Nationwide data from comprehensive genomic profiling assays for detecting driver oncogenes in non-small cell lung cancer.

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.

First Japanese case of disseminated blastomycosis imported from North America: A case report.

Blastomycosis is a fungal infectious disease that can occur in both immunocompromised and immunocompetent populations endemic in North America, with no previous reports in Japan. A 26-year-old Japanese female patient with no relevant medical history presented intermittent left back pain and an abnormal shadow in the left upper lung field eight months ago at a local clinic. She was referred to our hospital for further evaluation and treatment. The patient currently lives in Japan, but until two years ago had spent several years in New York, Vermont and California. Chest computed tomography revealed a 30 mm mass with a cavity in the left pulmonary apex. The specimens obtained by transbronchial biopsy showed periodic acid-Schiff stain (PAS)-positive and Grocott-positive yeast-like fungi scattered among the granulomas, with no malignant findings, and the initial pathology did not lead to a definitive diagnosis. She was empirically started on fluconazole because of onset of multiple subcutaneous abscesses and was referred to the Medical Mycology Research Center. Although antibody tests could not diagnose the disease, blastomycosis was suspected based on the pathology of the skin and lung tissue at the Medical Mycology Research Center, and Blastomyces dermatitidis was identified by ITS analysis of the rRNA region. Her symptoms and CT findings gradually improved with fluconazole. We reported the first Japanese case of blastomycosis with pulmonary and cutaneous involvement in Japan. As the number of overseas travelers is expected to continue increasing, we would like to emphasize the importance of travel history interviews and information of blastomycosis.

HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.

Impact of maintenance therapy following induction immunochemotherapy for untreated advanced non-small cell lung cancer patients.

PURPOSE: The primary objective of this study was to identify the potential predictors to assess the 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 8 hospitals in Japan between January 2019 and 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.

Early responders within seven days of dupilumab treatment for severe asthma evaluated by patient-reported outcome: a pilot study.

BACKGROUND: The management of severe asthma-associated symptoms is essential since they are distressing to the affected patients, and also greatly impair their quality of life. Dupilumab, a monoclonal antibody, blocks interleukin (IL)-4 and IL-13 signaling, both of which are crucial in acquired and innate immunity pathways through fast signal transduction, leading to an early response to treatment. Although rapid improvement within 1-3 days after dupilumab treatment was observed in moderate-to-severe atopic dermatitis, an early response within 7 days of dupilumab treatment in severe asthma has not been reported. METHODS: Twelve consecutive patients with severe asthma who were newly treated with dupilumab between July 2019 and April 2020 were retrospectively investigated. We evaluated the early response (within 7 days) of patients with severe asthma receiving dupilumab therapy. Asthma control test (ACT) and the daily ACT, which was modified from the ACT to evaluate daily symptoms associated with asthma, were adopted as patient-reported outcomes (PROs) at week 8 and within 7 days, respectively. Patients were stratified into early responders (7 days), late responders (week 8), and non-responders without significant improvement in PROs. Descriptive statistics were adopted due to the limited number of patients. RESULTS: Four of these 12 patients were early responders, with the following baseline characteristics: body mass index, <25 kg/m2; without depression; baseline forced expiratory volume in 1 second, <1.50 L; and more than one exacerbation in 1 year. On the other hand, five were late responders, and 44.4% of the nine responders were early responders. The higher the eosinophilic count and/or FeNO did not show any relationship between the early responder and nonresponder. CONCLUSIONS: The effect of dupilumab on severe asthma in patients with atopic features could be started earlier than 2 weeks, similar to atopic dermatitis. Daily ACT may be useful in monitoring the early efficacy of dupilumab in treating severe asthma.

Immune-Related Adverse Events Are Associated With Clinical Benefit in Patients With Non-Small-Cell Lung Cancer Treated With Immunotherapy Plus Chemotherapy: A Retrospective Study.

BACKGROUND: The 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 METHODS: We 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. RESULTS: We 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. CONCLUSION: Patients 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.

Predictors of survival among Japanese patients receiving first-line chemoimmunotherapy for advanced non-small cell lung cancer.

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.

Impact of preexisting antinuclear antibodies on combined immunotherapy and chemotherapy in advanced non-small cell lung cancer 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 < 1:160) groups. The ANA-positive group tended to have a shorter progression-free survival and significantly shorter overall survival in univariate (hazard ratio [HR], 2.11, 95% confidence interval [CI] 0.88-5.07, p = 0.093; and HR 3.11, 95% CI 1.14-8.49, p = 0.027, respectively) and multivariate (HR 1.90, 95% CI 0.77-4.68, p = 0.16; and HR 3.37, 95% CI 1.15-9.86, p = 0.027, respectively) analyses than ANA-negative group. The incidence of discontinuation of all treatment components due to severe adverse events was significantly higher in the ANA-positive than in ANA-negative group (50% vs. 15.9%, p = 0.042). The study showed that the presence of antinuclear antibodies may result in a poor prognosis in patients treated with combinatorial immunotherapy and chemotherapy, although further prospective investigations are needed.

Drug-induced interstitial lung disease associated with dasatinib coinciding with active tuberculosis.

A 69-year-old woman was diagnosed with a breakpoint cluster region-Abelson-positive chronic myeloid leukaemia and treated with dasatinib for 14 months. She presented with one month of high-grade fever and persistent dry cough. Chest computed tomography revealed non-segmental subpleural consolidation, ground-glass opacities, and interlobular septal thickening. The bronchoalveolar lavage (BAL) and transbronchial lung biopsy confirmed a diagnosis of drug-induced interstitial lung disease (ILD) associated with dasatinib. Then, systemic corticosteroid treatment was initiated, which was effective and the interstitial shadow disappeared after two weeks. The acid-fast bacilli culture test of BAL fluid after three weeks was positive for Mycobacterium tuberculosis, and combination therapy with four antituberculosis drugs was added. It is known that drug-induced ILD and susceptibility to infection associated with dasatinib occur in a dose-dependent manner. This is the first case of dasatinib-induced ILD which coincided with active tuberculosis.

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation-A Case Report and a Review of the Literature.

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.

IgG4-related lung disease progressing to respiratory failure.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic immune-mediated, fibroinflammatory disorder categorized as proliferative or fibrotic depending on the responsiveness of corticosteroid treatment. IgG4-related lung disease (IgG4-RLD) accounts for 13-14% of IgG4-RD cases, but respiratory failure is quite rare. A 71-year-old man diagnosed with interstitial lung disease was referred to our department after a 10-month observational period. He presented with respiratory failure at the first visit, with significant elevations in serum IgG4 levels and histopathological findings meeting the criteria of IgG4-positive plasma cells and IgG4/IgG-positive plasma cell ratio in transbronchial lung biopsy and inguinal lymph node biopsy, resulting in a diagnosis of IgG4-RD. Systemic corticosteroid treatment promptly ameliorated the respiratory failure. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography showed significant FDG accumulation in the lung fields, indicating the proliferative and reversible status of IgG4-RLD, which responded well to corticosteroid treatment. The patient recovered from respiratory failure even after a 10-month observational period.

Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer.

Atezolizumab was the first immune checkpoint inhibitor (ICI) to be introduced as a first-line treatment option for extensive-stage small cell lung cancer (ES-SCLC), in combination with carboplatin and etoposide (CE) chemotherapy. However, SCLC treatment options after progression to first-line chemotherapy are limited, warranting the readministration of previously used drugs. In combination with atezolizumab, CE readministration may theoretically be effective, based on two tentative mechanisms: its additive and synergistic effects on cytotoxic chemotherapy. The additive effect is based on the IFCT-1603 trial in which the Kaplan-Meier estimates of both progression-free survival (PFS) and overall survival (OS) in the atezolizumab group exhibited a tail plateau in the selected population. Conversely, an anti-PD-L1 antibody synergistic effect on platinum compounds was assessed in a preclinical study, which was reinforced by clinical data. Thus, atezolizumab in combination with CE may be a treatment option in heavily treated patients. Here, we describe the first case of a heavily treated ES-SCLC patient treated with chemoimmunotherapy, resulting in a partial response and a durable PFS. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY AND WHAT THIS STUDY ADDS: CE readministration with atezolizumab may be effective based on two tentative mechanisms. Additive and synergistic effects of atezolizumab on CE have been previously suggested via a clinical trial and preclinical study, respectively. This is reflected in the current case in clinical settings.