Risk factors for severe immune-related pneumonitis after nivolumab plus ipilimumab therapy for non-small cell lung cancer.

BACKGROUND: The efficacy of anti-CTLA-4 antibody (ipilimumab) plus anti-programmed cell death 1 antibody (nivolumab) in treating advanced non-small cell lung cancer (NSCLC) is impeded by an elevated risk of severe immune-related adverse events. However, our understanding of associations among pre-existing fibrosis, emphysematous changes, and objective indicators as predictive factors is limited for severe pneumonitis in NSCLC patients receiving this combination therapy. Thus, we retrospectively investigated these associations, including overall tumor burden, before treatment initiation in the Japanese population. METHODS: We focused on patients (n = 76) with pre-existing interstitial lung disease (ILD) to identify predictors of severe pneumonitis. Variables included age, sex, smoking status, programmed cell death ligand 1 expression, overall tumor burden, chest computed tomography-confirmed fibrosis, serum markers, and respiratory function test results. RESULTS: Severe pneumonitis was more frequent in patients with squamous cell carcinoma, fibrosis, low diffusing capacity for carbon monoxide (%DLCO), and high surfactant protein D (SP-D) level. Notably, squamous cell carcinoma, baseline %DLCO, and SP-D level were significant risk factors. Our findings revealed the nonsignificance of tumor burden (≥85 mm) in predicting severe pneumonitis, emphasizing the importance of pre-existing ILD. Conversely, in cases without pre-existing fibrosis, severe pneumonitis was not associated with %DLCO or SP-D level (93.2% vs. 91.9%, and 63.3 vs. 40.9 ng/mL, respectively) and was more common in patients with a large overall tumor burden (97.5 vs. 70.0 mm). CONCLUSION: Vigilant monitoring and early intervention are crucial for patients with squamous cell carcinoma, high SP-D level, or low %DLCO undergoing ipilimumab plus nivolumab therapy.

Small-cell Lung Carcinoma with Gastrointestinal Pseudo-obstruction as a Paraneoplastic Neurological Syndrome Elicited by an Immune Checkpoint Inhibitor.

Gastrointestinal pseudo-obstruction (GIPO) is a phenotype of the paraneoplastic neurological syndrome (PNS). We herein report a case of small-cell lung carcinoma (SCLC) with GIPO elicited by an immune checkpoint inhibitor (ICI). A 75-year-old man with SCLC developed intractable intestinal obstruction after receiving one course of anticancer drugs (durvalumab, etoposide, and carboplatin). The serum anti-Hu antibody (Hu-Ab) was positive, and the patient was diagnosed with GIPO. Corticosteroid treatment did not improve the GIPO, and the patient died. There are few reports of GIPO after ICI treatment in patients with lung cancer, so a further investigation will be required to elucidate the mechanism by which ICIs elicit PNS. Checking for neuronal antibodies may help identify patients with SCLC who are at risk of developing PNS due to ICI treatment.

Risk factors for severe immune-related adverse events after first-line pembrolizumab monotherapy or combination chemotherapy for non-small-cell lung cancer.

Pembrolizumab treatment is associated with a favorable prognosis in patients with non-small-cell lung cancer (NSCLC). Here, we investigated the associations among pre-treatment clinical factors, baseline overall tumor burden, and development of severe immune-related adverse events (irAEs; grade ≥ 3) after pembrolizumab treatment with or without chemotherapy. We retrospectively examined consecutive patients with advanced NSCLC who received pembrolizumab with or without chemotherapy at Hakodate Goryoukaku Hospital from March 2017 to February 2021. The baseline overall tumor burden was measured as the sum of the unidimensional diameters of up to five target lesions. We defined irAEs as toxicities related to immune checkpoint inhibitors based on the Common Terminology Criteria for Adverse Events, version 5.0. Tumor burden differed significantly between patients with and without severe irAEs (85 vs. 65 mm, p = 0.0367). The cutoff value for overall tumor burden was set to 80 mm. Good performance status (PS = 0) and PD-L1 expression > 80%, but not overall tumor burden, were correlated with severe irAEs, regardless of complementary chemotherapy. The multivariate odds ratios of good PS and high PD-L1 expression for severe irAEs were 3.27 (95% confidence interval [CI]: 1.22-8.77, p = 0.019) and 4.44 (95% CI: 1.59-12.42, p = 0.0044), respectively. Baseline overall tumor burden, good PS, and high PD-L1 expression were associated with severe irAEs in patients with NSCLC treated with first-line pembrolizumab with or without chemotherapy. Patients with these factors should be carefully monitored to prevent irAEs.

Relation of overall tumor burden with severe immune-related adverse events in nivolumab plus ipilimumab treatment for lung cancer.

Compared to chemotherapy alone, monoclonal antibodies like ipilimumab and nivolumab, with or without chemotherapy, improve the prognosis of patients with non-small cell lung cancer (NSCLC), albeit with a higher incidence of immune-related adverse events (irAEs) than those with immune checkpoint inhibitor (ICI) monotherapy. Therefore, we aimed to investigate if baseline overall tumor burden was associated with the development of Grade ≥ 3 irAEs (severe irAEs) when treated with first-line ipilimumab plus nivolumab with or without chemotherapy.We retrospectively examined consecutive patients with advanced NSCLC who received nivolumab plus ipilimumab with or without chemotherapy at Hakodate Goryoukaku Hospital between December 2020 and December 2021. Baseline overall tumor burden was measured as the sum of unidimensional diameters of up to five target lesions according to the Response Evaluation Criteria in Solid Tumors, version 1.1. We defined irAEs as ICI therapy-related toxicities according to the Common Terminology Criteria for Adverse Events, version 5.0.A significant difference in tumor burden was observed between patients with and without severe irAEs (100 mm vs. 67.5 mm, p = 0.001). We evaluated various clinical parameters, including baseline overall tumor burden, before treatment initiation. Of the various parameters, only high tumor burden correlated with severe irAEs, independent of complementary chemotherapy. The multivariate odds ratio of severe irAEs and high tumor burden was 6.62.Conclusively, baseline overall tumor burden may be a risk factor for severe irAEs in patients treated with first-line combination ICI therapy. Therefore, patients with large tumor burden should be carefully monitored to prevent irAEs.

Refractory flare-up of severe bronchial asthma controlled with mepolizumab due to Pneumocystis pneumonia: a case report.

BACKGROUND: Biologics dramatically improve symptoms of severe asthma; however, various exacerbating factors may induce flare-up. Pneumocystis spp. have not been reported as a cause of asthma exacerbation during biologic use, although patients with severe asthma have high levels of antibodies against Pneumocystis spp. CASE PRESENTATION: An 87-year-old female with severe asthma that was well-controlled with mepolizumab, who developed a steroid-resistant refractory flare-up. Chest computed tomography showed bilateral ground glass opacities, and results of polymerase chain reaction tests on induced sputum were positive for Pneumocystis DNA. Therefore, a diagnosis of Pneumocystis pneumonia was made. The clinical symptoms improved after treatment with sulfamethoxazole-trimethoprim. CONCLUSION: Clinicians should be aware of Pneumocystis pneumonia as a cause of refractory exacerbation of bronchial asthma during use of interleukin-5 inhibitors.

Successful management of severe bronchial asthma exacerbated by anti-PD-L1 treatment: A report of two cases.

Immune checkpoint inhibitors (ICIs) have been used for various carcinomas. However, immune-related adverse events have been observed. There have been few reports of treatment with biologics for severe bronchial asthma induced by ICI; therefore, their efficacy is unknown. We report two cases of severe bronchial asthma requiring systemic steroid administration while using anti-programmed death-ligand 1 (PD-L1) antibody for advanced non-small-cell lung cancer. The anti-interleukin-5 antibody, mepolizumab, was introduced, resulting in the discontinuation of systemic prednisolone and good asthma control. These reports suggest that treatment with biologics may be effective in severe cases of poorly controlled bronchial asthma during ICI therapy.

Lung squamous cell carcinoma with hemoptysis after vaccination with tozinameran (BNT162b2, Pfizer-BioNTech).

A 66-year-old man with squamous cell carcinoma had been receiving chemoradiation therapy after stereotactic radiotherapy for brain metastases. Atezolizumab was initiated as second-line therapy, after which the patient became progression- and recurrence-free. Four days after his second dose of tozinameran (BNT162b2, Pfizer-BioNTech), the patient developed persistent hemoptysis. The patient had no thrombocytopenia or coagulation abnormalities. Bronchoscopy revealed active bleeding from the left lingual tracheal branch. The patient was intubated and admitted to the intensive care unit because of increased bleeding. Subsequently, left bronchial artery embolization was performed using a Serescue. Hemostasis was achieved after the procedure, and the patient was discharged 7 days after the onset of hemoptysis. Vaccination against coronavirus disease has been reported to be associated with thrombosis and cerebral hemorrhage, and the hemoptysis in this case was suspected to be induced by vaccination. In summary, the benefits of vaccination exceeded the risks of adverse events in a patient with cancer. However, in conditions such as after chemoradiation, especially in patients with radiation pneumonitis wherein the vasculature is vulnerable, patients should be carefully monitored for hemorrhagic events after vaccination.

Delayed local reaction at a previous injection site reaction with dupilumab.

Clinicians should be aware that biologic agents, which include polysorbates, can cause delayed local skin reactions at a previous injection site.

Pseudocirrhosis due to liver metastasis from lung adenocarcinoma.

Pseudocirrhosis is a radiological diagnosis of cirrhosis without histological evidence and occurs as a complication of liver metastases from solid tumors. A 50-year-old man without any previous history of liver disease was diagnosed with adenocarcinoma of the left upper lung lobe and liver metastasis. After chemotherapy, the liver metastases shrank; however, over time, the liver shrank and showed cirrhosis-like morphological changes. His performance status deteriorated due to ascites and leg edema, and chemotherapy was terminated. Physicians treating lung adenocarcinoma with liver metastases should be aware that pseudocirrhosis is a rare but important complication that can worsen performance status (PS) and hinder treatment continuation.