (55 ℃) for ten minutes, and the suspension was administered through a nasogastric tube once daily. Dysphagia improved 15 days after the introduction of osimertinib. After 21 days, the patient could take foods and drugs orally, and her PS improved to 1. Administering an osimertinib suspension via a nasogastric tube was a viable option in managing esophageal strictures in patients with EGFR-sensitizing mutations.

We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy. We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy. On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38–3.37, p

Background Osimertinib monotherapy is currently the standard of care as a first-line treatment for patients harboring epidermal growth factor receptor (EGFR) mutations; however, some EGFR-mutated non-small cell lung cancer (NSCLC) patients exhibit primary resistance and an insufficient response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Elevated programmed death-ligand 1 (PD-L1) expression in tumors was reported as a negative predictive factor for outcomes of first- or second-generation EGFR-TKIs. Methods We prospectively assessed advanced NSCLC patients with EGFR mutations who were treated with osimertinib at 14 institutions in Japan between September 2019 and December 2020. Relationships between outcomes of osimertinib monotherapy and patients' characteristics were reviewed. Results Seventy-one patients who underwent the tumor PD-L1 test were enrolled. Multivariate analysis identified tumor PD-L1 expression as an independent predictor for progression-free survival (PFS) with osimertinib treatment (P=0.029). The objective-response and disease-control rates for osimertinib treatment were significantly lower in patients demonstrating elevated PD-L1 levels relative to those with low or negative PD-L1 level (P=0.043 and P=0.007, respectively). Furthermore, among patients treated with osimertinib, those with high PD-L1 levels exhibited shorter PFS relative to those with low plus negative PD-L1 level (median PFS: 5.0 vs. 17.4 months; P Conclusions Elevated tumor PD-L1 expression is associated with poor outcomes of osimertinib monotherapy in previously untreated advanced NSCLC patients with EGFR mutation. Further clinical trials are warranted to accumulate evidence demonstrating the effectiveness of combination therapy with osimertinib for EGFR-mutated advanced NSCLC patients with elevated tumor PD-L1 expression. Trial registration UMIN000043942.

Background First‐line chemoimmunotherapy (CIT) has improved overall survival (OS) and progression‐free survival (PFS) outcomes among patients with non‐small cell lung cancer (NSCLC). The immunological and nutritional statuses of patients fluctuate during treatment using immune checkpoint inhibitors, and are closely related to treatment outcomes. However, it is unclear whether these markers are significant in patients who are receiving CIT. Methods This retrospective single‐center study evaluated 34 consecutive Japanese patients with NSCLC who were treated using first‐line CIT. Previously reported markers that reflect immunological and nutritional statuses were evaluated at three time points: at the start of CIT, after three weeks, and at the end of induction therapy. Results The median PFS was 7.2 months (95% confidence interval: 6.3 months–not reached) and the median OS was not reached (95% confidence interval: 9.6 months–not reached). The PFS duration was significantly associated with the baseline neutrophil‐to‐lymphocyte ratio and the three‐week values for the modified Glasgow prognostic score, C‐reactive protein‐albumin ratio, prognostic nutrition index, and advanced lung cancer inflammation index. The OS duration was significantly associated with the pre‐treatment values for the neutrophil‐to‐lymphocyte ratio and advanced lung cancer inflammation index, as well as the prognostic nutrition index at the end of induction therapy. Conclusions Immunological and nutritional markers could be useful for predicting the outcomes of CIT for Japanese patients with advanced non‐small cell lung cancer. The timing of their evaluation may also be important. Key points Significant findings of the study Overall survival in patients receiving first‐line chemoimmunotherapy for advanced lung cancer were associated with pretreatment values of neutrophil‐to‐lymphocyte ratio, advanced lung cancer inflammation index, and the prognostic nutrition index at the end of induction therapy. What this study adds Repetitive evaluation of immunological and nutritional markers may be useful for guiding prognostication and treatment selection for Japanese patients with advanced lung cancer., Immunological and nutritional markers could be useful for predicting the outcomes of first‐line chemoimmunotherapy for Japanese patients with advanced non‐small cell lung cancer. Overall survival was significantly associated with the pretreatment values for the neutrophil‐to‐lymphocyte ratio and advanced lung cancer inflammation index, as well as the prognostic nutrition index at the end of induction therapy.

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Meanwhile, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associated with baseline PLR (hazard ratio (HR): 2.49, p = 0.0473), systemic immune-inflammation index (SII; HR: 2.65, p = 0.0337), prognostic nutrition index (PNI; HR: 4.15, p = 0.00185), and the 3-week values for SII (HR: 2.85, p = 0.0473) and PNI (HR: 3.04, p = 0.0125). Immunological and nutritional markers could be useful in predicting the outcomes of first-line treatment with alectinib. Since PLR and SII consist of platelet counts, platelet count could be an important constituent of these markers.

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., We report a patient with c‐ros oncogene 1 (ROS1)‐rearranged non‐small cell lung cancer, who developed drug‐induced interstitial lung disease 2 months after crizotinib treatment, and was sequentially treated with entrectinib, resulting in a stable disease with a marginal response.

Purpose The primary objective of this study was to identify the potential predictors to assess impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). Methods We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at eight hospitals in Japan between January 2019 to December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune-checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. Results Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). Conclusions This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

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.

Chemoimmunotherapy has become the standard of care as the first-line treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). The bevacizumab-containing chemoimmunotherapy regimen is theoretically more effective than a non-bevacizumab-containing regimen via two mechanisms: a superior outcome of bevacizumab-containing chemothrerapy than the standard platinum doublet regimen, and the synergistic effect of bevacizumab with an immune checkpoint inhibitor (ICI). Bevacizumab effectively normalizes vascularization, especially when the vascular bed is damaged by previous treatment. Bevacizumab promotes immunomodulation when used with ICI. We describe a patient with nonsquamous NSCLC who returned 2.5 years after definitive chemoradiotherapy for postoperative locoregional recurrence in the right supraclavicular lymph node. Considering the destroyed vascular bed due to prior chemoradiotherapy, attaining vascular normalization was critical for effective drug delivery. The patient was treated with a bevacizumab-containing chemoimmunotherapy regimen, which resulted in a complete metabolic response. The patient responded well for 23 months and is receiving ongoing treatment. Thus, bevacizumab-containing chemoimmunotherapy could be advantageous in some recurrent cases after chemoradiotherapy.

BackgroundIn recent years, immune checkpoint inhibitors (ICIs) in combination with chemotherapy have increased survival in patients with advanced non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF), which plays a key role in tumor angiogenesis, is an immunological modulator; therefore, it is expected that anti-VEGF therapy in combination with ICIs enhances the antitumor effect of ICIs. In the present study, we investigated the impact of VEGF inhibition on clinical outcomes of NSCLC patients, including the efficacy of ICI treatment.MethodsA total of 105 patients with advanced NSCLC who had been treated with ICIs were retrospectively analyzed to examine the relationship between the history of treatment with anti-VEGF agents and the clinical outcomes with ICI monotherapy.ResultsPatients who had received anti-VEGF therapy prior to ICIs showed shortened progression-free survival of ICI treatment and a decreased overall response rate to ICI treatment. By contrast, anti-VEGF therapy after ICI treatment was associated with increased survival, especially in patients who had also received anti-VEGF therapy prior to ICI therapy.ConclusionsThese retrospective observations suggest that anti-VEGF therapy prior to ICIs might be a negative predictor of response to ICIs. The sequence of anti-VEGF therapy might play a role in its ability to predict survival in NSCLC patients. Further investigation is warranted to identify the role of VEGF inhibition in altering clinical outcomes after immunotherapy.

Combination therapy of immune checkpoint inhibitors and chemotherapy is considered to be one of the standard treatment options for patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical significance of immune checkpoint inhibitors combined with chemotherapy in elderly patients with NSCLC has not yet been fully understood. Therefore, this study aimed to evaluate how aging affects the therapeutic impact of chemotherapy combine with immune checkpoint inhibitors in elderly patients.We retrospectively analyzed 203 patients with advanced NSCLC who were treated with the combination therapy of pembrolizumab and chemotherapy between January 2019 and December 2019 at 12 institutions in Japan. We analyzed the clinical impacts of age on the following two groups: those who received pembrolizumab with platinum and pemetrexed (pemetrexed regimen) and those who received pembrolizumab with carboplatin and nab-paclitaxel/paclitaxel (paclitaxel regimen). Progression-free and overall survival were assessed via the Kaplan-Meier method.Multivariate analysis demonstrated that progression-free and overall survival were significantly shorter in elderly patients (aged ≥75 years) with NSCLC than in non-elderly patients (aged75 years) with NSCLC in the pemetrexed regimen group. In contrast, there were no significant differences in progression-free and overall survival between elderly patients and non-elderly patients with NSCLC in the paclitaxel regimen group. In elderly patients with NSCLC, a programmed death-ligand 1 tumor proportion score of ≥50% was significantly associated with progression-free survival, and performance status of ≥2 was significantly associated with overall survival. Low albumin level (3.5 g/dL) was significantly associated with both progression-free and overall survival.The results of this retrospective study show that the pemetrexed regimen, but not the paclitaxel regimen, was related to poor clinical outcomes in elderly patients with NSCLC.

Although previous studies suggest that cancer cachexia is a poor prognostic factor for immune checkpoint inhibitor monotherapy, the impact of cancer cachexia on chemoimmunotherapy is unclear. We investigated the impact of cancer cachexia on the therapeutic outcomes of chemoimmunotherapy for non-small cell lung cancer (NSCLC). We retrospectively analyzed patients’ medical records with NSCLC who received chemoimmunotherapy in 12 institutions in Japan between January and November 2019. We defined cancer cachexia as weight loss exceeding 5% of the total body weight or a body mass index of < 20 kg/m2 and weight loss of more than 2% of the total body weight within 6 months before chemoimmunotherapy initiation, with laboratory results exceeding reference values. This study enrolled 235 patients with NSCLC, among whom 196 were eligible for analysis, and 50 (25.5%) met the criteria for cachexia diagnosis. Patients with cancer cachexia had a significantly higher frequency of a programmed death-ligand 1 (PD-L1) expression of ≥ 50% (48%, p = .01) and shorter progression-free survival (PFS; log-rank test: p = .04) than patients without cachexia. There was no significant difference in overall survival (OS) between the cachexia and no-cachexia groups (log-rank test: p = .14). In the PD-L1 ≥ 50% population, there was no significant difference in PFS and OS (log-rank test: p = .19 and p = .79, respectively) between patients with NSCLC in the cachexia or no-cachexia groups. Cancer cachexia might be a poor prognostic factor in patients with NSCLC receiving chemoimmunotherapy.

BackgroundThe immunotherapy plus chemotherapy combination is one of the most promising treatments in advanced non-small-cell lung cancer (NSCLC). Immunotherapy often causes immune-related adverse events (irAEs), which have been reported to be associated with the good clinical outcomes. However, the effects of immunotherapy plus chemotherapy remain unknown. In this study, we investigated the association between irAEs caused by immunotherapy plus chemotherapy and clinical efficacy in patients with advanced NSCLC.Materials and MethodsWe retrospectively analyzed the data of patients with advanced NSCLC, who received a combination of immunotherapy plus chemotherapy at six institutions in Japan between January 2019 and September 2019. We examined the effect of irAEs on various clinical outcomes.ResultsWe included 70 patients with advanced NSCLC. Patients were divided into two groups: patients with irAEs and patients without irAEs. Patients with irAEs had significantly longer progression-free survival than those without irAEs on univariate (hazard ratio 0.53, 95% confidence interval 0.30–0.93, p = 0.026) and multivariate (hazard ratio 0.53, 95% confidence interval 0.29–0.97, p = 0.041) analyses. In addition, patients with grade 1–2 irAEs (mild irAEs) had significantly longer progression-free and overall survival than those with grade 3-5 irAEs (severe irAEs) or without irAEs on univariate (398 days versus 189 days, respectively; p = 0.0061) and multivariate (not reached versus 412 days, respectively; p = 0.021) analyses.ConclusionPatients with NSCLC who experienced mild irAEs showed better response to treatment with immunotherapy plus chemotherapy than those with severe irAEs or without irAEs. Further large-scale research is warranted to confirm these findings.

Cancer immunotherapy, including atezolizumab monotherapy, is a promising alternative strategy for patients with advanced non-small-cell lung cancer (NSCLC). Several inflammatory indices have been reported as potential biomarkers regarding the effectiveness of various treatments. This study aimed to analyze the efficacy of atezolizumab monotherapy using baseline inflammatory markers in NSCLC patients. We retrospectively enrolled 81 NSCLC patients who received atezolizumab monotherapy at six different medical institutions in Japan. The Cox proportional hazards model was used to assess the impact of the clinical variables, including inflammatory indexes, on clinical outcomes. Median progression-free survival (PFS) and overall survival (OS) were 60 days and 252 days, respectively. The objective response rate was 7.4%, and the disease control rate was 54.3%. Patients with high neutrophil to lymphocyte ratio (NLR), low lymphocyte to monocyte ratio (LMR), and/or high platelet to lymphocyte ratio (PLR), at baseline, demonstrated substantially shorter PFS and OS compared to those with a low NLR, high LMR, and/or low PLR. The multivariate analysis demonstrated that a high baseline NLR was substantially associated with short PFS and short OS. Our retrospective observations suggest that inflammatory indices may be a potential negative prognostic factor of atezolizumab monotherapy outcomes in NSCLC patients.

Combined immunotherapy and chemotherapy is a promising standard treatment in patients with advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the relationship between the combined therapy and pretreatment serum antinuclear antibody (ANA) levels as a prognostic indicator in patients with NSCLC. We retrospectively analyzed patients with advanced NSCLC who were treated with combinatorial immunotherapy and chemotherapy between January and December 2019 at six institutions in Japan. Relationship between ANA status and patients’ characteristics were reviewed. A total of 77 patients with advanced NSCLC were enrolled in the study. Patients were divided into ANA-positive (ANA ≥ 1:160) and ANA-negative (ANA

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare—thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient’s trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky’s sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

Background Currently used biomarkers for immunotherapy are inadequate because they are only based on tumor properties. In view of microenvironment changes by tumors, host immunity should be considered, which may result in identifying more accurate and easily detectable biomarkers for daily clinical practice. Here, we assessed serum immune‐modulating factor levels for the response to anti‐PD‐1 antibodies during the first cycle in non‐small cell lung cancer (NSCLC) patients. Methods Serum was collected from patients with advanced NSCLC treated with nivolumab or pembrolizumab at several time points during the first cycle. We applied the enzyme‐linked immunosorbent assays (ELISAs) and multiplex assays to measure the levels of immune modulators. Results A total of 40 patients treated with nivolumab and 26 patients treated with pembrolizumab were studied. By ELISA, serum perforin, but not granzyme B, was measured in all samples. By multiplex assay, 10 immune modulators, including granzyme B, were measured in some, but not all, samples. Serum baseline perforin levels were strongly associated with increased progression‐free survival (PFS) and overall survival (OS) times. Sequential changes in perforin levels during the first cycle were weakly associated with the clinical outcome. Conclusions Serum baseline perforin levels may be used to predict the prognosis of NSCLC patients treated with anti‐PD‐1 antibody therapy. Key points To identify a useful predictive marker for anti‐PD‐1 antibody therapy, using blood samples might be helpful.Serum baseline perforin levels were closely associated with prognosis with anti‐PD‐1 antibody therapy in non‐small cell lung cancer., This study demonstrates immune‐modulator changes in serum during the first cycle of anti‐PD‐1 antibody therapy in non‐small cell lung cancer. Serum baseline perforin levels were found to be closely associated with clinical outcome with anti‐PD‐1 antibody therapies.

Vogt–Koyanagi–Harada disease (VKHD) is a rare systemic granulomatous autoimmune disease that affects melanocyte‐rich organs such as eye, inner ear, meninges, skin, and hair. VKHD leads to chronic uveal inflammation accompanied by a decline in visual acuity in some patients when appropriate corticosteroid treatment was not initiated in an early phase. Immune checkpoint inhibitors (ICIs) are widely used in the treatment of several kinds of cancers and chemoimmunotherapy has become the standard of care in the first‐line treatment of non‐small cell lung cancer (NSCLC). While ICIs induce immune‐related adverse events, drug‐induced VKHD is quite rare with only four reports in the ICI monotherapy; three patients with melanoma and one patient with NSCLC. We describe the first case of VKHD during chemoimmunotherapy including pembrolizumab in a patient with NSCLC, which was successfully treated with corticosteroid without any sequela., Vogt–Koyanagi–Harada disease (VKHD) is very rare and drug‐induced VKHD is quite rare. This would be the first report on VKHD during chemoimmunotherapy.

BACKGROUND Although phase III trials have shown improved overall and progression-free survival (PFS) using nivolumab compared to docetaxel in patients with non-small-cell lung cancer, the progressive disease ratio of nivolumab is higher than docetaxel. Furthermore, nonconventional response patterns of nivolumab make it difficult to determine the time point for nivolumab discontinuation. Therefore, a method to detect non-responders to nivolumab at an early time point is crucial. This retrospective study was conducted to identify immunological and nutritional markers, including neutrophil-to-lymphocyte ratios (NLR), which would predict the efficacy of nivolumab treatment. Because the expression of these markers fluctuates dramatically during treatment, repeat evaluation was performed. METHODS We retrospectively investigated 30 patients with non-small-cell lung cancer who were treated with nivolumab. The stratified data of each marker obtained during four weeks after nivolumab treatment were evaluated by Cox proportional hazards regression to verify the differences in PFS. RESULTS One and four patients experienced progressive disease within two and four weeks, respectively. Therefore, 29 and 26 patients were analyzed two and four weeks after nivolumab administration, respectively. The results showed that the NLR after four weeks could predict PFS. The median PFS in 21 patients with NLR < 5 after four weeks of nivolumab administration was 95 days (95% confidence interval [CI] 50-NA), while the mPFS in five patients with NLR ≥ 5 was 10 days (95% CI 6-NA). NLR ≥ 5 showed a hazard ratio of 5.995 (95% CI 1.225-29.35). CONCLUSION Clarifying NLR four weeks after nivolumab administration may be useful to predict outcomes in nivolumab-treated patients.

The current standard-of-care treatment for patients with limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy for local and systemic control. However, standard-of-care treatment strategies have not been established for those with limited-stage SCLC who have a history of thoracic radiotherapy due to concerns with complications associated with radiation overdose. A 37-year-old male developed an aspergilloma in the postoperative left thoracic space after he was treated with concurrent chemoradiotherapy for mediastinal type lung adenocarcionoma and subsequent left upper lobectomy for heterochronous dual adenocarcinoma. Fiberoptic bronchoscopy was performed to examine the status of the suspected bronchopleural fistula when a polypoid mass was observed in the right mainstem bronchus. A histological examination showed that the mass was SCLC at a clinical stage of cTisN0M0, stageIA, without local invasion. Since thoracic radiotherapy was not an option due to a previous history of thoracic irradiation, a combination treatment of carboplatin and etoposide was administered for 4 cycles and resulted in good partial response. In addition, argon plasma coagulation (APC) was performed as an alternative to curative radiotherapy on day 22 of the 4th cycle. The 5th cycle was administered 7 days after APC at which the anticancer therapy was completed. The patient remains disease-free 60 months after the completion of treatment, which suggests that this combination therapy may resolve very early-stage SCLC.

PURPOSE The complexity of lung cancer treatment is rapidly increasing, necessitating the use of multidisciplinary approaches for improving outcomes. Although it is common for institutions to have their own tumor boards, tumor boards connecting several general hospitals, and therefore allowing for more diverse opinions, are not prevalent. MATERIALS AND METHODS A tumor board connecting eight hospitals was formed to discuss patients for whom formulating a treatment strategy was difficult. Physicians and hospital staff accessed a high-security communication line via LiveOn ( Japan Media Systems Corporation, Tokyo, Japan), which is completely isolated from the Internet and password protected, that enables each hospital to share the electronic medical records and images of relevant patients at other hospitals on desktop computers in real time. The lung cancer tumor board began in April 2017 and has since been held every Tuesday evening for 1 hour. Preparatory records containing the age, sex, histology, TNM classification, background, and discussion points for each patient are created before each tumor board meeting. After the tumor board discussion, all conclusions and related articles used in the board are added to the minutes, which are finalized as Microsoft Word files, consolidated, and archived. These files can be retrieved later using key words. RESULTS From April 2017 to June 2018, 202 patients were discussed. Although TNM classification was not changed for any patient, diverse opinions led to a change in the proposed strategy for 49 of 202 patients. CONCLUSION The multidisciplinary tumor board was useful in obtaining various opinions from the perspectives of different experts. This should be evaluated in a prospective study.

BACKGROUND: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. METHODS: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. RESULTS: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). CONCLUSIONS: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients. Citation Format: Rui Kitadai, Akihiro Yoshimura, Tadaaki Yamada, Yusuke Okuma, Takayuki Takeda, Takanori Kanematsu, Junji Uchino, Yasuhiko Nishioka, Koichi Takayama. Retrospective analysis of docetaxel in combination with ramucirumab for previously treated non-small cell lung cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4306.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were &ge, 75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9&ndash, 17.5), and the median OS was 22.0 months (95% CI: 16.0 months&ndash, not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3&ndash, 4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were &ge, 75 years old.

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

Central airway obstruction caused by cancer requires urgent interventional pulmonology. Malignant main carinal involvement is one of the most challenging situations, usually treated by rigid bronchoscopic intervention under general anaesthesia. However, these patients tend to be in poor condition due to underlying malignancy. Therefore, less‐invasive strategies are needed. Six patients with lung cancer exhibiting malignant carinal involvement treated using the ‘side‐by‐side’ method of bilateral self‐expandable metallic stents using fibre‐optic bronchoscopy under topical anaesthesia were retrospectively investigated. The median procedure time was 29.5 min (range: 23–38), and the palliation of dyspnoea was achieved in all cases. The median survival time after intervention was 58.5 days (range: 23–172). The cause of death was acute coronary syndrome in two patients, aspiration pneumonia in two, upper gastrointestinal perforation in one, and catheter‐related blood stream infection in one. This strategy was less invasive and suitable for patients with poor performance status.

Background The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples. Methods Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles. Results Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p

Central airway obstruction needs interventional pulmonology and malignant main carinal involvement is one of the most challenging scenarios requiring rigid bronchoscopic intervention under general anesthesia. However, these patients tend to be in poor condition for such interventions. A 91-year-old male patient with lung cancer accompanied by obstructive pneumonia underwent an Ultraflex self-expandable metallic stent placement in the right mainstem bronchus. The extranodal extension of the carcinoma from mediastinal lymph nodes metastases to the carina was so fast that severe stenosis of the bilateral mainstem bronchi was observed 6 weeks later accompanied by the deterioration of dyspnea. To salvage the carina, bilateral Ultraflex covered stents were placed by “side-by-side” method using fiberoptic bronchoscopy under topical anesthesia. This strategy was quite safe and the time needed for the entire procedure was within 20 min. He never experienced dyspnea thereafter and died of a cardiac sudden death 7 months after the initial stenting.

Background: Anti-Programmed death 1 (PD-1) antibody which enhances anti-tumor activity of cytotoxic-T-lymphocytes by blockade of PD-1/PD-L1 pathway has demonstrated improvement of survival in the patients with advanced non-small-cell lung cancer (NSCLC). PD-1 and its ligand PD-L1 is also known as key players in the formation of tumor microenvironment, closely related with inflammatory cytokines. Here, we retrospectively analyzed the peripheral blood cells as a surrogate marker for predicting outcome of immune checkpoint inhibitors (ICI). Method: Total of 78 cases treated with anti-PD-1 antibodies, nivolumab or pembrolizumab from February 2016 to September 2017 were registered retrospectively. We investigated the differential leukocyte counts, C-reactive protein (CRP) and other peripheral blood parameter on the treatment progress with ICI, and evaluated correlation between response to ICI and peripheral blood cells. Result: Out of 78 cases, 56 cases (77%) were treated with nivolumab, 18 cases (23%) were treated with pembrolizumab, and 4 cases (5%) have treatment history of both agents. Median follow up period was 5.7 months (range: 0.4-18.7 months). Median progression free survival (PFS) and median overall survival (OS) were 2.4 and 8.7 months, respectively. Overall response rate was 21.8%. Of some parameters in peripheral blood cells, higher absolute neutrophil count (ANC), CRP at baseline were associated with shorter OS. Furthermore, we determined neutrophil / lymphocyte ratio (NLR), platelet / lymphocyte ratio (PLR), lymphocyte / monocyte ratio (LMR) and prognostic nutritional index (PNI), which were known as predictive biomarkers in various tumor type. In patients with longer PFS for ICI treatment, ANC, NLR and CRP remained low level until disease progression, whereas these markers increased during ICI treatment in the patients with shorter PFS for ICI. Conclusion: Our retrospective analysis showed that ANC, NLR and CRP may predict response and acquisition of resistance to anti-PD-1 therapy in NSCLC patients. These results suggest that peripheral blood findings might be promising as a predictive biomarker of ICI treatment. Citation Format: Keiko Tanimura, Tadaaki Yamada, Nobuyo Tamiya, Yoshiko Kaneko, Takayuki Takeda, Junji Uchino, Yutaka Kubota, Koichi Takayama. The impact of neutrophil/lymphocyte ratio as the predictive marker to anti-PD-1 antibody treatment in NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1692.

Conventional therapies still remain less effective for metastasis of lung cancer, thus leading to a poor prognosis for this disorder. Although the processes involved in metastasis have not yet been clearly elucidated, our previous studies have shown that higher expression levels of MRP-1/CD9 and KAI1/CD82 in cancer cells are significantly correlated with less metastatic potency. To determine whether the gene transfer of these tetraspanins into lung tumor cells may be a useful strategy to regulate metastasis, we adopted an orthotopic lung cancer model produced by the intrapulmonary implantation of Lewis lung carcinoma (LLC) cells and evaluated the metastatic growth in the mediastinal lymph nodes using two different methods of gene delivery as follows: (a) the implantation of LLC cells preinfected with adenovirus encoding either MRP-1/CD9 cDNA, KAI1/CD82 cDNA, or LacZ gene into the mouse lung and (b) the intratracheal administration of these adenoviruses into the mice orthotopically preimplanted with LLC cells. In both cases, we found that the delivery of either MRP-1/CD9 or KAI1/CD82 cDNA dramatically reduced the metastases to the mediastinal lymph nodes in comparison with those of LacZ gene delivery, without affecting the primary tumor growth at the implanted site. These results reemphasize the important role of MRP-1/CD9 and KAI1/CD82 in the suppression of the metastatic process and also show the feasibility of gene therapy when using these tetraspanins for lung cancer to prevent metastasis to the regional lymph nodes. This strategy may therefore be clinically applicable as a prophylactic treatment to suppress the occurrence of lymph node metastasis. [Cancer Res 2007;67(4):1744–9]

Lung cancer has aggressive behaviour which often progresses rapidly with disseminated disease and leads to poor performance status (PS) in patients. Because cytotoxic chemotherapy is not recommended under these conditions, there are currently no alternative therapeutic options other than providing supportive care. Immune checkpoint inhibitors have been developed, but their efficacy and tolerability have not been fully investigated in patients with poor PS. A 72-year-old male patient with lung adenocarcinoma harbouring no EGFR-sensitizing mutation or ALK translocation was receiving second-line chemotherapy with S-1 monotherapy when he complained of worsening dyspnea. Chest computed tomography (CT) demonstrated disease progression at the primary site that was accompanied by bilateral pulmonary lymphangitic carcinomatosis, which was the cause for respiratory failure. Oxygen administration at 10 L/min was required due to the rapid progression of the tumour that resulted in poor PS. A retrospective study was conducted to assess the upregulation of programmed death ligand 1 (PD-L1) using anti-PD-L1 22C3 mouse monoclonal primary antibody and found that the PD-L1 expression was 50–60% (i.e. tumour proportion score ≥50%). Since cytotoxic chemotherapy could not be considered due to a poor PS of 4, nivolumab was cautiously administered. After the introduction of nivolumab, ground glass opacities, and consolidations on chest CT temporarily deteriorated on day 4 without any other clinical signs and symptoms. The reevaluation on day 10 demonstrated significant improvements on chest X-ray. Then the patient was subsequently diagnosed with pseudoprogression. Thereafter, both the respiratory status and the PS improved gradually. The PS recovered to baseline conditions with oxygen administration at 1 L/min after four cycles of treatment. The patient currently remains at a PS of 1 and is progression-free for eight months after the introduction of nivolumab.

Patients with an epidermal growth factor receptor (EGFR) mutation are usually administered EGFR-tyrosine kinase inhibitors (TKIs) as standard-of-care treatment. However, acquired resistance occurs between 9 and 13 months. The T790M-resistant mutations are the most common, and osimertinib has been found to be effective in treating EGFR-T790M-positive patients. A 73-year-old female lung cancer patient with an EGFR-sensitizing mutation was receiving fourth-line chemotherapy when she complained of anorexia, headache, and irritability. A lumbar puncture showed adenocarcinoma in the cerebrospinal fluid (CSF), which led to the diagnosis of leptomeningeal metastasis. Her performance status (PS) deteriorated quickly and she also developed dysphagia. The EGFR mutation testing of the CSF demonstrated L858R+T790M double mutations, and an osimertinib suspension was subsequently administered through a nasogastric tube. The PS improved to 1, oral intake became possible after 20 days, and further improvements were observed by gadolinium-enhanced magnetic resonance imaging. The patient remains progression-free for 10 months after osimertinib administration.

Brain metastases are quite common during the management of lung carcinomas. Most are solid masses with necrosis and surrounding edema, whereas purely cystic lesions are uncommon and malignant cells creating the wall are usually resistant to radiotherapy, sometimes requiring neurosurgical strategies. Cystic brain metastases from small-cell lung carcinomas are exceedingly rare and neurosurgical operations are not suitable for those cases considering invisible micrometastases. A 34-year-old female patient presented with small-cell lung carcinoma that metastasized to the brain as a solitary cyst with a thin wall 24 months after a good partial response to initial chemoradiotherapy. The brain mass volume and the main symptom of left hemiplegia, which made the Karnofsky performance status (KPS) fall to 30%, did not respond to whole brain irradiation. Therefore, an Ommaya reservoir was inserted, which dramatically improved the KPS to 70%. This minimally invasive surgical strategy is suitable even for patients with a poorer KPS bearing cystic brain metastases.