A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.

ObjectivesAlthough immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.MethodsWe retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.ResultsOf 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].ConclusionThe current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Background: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined.We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. Methods:We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021.Results: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 months (95% CI: 2.7-4.2) and 10 months (95% CI: 7.4-14.8), respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 months (95% CI:1.1-4.0) vs. 4.2 months (95% CI: 2.3-4.8), P=0.1142, OS; 10.0 months (95% CI: 5.2-14.8) vs. 10.4 months (95% CI: 3.8-NE), P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events.Conclusions: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

Background: Previous phase III study has demonstrated that osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI), exhibits superior antitumor effects compared to first-generation EGFR-TKIs and successfully prolonged overall survival (OS) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Although first-and second-generation EGFR-TKIs are risk factors for venous thromboembolism (VTE), whether osimertinib increases the VTE risk remains unclear. In addition, no treatment strategy exists for patients with VTE during osimertinib. Here we present the clinical course of three patients with suspected osimertinib-induced VTE who were successfully treated with direct oral anticoagulation without recurrence VTE during osimertinib therapy.Case Description: Three male patients, aged 66-74 years, with NSCLC harboring EGFR mutations had been treated with osimertinib as the first-and second-line treatments, and developed VTE. All patients responded to osimertinib, and none showed disease progression at VTE onset. All patients were treated with direct oral anticoagulation and could resume osimertinib treatment. The progression-free survival (PFS) from VTE onset in each of the three cases was 11.4+, 7.7, and 6.1 months, respectively. The OS from VTE onset was 11.4+, 26.0, and 25.9+ months, respectively. Conclusions:We report the cases of three NSCLC patients who developed VTE during osimertinib.Osimertinib may cause VTE and should be used cautiously. In such cases, osimertinib treatment may be continued with direct oral anticoagulation therapy.