Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy.

BACKGROUND: Platinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear. METHODS: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort. RESULTS: The LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell-inflamed gene expression profiles), and epithelial-mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TILHigh patients was significantly longer than that of TILLow patients (PFS: 7.3 months vs. 4.0 months, p < 0.001). CONCLUSION: Tumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy.

Herpes zoster in patients with lung cancer treated with PD-1/PD-L1 antibodies.

Background: There are no available clinical data on immunotherapy and the risk of herpes zoster. Materials & methods: This retrospective study included patients with recurrent or advanced lung cancer who were inoperable and ineligible for radiotherapy and were treated with either a PD-1/PD-L1 antibody (136 patients) or an EGFR tyrosine kinase inhibitor (149 patients) at Jichi Medical University Hospital between January 2016 and December 2018. Results: Herpes zoster-free survival was significantly shorter in the PD-1/PD-L1 antibody-treated group compared with the EGFR tyrosine kinase inhibitor-treated group (hazard ratio: 0.20; 95% CI: 0.048-0.84; p = 0.016). PD-1/PD-L1 antibody administration was independently and significantly associated with herpes zoster occurrence. Conclusion: Clinicians should anticipate herpes zoster in patients with lung cancer during treatment with PD-1/PD-L1 antibodies.

There are no available clinical data on immunotherapy and the risk of herpes zoster. This retrospective study included patients with recurrent or advanced lung cancer who were inoperable and ineligible for radiotherapy and were treated with either an immune checkpoint inhibitor (136 patients) or an EGFR tyrosine kinase inhibitor (149 patients) through the authors' university between January 2016 and December 2018. The herpes zoster-free period was significantly shorter in the immune checkpoint inhibitor-treated group compared with the EGFR tyrosine kinase inhibitor-treated group (hazard ratio: 0.20; 95% CI: 0.048­0.84; p = 0.016). Immune checkpoint inhibitor antibody administration was independently and significantly associated with herpes zoster occurrence. Clinicians should be cautious of herpes zoster in patients with lung cancer during treatment with immune checkpoint inhibitors.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor: A retrospective multicenter study of its real-world efficacy and safety in advanced/recurrent non-small cell lung carcinoma.

BACKGROUND: Osimertinib is recommended for T790M mutation-positive advanced non-small cell lung cancer (NSCLC) resistant to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real-world use of osimertinib; however, reports involving third/later-line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M-positive NSCLC patients. METHODS: This retrospective, observational, multicenter study included T790M-positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). PFS-associated clinical characteristics were evaluated using the Cox proportional hazards model. RESULTS: The objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second-line and third-/later-line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any-grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis. CONCLUSIONS: Osimertinib demonstrated efficacy even when administered as third-/later-line treatment to NSCLC patients. Osimertinib-related pneumonitis was observed more frequently than previously reported. KEY POINTS: Significant findings of the study Osimertinib shows efficacy even as later-line treatment in T790M mutation-positive NSCLC patients previously treated with EGFR-TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies. What this study adds Osimertinib was approved for previously EGFR-TKI-treated EGFR T790M-positive NSCLC. With the increasing frequency of its use as first-line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR-TKI-treated NSCLC.

Pazopanib Confers a Progression-free Survival in a Patient with Ewing's Sarcoma/Primitive Neuroectodermal Tumor of the Lung.

Ewing's sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are highly malignant neoplasms that usually affect the bones and soft tissues in children and young adults. ES/PNET of the lung is very rare and is associated with a poor prognosis. We herein report a case of ES/PNET of the left lung in a 45-year-old man. He was treated with neoadjuvant chemotherapy and pneumonectomy, but unfortunately his disease recurred 1.5 months after surgery. He was started on pazopanib, which resulted in a five-month progression-free survival. To our knowledge, this is the first demonstration of pazopanib efficacy in ES/PNET of the lung.

Giant solitary fibrous tumor of the pleura with high-grade sarcomatous overgrowth accompanied by lipid-rich, rhabdomyosarcomatous, and pleomorphic components: A case report.

RATIONALE: Solitary fibrous tumors are mesenchymal tumors presenting as fibroblastic neoplasms with prominent branching vascular patterns, which are often generated from the pleura. Most solitary fibrous tumors are benign; however, some can turn malignant. High-grade sarcomas from solitary fibrous tumors include multidirectional histopathological components. PATIENT CONCERNS: We describe our experience of a giant high-grade sarcoma with mixed components generated from a solitary fibrous tumor of the pleura in a 67-year-old female patient presenting with cough and left-sided chest pain. The patient had been diagnosed with a pleural mass in the left chest by X-ray about 30 years earlier. However, the tumor was allowed to grow, without surgical intervention, for a long time. INTERVENTIONS: Thoracic surgeons performed the removal of the giant pleural tumor; the tumor measured 18.0 × 14.5 × 10 cm in size, and was considered a giant tumor generated from the pleura of the left chest cavity. DIAGNOSES: The surgically removed tumor was solid and light brownish, and included myxoid and arabesque pattern lesions. The tumor also showed hemorrhagic and necrotic lesions. Moreover, spindle cells with less atypia, resembling fibroblasts, were noted. These spindle tumor cells were CD34- and Stat6-positive, suggesting a solitary fibrous tumor. Some of the spindle tumor cells were surrounded by thick collagenous fibers. Considering that the tumor originated from the parietal pleura, the tumor was defined as a solitary fibrous tumor in origin. The tumor also comprised high-grade sarcomatous components; these included lipid-rich, rhabdomyosarcomatous, and pleomorphic components. The high-grade sarcoma component included bizarre tumor cells with severe atypia. OUTCOMES: Tumor recurrence occurred in the left chest about 4 months after the surgery, and the patient died 8 months postoperatively. LESSONS: The present case clearly demonstrates that a solitary fibrous tumor can develop into high-grade sarcomatous overgrowth, including lipid-rich, rhabdomyosarcoma, and pleomorphic sarcoma components, if left untreated for a prolonged period. This case provides profound insights about the natural history, histogenesis, differentiation, and malignant transformation of solitary fibrous tumors.