pm-01183 and Mesothelioma

The SAKK 17/16 study showed promising efficacy data with lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma. Here, we evaluated long-term outcome and analyzed the impact of lurbinectedin monotherapy on the tumor microenvironment at the cellular and molecular level to predict outcomes.. Forty-two patients were treated with lurbinectedin in this single-arm study. Twenty-nine samples were available at baseline, and seven additional matched samples at day one of cycle two of treatment. Survival curves and rates between groups were compared using the log-rank test and Kaplan-Meier method. Statistical significance was set at P value <0.05.. Updated median overall survival (OS) was slightly increased to 11.5 months [95% confidence interval (CI) 8.8-13.8 months]. Thirty-six patients (85%) had died. The OS rate at 12 and 18 months was 47% (95% CI 32.1% to 61.6%) and 31% (95% CI 17.8% to 45.0%), respectively. Median progression-free survival was 4.1 months (95% CI 2.6-5.5 months). No new safety signals were observed. Patients with lower frequencies of regulatory T cells, as well as lower tumor-associated macrophages (TAMs) at baseline, had a better OS. Comparing matched biopsies, a decrease of M2 macrophages was observed in five out of seven patients after exposure to lurbinectedin, and two out of four patients showed increased CD8+ T-cell infiltrates in tumor.. Lurbinectedin continues to be active in patients with progressing malignant pleural mesothelioma. According to our very small sample size, we hypothesize that baseline TAMs and regulatory T cells are associated with survival. Lurbinectedin seems to inhibit conversion of TAMs to M2 phenotype in humans.

Topics: Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Palliative Care; Tumor Microenvironment

Lurbinectedin is a promising new drug being investigated in pre-treated patients with small cell lung cancer (SCLC) or malignant pleural mesothelioma (MPM). Its clinical activity in the real-world setting has not been investigated yet.. Clinical data of patients with SCLC and MPM who were treated with lurbinectedin were prospectively collected. Comprehensive immune cell profiling by flow cytometry was performed on screening and treating peripheral blood samples.. A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as ≥3-line of therapy. In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95% CI: 1.4-3.0), and median overall survival was 7.0 months (95% CI: 4.7-not reached). Objective radiological response and disease control rate after 12 weeks were 16% and 28%, respectively. In the MPM cohort, median progression-free survival was 2.8 months (95% CI: 1.4-4.2), and median overall survival was 7.2 months (95% CI: 5.9-not reached). Disease control rate after 12 weeks was 29%, whereas no partial responses were registered. No new safety signals were observed. Lurbinectedin treatment was significantly associated with the depletion of circulating classical monocytes, which correlated with a better PFS in patients with SCLC. Lurbinectedin increased the proliferation of CD4. Lurbinectedin has a manageable safety profile and shows clinical activity in pre-treated patients with SCLC and MPM. Its immune-modulatory functions make lurbinectedin a potential platform for immunotherapy combinations.

Topics: Carbolines; CD8-Positive T-Lymphocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Small Cell Lung Carcinoma

Malignant mesothelioma is an aggressive disease with dismal prognosis despite multimodal treatment including chemotherapy, surgery and radiotherapy. At progression it is possible to provide systemic second-line treatment but its effects are limited. Herein we report two patient cases with mesothelioma who received second-line chemotherapy with the combination of cisplatin and the novel compound lurbinectedin. The combination showed promising activity in both cases with manageable toxicity. We discuss the results of this regime in the light of historical as well as emerging data in mesothelioma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbolines; Cisplatin; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Palliative Care; Pleural Neoplasms; Prognosis