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Kazuhito Misawa,1 Shinji Nakamichi,1 Hiroki Iida,1 Atsuhiro Nagano,1 Erika Mikami,1 Takehiro Tozuka,1 Masaru Matsumoto,1 Akihiko Miyanaga,1 Rintaro Noro,1 Kaoru Kubota,1 Hiroki Yamaguchi,2 Masahiro Seike1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, 113-8603, Japan; 2Department of Hematology, Nippon Medical School, Tokyo, 113-8603, JapanCorrespondence: Shinji Nakamichi, Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan, Tel +81-3-3822-2131, Email snakamichi@nms.ac.jpAbstract: Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor as standard therapy for ALK-rearranged non-small cell lung cancer (NSCLC). Hemolytic anemia is considered as a rare but significant adverse event with alectinib. Here, we report a case of a 73-year-old female with lung adenocarcinoma, harbouring an ALK fusion gene, who received alectinib as second-line therapy and developed gradually progressive grade 4 (6.4 g/dL) drug-induced hemolytic anemia (DIHA) after complete response. We discontinued alectinib and performed a blood transfusion for the severe anemia. The anemia improved with no recurrence of lung adenocarcinoma over 10 months. Regular hematologic monitoring and the possibility of DIHA should be considered in case of progressive hemolytic anemia during alectinib treatment.Keywords: non-small cell lung cancer, ALK, alectinib, drug-induced hemolytic anemia

Anna Hayashi,1 Shinji Nakamichi,1 Yukako Nakayama,1 Atsuhiro Nagano,1 Erika Mikami,1 Natsuki Takano,1 Takehiro Tozuka,1 Masaru Matsumoto,1 Akihiko Miyanaga,1 Rintaro Noro,1 Yasuhiro Terasaki,2 Kaoru Kubota,1 Masahiro Seike,1 Akihiko Gemma1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Bunkyo-ku, Japan; 2Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Bunkyo-ku, JapanCorrespondence: Anna Hayashi, Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Tokyo, Bunkyo-ku, 113-8603, Japan, Tel +81-3-3822-2131, Fax +81-3-5685-3075, Email k-anna@nms.ac.jpAbstract: Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.Keywords: combination immunotherapy, immune checkpoint inhibitor, immune-related adverse events, irAEs, hepatotoxicity, liver biopsy, short-term steroid

Yuki Kato,1 Yasuhiro Kato,1 Yuji Minegishi,1,2 Takahiro Suzuki,1 Shinji Nakamichi,1 Masaru Matsumoto,1 Akihiko Miyanaga,1 Rintaro Noro,1 Kaoru Kubota,1 Yasuhiro Terasaki,3 Masahiro Seike,1 Akihiko Gemma1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 2Department of Pulmonary Medicine, Mitsui Memorial Hospital, Tokyo, Japan; 3Department of Analytic Human Pathology, Nippon Medical School, Tokyo, JapanCorrespondence: Yasuhiro KatoDepartment of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Sendagi 1-1-5 Bunkyo-ku, Tokyo, 113-8603, JapanEmail y-kato@nms.ac.jpAbstract: Antibody–drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.Keywords: lung cancer, HER2 exon 20 insertion mutation, poor PS, trastuzumab deruxtecan

Teppei Sugano,1 Masahiro Seike,1 Rintaro Noro,1 Syota Kaburaki,1 Takehiro Tozuka,1 Akihiko Takahashi,1 Natsuki Takano,1 Toru Tanaka,1 Takeru Kashiwada,1 Susumu Takeuchi,1 Yuji Minegishi,1 Yoshinobu Saito,1 Kaoru Kubota,1 Yasuhiro Terasaki,2 Akihiko Gemma1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 2Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Abstract: We herein describe the case of a 67-year-old woman with advanced lung adenocarcinoma who developed interstitial lung disease (ILD) with alveolar hemorrhage induced by pembrolizumab. She received four courses of pembrolizumab therapy and achieved a partial response. She had no respiratory symptoms; however, chest radiography and computed tomography (CT) revealed ground-glass opacities (GGOs) and crazy-paving pattern. Based on findings of bloody bronchoalveolar lavage fluid and transbronchial lung biopsy samples, pembrolizumab-induced ILD with alveolar hemorrhage was diagnosed. Corticosteroid therapy rapidly improved alveolar hemorrhage and regressed GGOs on CT scan. This is the first report on ILD with alveolar hemorrhage induced by pembrolizumab. Keywords: pembrolizumab, PD-1, pneumonitis, alveolar hemorrhage

Takehiro Tozuka,1 Masahiro Seike,1 Yuji Minegishi,1 Shingo Kitagawa,1 Tomomi Kato,1 Natsuki Takano,1 Kakeru Hisakane,1 Satoshi Takahashi,1 Kenichi Kobayashi,1 Takeru Kashiwada,1 Teppei Sugano,1 Susumu Takeuchi,1 Shinobu Kunugi,2 Rintaro Noro,1 Yoshinobu Saito,1 Kaoru Kubota,1 Akihiko Gemma1 1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 2Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan Abstract: Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from 90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression. Keywords: programmed cell death ligand 1, epidermal growth factor receptor mutation, lung cancer, chemotherapy post immunotherapy