Daiki Ogawara

Efficacy and safety of amrubicin hydrochloride for treatment of relapsed small cell lung cancer.

Long-term survival is quite uncommon in refractory small cell lung cancer (SCLC) patients, with less than 25% of patients with limited-stage disease and 1%–2% of patients with extensive-stage disease remaining alive at five years. Recent clinical studies have demonstrated the promising efficacy of amrubicin for patients with relapsed SCLC. This review presents the results of clinical studies showing the efficacy and safety of amrubicin for the treatment of relapsed SCLC. Amrubicin is a synthetic anthracycline agent with a similar structure to doxorubicin, in which the hydroxyl group at position 9 in amrubicin is replaced by an amino group to enhance efficacy. It is converted to an active metabolite, amrubicinol, which is 5–54 times more active than amrubicin. Amrubicin and amrubicinol are inhibitors of DNA topoisomerase II, exerting their cytotoxic effects by stabilizing a topoisomerase II-mediated cleavable complex. The toxicity of amrubicin is similar to that of doxorubicin, although amrubicin shows almost no cardiotoxicity. In the relevant trials, amrubicin was administered intravenously at a dose of 35–40 mg/m2 on days 1–3 every three weeks. The response rate was 34%–52% and median survival times were 8.1–12.0 months. Common hematologic toxicities included neutropenia, leucopenia, anemia, thrombocytopenia, and febrile neutropenia. Nonhematologic adverse events included Grade 3–4 anorexia, asthenia, hyponatremia, and nausea. The results of the studies which demonstrated the efficacy of monotherapy for relapsed SCLC involved mainly Japanese patients. Therefore, it is necessary to conduct more clinical studies in non-Japanese patients to confirm the efficacy of amrubicin.

Remarkable response of nivolumab-refractory lung cancer to salvage chemotherapy

Promising outcomes of salvage chemotherapy after nivolumab therapy have been reported; however, little is known about the detailed clinical and immunologic features in lung cancer patients in whom nivolumab is unsuccessful. We report two cases of nivolumab‐refractory lung cancer, in which chemotherapy resulted in rapid regression of the lung cancer. Upon initial diagnosis, the biopsy specimens showed PD‐ligand 1 (PD‐L1)‐expressing cancer cells, accompanied by tumor‐infiltrating lymphocytes with a favorable CD8/CD4 ratio. Immunosuppressive regulatory T cells and cells positive for TIM‐3 were also observed. Physicians should take caution in treating lung cancer patients after progression on nivolumab. Further studies with a large cohort are warranted to identify the patients that may benefit from salvage chemotherapy.

Successful treatment with nivolumab for lung cancer with low expression of PD-L1 and prominent tumor-infiltrating B cells and immunoglobulin G: Humoral immunity and nivolumab therapy

Little is known about the anti‐tumor activity of humoral immunity in lung cancer patients treated with nivolumab, an immune checkpoint inhibitor. Herein, we report a case of lung cancer with 5% expression of PD‐L1, in which a partial response to nivolumab was sustained for > 7 months. Immunohistochemical analysis of the metastatic lymph node biopsy specimen showed prominent accumulation of plasma cells and immunoglobulin G. These findings suggest that pre‐existing humoral immunity may be worth considering as a candidate therapeutic biomarker of nivolumab in some lung cancer patients.

Pulmonary pleomorphic carcinoma with few PD-1-positive immune cells and regulatory T cells that showed a complete response to nivolumab

Pulmonary pleomorphic carcinoma has been shown to respond remarkably to PD‐1 inhibitors; however, the biomarkers for this therapy have not been fully proven. We report a case of pulmonary pleomorphic carcinoma with overexpressed PD‐L1, in which a complete response to nivolumab was sustained for >14 months. Immunohistochemical analysis revealed few PD‐1+ immune cells and regulatory T cells in the tumor, in addition to predominant infiltration of CD8+ cells and macrophages. Our findings suggest that the presence of a small number of PD‐1+ immune cells and regulatory T cells should be investigated as candidate therapeutic biomarkers.

Nivolumab infusion reaction manifesting as plantar erythema and pulmonary infiltrate in a lung cancer patient

Infusion reaction is an adverse event of therapeutic monoclonal antibodies. Nivolumab, an anti‐programmed death‐1 antibody, directly activates T cells, which could probably interact with endothelial cells. The etiology of infusion reaction induced by nivolumab may differ from that of other antibodies; however, the detailed clinical features are unknown. We report a case of lung cancer treated with nivolumab, in which the infusion reaction manifested as plantar erythema, followed by a transient local pulmonary infiltrate around the tumor. Physicians should be aware that an infusion reaction induced by anti‐programmed death‐1 antibodies could appear as local cutaneous and pulmonary adverse events.

Presence of few PD-1-expressing tumor-infiltrating immune cells is a potential predictor of improved response to salvage chemotherapy following nivolumab for non-small cell lung cancer: An exploratory case series: Salvage chemotherapy following nivolumab

The combination of PD‐1 inhibitors and cytotoxic drugs is reported to enhance anti‐tumor activity in non‐small cell lung cancer; however, the underlying synergistic mechanisms remain uncertain. This retrospective case series was designed to investigate objective response and survival rates of salvage chemotherapy following nivolumab and explore the immunohistochemical profiles of tumor‐infiltrating immune cells.

Pitfalls in diagnosis with the use of circulating tumor-derived epidermal growth factor receptor mutations in lung cancer harboring pretreatment T790M

The circulating tumor DNA (ctDNA) assay has recently been approved for the selection of EGFR‐tyrosine kinase inhibitors as first‐line treatment in lung cancer. However, it remains to be determined whether this assay can detect all complex EGFR mutations within a single tumor. We report a case of an elderly woman with stage IV lung adenocarcinoma, in which EGFR mutation assays detected L858R and pretreatment T790M from a tissue biopsy. In contrast, the circulating tumor DNA assay detected L858R, but not pretreatment T790M in the plasma, regardless of the fact that similar amounts of each mutation were present in the biopsy specimen. Treatment with afatinib was not effective, but subsequent treatment with osimertinib remarkably regressed the tumor. Our findings indicate that physicians should accurately evaluate EGFR‐tyrosine kinase inhibitor‐insensitive mutations using tissue samples in the first‐line setting, even when L858R and exon 19 deletions are detected in the plasma.

Pulmonary Artery Sarcoma Overexpressing Platelet-derived Growth Factor Receptor α

Pulmonary artery sarcoma is highly malignant and easily metastasizes to the systemic organs. Both the introduction of novel diagnostic procedures and the development of new treatment modalities are required to achieve long-term survival. Several studies have shown that platelet-derived growth factor receptor α (PDGFRα) gene amplification is frequently observed in pulmonary artery sarcoma. PDGFRα is known to be involved in cell proliferation in certain malignancies. PDGFRα may become a potential biological marker in pulmonary artery sarcoma. We report a case in which a diagnosis of pulmonary artery sarcoma overexpressing PDGFRα was made using endovascular catheter biopsy following positron emission tomography with integrated computed tomography (PET/CT) scans.

Acute exacerbation of airspace enlargement with fibrosis

In 2008, Kawabata et al. described a lesion which they termed “airspace enlargement with fibrosis” that could be included on the spectrum of smoking-related interstitial lung diseases. This group also reported that patients with airspace enlargement with fibrosis but without coexisting interstitial pneumonia of another type had no acute exacerbations and favorable prognoses on clinical follow-up. Here we describe the first case, to our knowledge, of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of another type. An 82-year-old man was referred to our department for worsening dyspnea and new alveolar opacities on chest radiograph following left pulmonary segmentectomy (S6) for cancer. A diagnosis of acute exacerbation of airspace enlargement with fibrosis without coexisting interstitial pneumonia of other types was made, based on pathological evidence of airspace enlargement with fibrosis and organizing diffuse alveolar damage. Treatment with high-dose methylprednisolone followed by tapered oral prednisolone resulted in gradual improvement of the clinical condition and chest radiographic findings. Clinicians should be aware that patients with airspace enlargement with fibrosis may experience acute exacerbation.

Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced, non-small cell lung cancer.

A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1-3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m2 was escalated in 5-mg/m2 increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m2. In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (α = 0.05 and β = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m2 and amrubicin 25 mg/m2 was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC.