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Immune checkpoint inhibitors can cause immune-related toxicity in various systems, and myocarditis is the most serious life-threatening toxicity. This report introduces diagnosis and treatment of two cases which developed myocarditis after receiving PD-1 inhibitors therapy. The first case was a 77-year-old male with chordoma, who was treated by third-line sintilimab combined with anlotinib, and presented with symptoms of chest tightness, shortness of breath and upper eyelid ptosis three weeks later. He was diagnosed as immune-checkpoint-inhibitors-related myocarditis and myositis-myasthenia-gravis overlap syndrome based on his clinical symptoms, serum biomarkers, electrocardiogram, echocardiogram, and characteristic findings on cardiac 18F-FDG PET-MRI. Methylprednisolone was given 480 mg/d initially and was gradually reduced to 40 mg/d in 4 weeks, with the myocardial injury biomarkers declined in the same time. The second case was a 69-year-old female with advanced non-small cell lung cancer, who was treated by pemetrexed combined with bevacizumab and camrelizumab, and presented with palpitations 20 days later. She was diagnosed as immune-checkpoint-inhibitors-related myocarditis based on her clinical symptoms, serum biomarkers, electrocardiogram and echocardiogram. Methylprednisolone was given 240 mg/d initially and was gradually reduced to 40 mg/d with good response of myocardial injury biomarkers decline. However, the patient developed fatal myasthenia gravis afterwards, with little response to all treatments. These two cases revealed that, early detection and timely intervention, including discontinuation of immune checkpoint inhibitors and initiation of adequate steroid therapy, can reduce morbidity and mortality and improve prognosis.

Background Resistance is almost inevitable and is still a major obstacle in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Only limited relevant clinical studies evaluated the therapeutic effects by combing metformin and EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Therefore, we evaluated the efficacy of concurrent use of metformin with EGFR-TKIs, and assessed whether the addition of metformin may improve clinical outcomes and delay the occurrence of EGFR-TKI resistance. Methods We conducted cell proliferation and apoptosis assay for investigation of metformin in combination with EGFR-TKIs to overcome EGFR-TKI resistance in vitro. Furthermore, we retrospectively reviewed clinicopathological characteristics and therapeutic outcomes of EGFR-mutant advanced NSCLC diabetic patients who received EGFR-TKIs with or without concurrent use of metformin. Results In vitro experiment, metformin showed synergistic interaction both with gefitinib in PC9R (CI =0.77) and with osimertinib in PC9R/OR (CI =0.77) in proliferation inhibition assay. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs. In retrospective cohort, a total of 85 patients were identified (cohort A), in which 28 patients had concurrent use of metformin. The objective response rate in metformin use group was significantly higher (85.7% vs. 47.4%, P=0.001). The median progression-free survival (PFS) and overall survival (OS) in metformin use group were significantly longer (21.6 vs. 9.2 months, P=0.000; 48.4 vs. 36.6 months, P=0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs due to secondary EGFR T790M mutation (cohort B). Conclusions Our study suggest that concurrent use of metformin could be beneficial to EGFR-mutant NSCLC patients treated with either first-line EGFR-TKIs or second-line osimertinib.

Background A strong association between M descriptors and prognosis of non-small cell lung cancer (NSCLC) has been demonstrated recently. However, its predictive and prognostic significance for advanced NSCLC patients treated with immune checkpoint inhibitors (ICIs) remain unclear. In this study, we aimed at investigating the impact of M descriptors on clinical outcomes in those patients. Methods A retrospective analysis was conducted. Patients treated with more than two cycles of ICIs were included. Detailed characteristics and clinical response after immunotherapy were recorded. M descriptors were classified into M1a, M1b, and M1c according to the 8th TNM classification. Results A total of 103 patients were enrolled, including 42 with M1a disease, 16 with M1b disease and 45 with M1c disease. Patients with M1a disease demonstrated significant longer median progress-free survival (PFS) (11.9 vs. 4.1 and 3.2 months, respectively, P=0.0002) and overall survival (OS) (35 vs. 22.1 and 12 months, P=0.02) than those with M1b and M1c disease. Patients with M1a disease showed higher objective response rate (ORR) (28.6% vs. 14.8%, P=0.08) and disease control rate (DCR) (81% vs. 59%, P=0.02) compared with those with M1b and M1c disease. Multivariate analysis identified M1a stage as being independently associated with prolonged PFS and had better OS than those with M1c disease (P=0.05) but not M1b disease (P=0.06). Conclusions The current study demonstrated a clear association between M descriptors and the therapeutic response to ICIs and confirmed its prognostic role in advanced patients treated with ICIs monotherapy. M descriptors may need to be stratified in future study design.