Bevacizumab-Containing Chemoimmunotherapy for Recurrent Non-Small-Cell Lung Cancer after Chemoradiotherapy: Case Report.

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.

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.

Safety of First-Line Nivolumab Plus Ipilimumab in Very Old (≥ 80 Years) Patients With Unresectable Malignant Pleural Mesothelioma: A Retrospective Single-Center Case Series.

Nivolumab plus ipilimumab as the first-line treatment results in superior survival outcomes in patients with malignant pleural mesothelioma (MPM). However, its safety in old (≥ 80 years) patients with MPM has not been elucidated yet. Three male patients with MPM, aged 80-90 years, were treated with nivolumab plus ipilimumab as the first-line treatment in our hospital. All of them discontinued the treatment due to adverse events. The overall survival from treatment initiation was 2.5, 3.5, and 4.0 months, respectively. Nivolumab plus ipilimumab should be used cautiously in very old patients with MPM.

Durable Response to Chemoimmunotherapy of a Lung Adenocarcinoma Harboring a MET Exon 14 Skipping Mutation.

Chemoimmunotherapy is the first-line standard treatment for patients with non-small cell lung cancer (NSCLC). However, there are few reports on the efficacy of chemoimmunotherapy in patients with NSCLC who harbor the MET exon 14 skipping mutation. We report the case of an 81-year-old male patient with lung adenocarcinoma with a MET exon 14 skipping mutation who was treated with chemoimmunotherapy and achieved a durable response. Chemoimmunotherapy may be a promising treatment option for patients with a MET exon 14 skipping mutation. However, further studies are needed to characterize the objective response rate and response duration in these populations.

Comparison of the prognosis of symptomatic cerebral infarction and pulmonary embolism in patients with advanced non-small cell lung cancer.

BACKGROUND: Lung cancer patients face a high risk of thromboembolism (TE), which is considered to be a poor prognostic factor. However, the impact of symptomatic cerebral infarction (CI) and pulmonary embolism (PE) on the prognosis of advanced non-small cell lung cancer (NSCLC) patients is not fully understood. METHODS: We retrospectively identified 46 patients with advanced NSCLC who developed symptomatic CI or PE at five hospitals in Japan between January 2010 and December 2019. Prognosis and biomarker levels after incident CI and PE were investigated. RESULTS: Of the 46 patients, 36 developed symptomatic CI, and 10 developed symptomatic PE. The median follow-up duration after incident CI and PE was 18.2 months. Although the proportion of Common Terminology Criteria for Adverse Events grade 4 tended to be higher in patients with PE than in those with CI (30% vs. 11%, p = 0.16), the overall survival (OS) after incident TE tended to be worse in patients with CI than in those with PE (median 2.3 months vs. 9.1 months, log-rank test p = 0.17). Multivariate analysis showed that OS after CI was worse in patients with high D-dimer (DD) levels than in those with low DD levels at the time of incident CI (median 1.3 months vs. 8.3 months, log-rank p < 0.001). CONCLUSIONS: This retrospective study demonstrated that the prognosis of patients tended to be poorer after CI than after PE. The DD levels at the time of incident CI might be a promising predictor of clinical outcomes in advanced NSCLC patients who develop CI.

Nasogastric administration of osimertinib suspension for an epidermal growth factor receptor-mutated lung cancer causing an esophageal stricture: case report.

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.

Prognostic Nutritional Index and Lung Immune Prognostic Index as Prognostic Predictors for Combination Therapies of Immune Checkpoint Inhibitors and Cytotoxic Anticancer Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer.

Combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapies (chemoimmunotherapy) is associated with significantly better survival outcomes than cytotoxic chemotherapies alone in patients with advanced non-small cell lung cancer (NSCLC). However, there are no prognostic markers for chemoimmunotherapy. The prognostic nutritional index (PNI) and lung immune prognostic index (LIPI) are prognostic biomarkers for immune checkpoint inhibitor (ICI) monotherapy or cytotoxic chemotherapies. Thus, we aimed to examine whether these factors could also be prognostic markers for chemoimmunotherapy. We retrospectively examined 237 patients with advanced NSCLC treated with chemoimmunotherapy. In the total group, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 8.6 months. Multivariate analysis of OS and PFS revealed significant differences based on PNI and LIPI. Programmed cell death ligand 1 (PD-L1) was also significantly associated with OS and PFS. PNI and a PD-L1 tumor proportion score (TPS) of <50% and poor LIPI (regardless of PD-L1 TPS) were associated with poor prognosis. PNI and LIPI predicted survival outcomes in patients with advanced NSCLC treated with chemoimmunotherapy, especially in patients with PD-L1 TPS <50%. For patients in this poor category, chemoimmunotherapy may result in a worse prognosis than expected.

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.

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.

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.

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.

Improvement in Subjective Symptoms and Tolerability in Response to Nintedanib Treatment in Elderly Patients with Idiopathic Pulmonary Fibrosis.

The efficacy of nintedanib treatment in patients with idiopathic pulmonary fibrosis (IPF) was demonstrated in phase III trials. However, there is limited data on the significance of nintedanib in elderly patients aged ≥75 years. We have retrospectively evaluated 54 newly nintedanib-treated patients including 32 elderly individuals. Potential changes in modified medical research council (mMRC) grade and COPD (chronic obstructive pulmonary disease) assessment test (CAT) score, as well as in forced vital capacity (FVC) were obtained 6 months before, at the time of, and 6 and 12 months after initiation of nintedanib treatment. Significant differences were observed in CAT scores between 6 months before treatment and baseline (p < 0.001), and between baseline and 6 months (p < 0.001) and 12 months (p < 0.001) after treatment. If subjective improvement is defined as an improvement in mMRC grade or CAT score by 1 or 3 points, respectively, 25 patients (46.3%) have significantly improved after 6 months of treatment. Out of these, all have improved in CAT score. The tolerability of nintedanib was similar in elderly and younger patients. These findings suggest that CAT scores could be useful in the subjective assessment during nintedanib treatment, and that nintedanib is safe and efficient for the treatment of the elderly population.

Vogt-Koyanagi-Harada disease during chemoimmunotherapy for non-small cell lung cancer.

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.

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.