Efficacy and Safety of Anti-Programed Death-1 Blockade in Previously Treated Large-Cell Neuroendocrine Carcinoma.

BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC. METHODS: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety. RESULTS: Of a total of 11 patients (median [range] age, 66 [37-79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0-1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1-12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event. CONCLUSION: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option.

Protocol for a multi-site, cluster-randomized, phase III, comparative clinical trial of geriatric assessment of older patients with non-small-cell lung cancer: the ENSURE-GA study.

BACKGROUND: In Japan, approximately half of all lung cancer patients are aged > 75 years, and the proportion of older patients is increasing. In older patients, it is necessary to consider comorbidities and concomitant drug use to ensure optimal cancer treatment; however, geriatric assessment (GA) is not widely performed. We plan to conduct a study (ENSURE-GA) of GA in older lung cancer patients to determine whether GA with intervention improves patient satisfaction with their treatment. METHODS: The study will be a phase III comparative clinical trial with a cluster-randomized design, and it will be conducted at 81 sites distributed throughout Japan. Approximately 1000 lung cancer patients aged ≥ 75 years will be enrolled in the study. All participants will undergo a standardized GA before starting treatment (using an iPad). At the intervention sites, the GA results and intervention method recommended on the basis of the GA results will be returned as an instant report to guide the physician's choice of intervention. At the control sites, the physician will decide on interventions based on standard practice. All participants will complete a patient satisfaction survey before treatment initiation (after the GA) and 3 months later. DISCUSSION: The purpose of the ENSURE-GA study is to evaluate whether GA with interventions improves patient satisfaction with treatment outcomes. The study may lead to the increased use of GA and improved treatment of cancer in older adults. The results will also be used to prepare guidelines for treating older cancer patients and will provide a foundation for the development of a standardized geriatric oncology system. TRIAL REGISTRATION: The study has been registered in the University Hospital Medical Information Network database (no. UMIN000037590). The registration date is August 4, 2019, and the protocol version is 2.0. ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042853 .).

Nintedanib-associated enterocolitis with intractable diarrhea: a case report.

Revised idiopathic pulmonary fibrosis treatment guidelines were published in 2015, and nintedanib was conditionally recommended. Although diarrhea is reported to be a common major adverse event associated with nintedanib, there have been few reports on detailed endoscopic findings of nintedanib-associated enterocolitis. A 74-year-old woman was diagnosed with idiopathic pulmonary fibrosis 4 years ago in May. She was started on nintedanib (300 mg). Three months later, hepatic dysfunction was observed; therefore, the drug was temporarily discontinued and then resumed at a dose reduction of 200 mg. Five months later, the patient developed diarrhea, and the dose was reduced to 150 mg. However, no effect was noted; hence, colonoscopy was performed. Various inflammatory lesions, such as erythema and erosions, were observed continuously at the rectum, which resembled ulcerative colitis. No improvement was observed 2 months after follow-up colonoscopy, and nintedanib-related enterocolitis was suspected. The dose was further reduced to 100 mg. Since the endoscopic findings of nintedanib-associated enterocolitis are similar to those of ulcerative colitis, it is critical to consider patients with diarrhea who are taking nintedanib as having associated enterocolitis and attempt to reduce or discontinue the drug if diarrhea does not improve with antidiarrheal agents.

Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea.

STUDY OBJECTIVES: Poor adherence to continuous positive airway pressure (CPAP) has been a critical issue in treating obstructive sleep apnea. Because long-term CPAP adherence may be established shortly after treatment begins, early intervention is essential. This study aimed to identify the potential factors affecting CPAP therapy adherence during diagnostic polysomnography and auto CPAP titration polysomnography. METHODS: This retrospective observational study included 463 patients with obstructive sleep apnea who underwent consecutive diagnostic polysomnography and titration polysomnography. We recorded their demographic, anthropometric, and lifestyle factors and obtained self-reported comments regarding their sleep status following both polysomnography evaluations. CPAP adherence was evaluated following 3 months of treatment. RESULTS: A total of 312 patients (67.4%) fulfilled the criteria for good adherence. Each patient's CPAP adherence was categorized as "poor" (< 4 hours/night or <70% of nights), "good" (≥ 4 hours/night and ≥ 70% of nights), or "excellent" (≥ 6 hours/night and ≥ 80% of nights). There were no significant differences in arterial oxyhemoglobin saturation measured by pulse oximetry and apnea-hypopnea index during diagnostic polysomnography among 3 groups. The polysomnographic evaluations indicated that patients with better adherence displayed more significant improvements in sleep parameters, including apnea-hypopnea index, sleep efficacy, sleep latency, and sleep architecture, which were correlated with an improvement in self-reported sleep quality. CONCLUSIONS: Polysomnographic evaluations enabled CPAP adherence prediction and a comparison of self-reported sleep quality with and without CPAP; CPAP adherence led to improvements in polysomnographic parameters. Our findings suggest that titration polysomnography and self-reported sleep improvement with CPAP could be used for adherence prediction in clinical practice. CITATION: Shirahata T, Uchida Y, Uchida T, et al. Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea. J Clin Sleep Med. 2023;19(8):1465-1473.

Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.

Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Combination of immune check inhibitor and immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis: A case report.

The present study selected two patients with lung cancer and epidermal growth factor receptor (EGFR) mutations who were treated with a programmed cell death protein 1 (PD-1) antibody and an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis. In the first case, a 67-year-old female was diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion) and Stage IVB disease. Initial treatment with an EGFR mutation-targeted tyrosine kinase inhibitor (TKI), erlotinib, demonstrated a partial response. After disease progression this was followed by carboplatin and pemetrexed with bevacizumab, and re-challenged by erlotinib plus bevacizumab; however, the tumor eventually progressed. Subsequently, the patient was treated with immunomodulatory arabinomannan for 3 months. Immediately after, she was treated with nivolumab and showed a partial response. In the second case, a 57-year-old male with a history of smoking was diagnosed with stage IVB pulmonary adenocarcinoma with an EGFR mutation (exon 19 deletion). He was treated with afatinib, followed by osimertinib when a T790M mutation was identified later. After disease progressed with TKIs, cisplatin plus pemetrexed and re-challenge with erlotinib plus bevacizumab were administered subsequently. Nivolumab was administered for recurrent disease. Although he experienced tumor remission, regrowth of the tumors was observed. Under continuing nivolumab, he was treated by palliative irradiation treatments to the right pelvic bone metastasis and left adrenal metastasis with immunomodulatory arabinomannan. A chest computed tomography scan showed a reduction in the sizes of the primary site and pulmonary metastases, with a decreasing trend of carcinoma embryonic antigen. Overall, these cases may indicate that the immune adjuvant actions of immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis improves the effect of PD-1 antibody treatments.

Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce. METHODS: This study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed. RESULTS: One hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39-84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups. CONCLUSION: The administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.

Yellow Nail Syndrome in Which Intranodal Lymphangiography Contributed to the Diagnosis.

Yellow nail syndrome (YNS) is a rare disease comprising the clinical triad of yellow nail discoloration, pleural effusion, and lower limb lymphedema. We encountered a difficult-to-treat case of YNS in which the diagnosis was finally made based on intranodal lymphangiography. An 84-year-old man was admitted to our hospital with pleural effusion and yellow-green discoloration of the nails, accompanied by onychomycosis and limb lymphedema. Intranodal lymphangiography revealed a slow contrast flow and narrowing of the thoracic duct, suggesting lymphatic duct dysplasia and leading to the diagnosis of YNS.

Effect of Systemic Steroid Use for Immune-Related Adverse Events in Patients with Non-Small Cell Lung Cancer Receiving PD-1 Blockade Drugs.

OBJECTIVES: Programmed death-1(PD-1)/programmed death ligand-1 (PD-L1) antibodies have clinical benefits for cancer patients facing immune-related adverse events (irAEs). However, the effect of steroid use on the prognosis of patients with non-small cell lung cancer (NSCLC) receiving PD-1 blockade remains unclear. METHODS: NSCLC patients with complete response (CR)/partial response (PR) or stable disease (SD)/not evaluable (NE) status plus progression-free survival (PFS) of 180 days after PD-1 blockade from December 2015 to December 2018 were retrospectively registered in our study and were divided into two groups: those with and without systemic steroid use for irAEs. RESULTS: In total, 126 patients who had benefitted from PD-1 blockade were enrolled in our study; among them, 44 received systemic steroids for irAEs, and 82 had no adverse events or, if they did, did not receive systemic steroids. Among the 44 patients requiring steroids, interstitial lung disease (ILD), adrenal insufficiency, diarrhea, and liver dysfunction were observed in 19, 9, 4, and 4 patients, respectively. More side effects were observed in the group treated by steroids. The median PFS and overall survival (OS) in patients with and without systemic steroid use were 11.7 and 16.0 months (p < 0.037) and 35.0 and 41.0 months (p < 0.28), respectively. In univariate and multivariate analyses of survival, systemic steroid treatment for irAEs was significantly associated with PFS. The occurrence of ILD, adrenal insufficiency, and fever was significant in patients who used systemic steroids for irAEs. CONCLUSIONS: Patients administered systemic steroids for irAEs due to PD-1 blockade treatment exhibited shorter PFS than those who were not. Systemic steroids might affect survival after PD-1 blockade even for patients who once acquired its clinical benefit.

Effectiveness of EGFR-TKI rechallenge immediately after PD-1 blockade failure.

BACKGROUND: There is currently insufficient information available on effective therapies that can be administered to patients with non-small cell cancer (NSCLC) who develop resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, sequential treatment via programmed death-1 (PD-1) blockade followed by EGFR-TKI rechallenge is suggested to improve the therapeutic efficacy in such patients. METHODS: A total of 75 patients with advanced NSCLC harboring sensitive EGFR mutations treated with afatinib, erlotinib, or gefitinib after EGFR-TKI treatment failure were retrospectively analyzed. Among them, 13 patients were treated with EGFR-TKI rechallenge immediately after the failure of PD-1 blockade therapy (experimental group) and the remaining 62 patients did not receive PD-1 inhibitor therapy before EGFR-TKI rechallenge (control group). Blood samples were collected at two time points; before the initiation of anti-PD-1 therapy and at EGFR-TKI rechallenge. RESULTS: The objective response rates of EGFR-TKI rechallenge in the experimental and control groups were 46.1% and 16.1%, respectively, with a significant difference (p = 0.026). In the experimental group, the median progression-free survival (PFS) and overall survival (OS) after EGFR-TKI rechallenge were 5.0 and 25.0 months, respectively, and no statistically significant difference in the percentage of lymphocytes before immune checkpoint inhibitor (ICI) therapy and EGFR-TKIs was observed in patients with partial response (PR) and without PR after EGFR-TKI rechallenge. In particular, the sequential treatment of PD-1 blockade therapy followed by EGFR-TKI rechallenge was consecutively repeated three times in two out of 13 patients in the experimental group, and EGFR-TKI rechallenge consecutively for the third time yielded a PR without increased toxicities. CONCLUSIONS: EGFR-TKI rechallenge immediately after PD-1 blockade treatment was identified as an effective therapy for NSCLC patients with resistance to EGFR-TKIs.

Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab.

BACKGROUND: The safety of pembrolizumab monotherapy in treatment-naïve non-small cell lung cancer (NSCLC) patients with high programed death-ligand 1 (PD-L1) expression and pre-existing interstitial lung disease (ILD) has not yet been determined. Here, we aimed to evaluate the prognosis, efficacy and safety associated with pembrolizumab in such settings. METHODS: In this single-institution retrospective study conducted from May 2017 to October 2019, pembrolizumab was administered to 72 Japanese patients with treatment-naïve advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50%. Patients with ILD were assigned to the ILD group, and those without to the non-ILD group. Between-group comparisons were then performed. RESULTS: Of the 72 patients, 61 (84.7%) were male. The median age was 70 years. A total of 64 patients (88.9%) had a smoking history, median PD-L1 TPS status was 77.5%, and 10 of the 72 patients (13.9%) had ILD on pretreatment computed tomography. The objective response rate (ORR) was 45.8% and disease control rate (DCR) was 75.0%. The ORR was 70.0% and DCR was 90.0% in the ILD group, while the ORR was 41.9% and DCR was 72.6% in the non-ILD group. The median overall survival was 568 days; the value in the non-ILD group was 521 days, while in the ILD group was not reached. There was no significant difference between the two groups (log-lank, P = 0.73). CONCLUSIONS: Pembrolizumab was administered to patients with pre-existing ILD with no difference in prognosis compared to patients without ILD. In patients with ILD, physicians should consider the expected long-term prognosis and risk of adverse events.

Clinical impact of post-progression survival on overall survival in patients receiving nivolumab monotherapy as a second-line treatment for advanced non-small cell lung cancer.

BACKGROUND: The effect of second-line treatment on overall survival (OS) may be affected by subsequent treatment in patients with non-small cell lung cancer (NSCLC); however, in such patients, the correlation between post-progression survival (PPS) and OS is unclear. Our study assessed the correlation of progression-free survival (PFS) and PPS with OS, using individual patient data, in advanced NSCLC patients who were treated with second-line nivolumab monotherapy, METHODS: Between January 2016 and March 2019, we evaluated 92 NSCLC patients who received second-line nivolumab treatment after first-line platinum-based combination chemotherapy. Using individual patient data, the correlations of PFS and PPS with OS were examined. RESULTS: Linear regression and Spearman rank correlation analysis demonstrated that PPS was strongly correlated with OS (r = 0.85, p < 0.05, R2 = 0.75), while PFS was moderately correlated with OS (r = 0.65, p < 0.05, R2 = 0.42). Performance status at the beginning of second-line treatment, immune checkpoint inhibitor rechallenge, and the number of treatment regimens used post-progression, after the second-line treatment significantly correlated with PPS (p < 0.05). In advanced NSCLC patients who underwent second-line treatment with nivolumab, in comparison to PFS, there was a stronger correlation between PPS and OS. CONCLUSIONS: Our findings suggest that subsequent treatment for disease progression after a second-line nivolumab treatment had a significant impact on OS.

Osimertinib induced cardiomyopathy: A case report.

RATIONALE: Cardiotoxicity related to osimertinib, including cardiac failure, QT prolongation, and atrial fibrillation, has been reported as an extremely rare incidence in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the occurrence of osimertinib-induced cardiomyopathy. PATIENT CONCERNS: A 76-year old woman was treated with afatinib (40 mg/day) as the 1st line treatment due to recurrence after surgical resection for pulmonary adenocarcinoma. However, she experienced recurrence with positive T790 M, and osimertinib (80 mg/day) was administered as the 2nd line therapy. DIAGNOSIS: Four months after osimertinib initiation, she complained of fever and progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating osimertinib-induced cardiomyopathy. INTERVENTIONS AND OUTCOMES: She was treated with furosemide, carvedilol, and enalapril, and her cardiac function, her symptoms, and condition improved 3 weeks after the withdrawal of osimertinib. LESSONS: Physicians should be alert of the cardiomyopathy-causing potential of osimertinib in advanced NSCLC patients.

Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non-small cell lung cancer harboring EGFR mutation.

BACKGROUND: Osimertinib is the most promising treatment option for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) with acquired T790M resistance. However, recent studies have suggested that osimertinib could increase the frequency of serious adverse events (AEs) if administered immediately after immune checkpoint inhibitor (ICI) treatment. METHODS: In this single-institution retrospective study conducted from May 2016 to January 2019, osimertinib was administered to 47 patients with pretreated advanced NSCLC harboring the EGFR mutation. RESULTS: Of the 47 patients, 20 (42.6%) were men and 27 (57.4%) were women. The median age was 71 years (range 37-83 years). A total of 19 patients (40.4%) had a smoking history. Furthermore, seven patients (14.9%) received osimertinib immediately after nivolumab therapy, while 40 patients (85.1%) were treated with osimertinib after treatment with drugs other than nivolumab. The frequency of grade 3 or 4 hepatotoxicity was significantly higher in patients with nivolumab prior to osimertinib (4/7; 57.1%) than in those treated with drugs other than nivolumab prior to osimertinib (2/40; 5.0%) (P = 0.0026). Liver biopsies were performed in two patients who received osimertinib immediately after nivolumab. In both patients, CD-8-positive T cell infiltration was predominantly observed in the liver tissues. CONCLUSIONS: The use of osimertinib immediately after nivolumab significantly increased the frequency of grade 3 or higher hepatotoxicity in patients with advanced NSCLC harboring EGFR mutation acquired T790M resistance.

Chemoradiotherapy followed by durvalumab in patients with unresectable advanced non-small cell lung cancer: Management of adverse events.

BACKGROUND: Chemoradiotherapy followed by durvalumab is the standard treatment for the patients with local advanced non-small cell lung cancer (NSCLC). There is a real-world data about the management of adverse events, such as pneumonitis, according to the different institutions. Here, we present the experience regarding the management of adverse events after the initiation of durvalumab as daily practice. METHODS: From July 2018 to August 2019, 41 patients with locally advanced NSCLC, who underwent chemoradiotherapy followed by durvalumab, were retrospectively analyzed in the study using our medical records. RESULTS: The median age of patients was 72 years (range: 51-80 years). A total of 33 patients were male and eight were female, and 40 patients (98%) received a total radiation dose of 60 Gy as concomitant chemoradiotherapy. The median V20 for the entire cohort was 18.9% (range: 3.5-29.9). Any adverse events during chemoradiotherapy and durvalumab were observed in 32 patients (78.0%), while three patients (7.3%) experienced grade 3 toxicities. In total, 25 (61.0%) patients experienced pneumonitis, four (9.8%) thyroid dysfunction, three (7.3%) myopathy, two (4.9%) rash or eruption, one (2.4%) bowel disease and one (2.4%) malaise. Grade 3 pneumonitis, thyroid dysfunction and myopathy were observed in one (2.4%), one (2.4%) and one (2.4%), respectively. A total of 22 (53.7%) patients were unable to continue durvalumab due to pneumonitis. However, durvalumab was finally readministered to six patients. CONCLUSIONS: The adherence to lung dose constraints such as V20 as well as close treatment monitoring are a prerequisite for the management of pneumonitis during maintenance therapy with durvalumab.