pm-01183 and Lung-Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbolines; Humans; Lung Neoplasms; Platinum; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma; Topotecan

Lurbinectedin was approved on June 15, 2020 by the Food and Drug Administration with the brand name ZEPZELCA as the first systematic approved therapy for patients having Small Cell Lung Cancer (SCLC).. In this review, an attempt is made to summarize different aspects of Lurbinectedin, including the pathophysiology, chemistry, chemical synthesis, mechanism of action, adverse reactions, and pharmacokinetics. Special attention is given to various reported clinical trials of lurbinectedin.. A comprehensive literature search was conducted in the relevant databases like ScienceDirect, PubMed, ResearchGate and Google Scholar to identify studies. After a thorough study of these reports, significant findings/data were collected and compiled under suitable headings. Important findings related to clinical trials have been tabulated.. Lurbinectedin is known to act by inhibiting the active transcription of encoding genes, thereby suppressing tumor-related macrophages with an impact on tumour atmosphere. Lurbinectedin has emerged as a potential drug candidate for the treatment of Small-Cell Lung Cancer (SCLC).

Topics: Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Small Cell Lung Carcinoma

Lurbinectedin is a marine-derived drug that inhibits transcription, a process that is frequently dysregulated in small cell lung cancer. The activity of lurbinectedin has been studied in many solid tumors, showing not only promising results but also a favorable safety profile. In relapsed small cell lung cancer, the drug has shown encouraging activity both as a single agent and in combination with doxorubicin, paclitaxel or irinotecan. The USA FDA has recently granted accelerated approval to lurbinectedin monotherapy in this setting. This article provides an update on available data and ongoing studies of lurbinectedin in small cell lung cancer, including Phase I combination trials, the basket Phase II trial and the ATLANTIS Phase III trial.. Lay abstract Lung cancer is currently responsible for a large number of cancer deaths worldwide. Small cell lung cancer (SCLC) is considered the most aggressive subtype of lung cancer. When a patient presents with extensive SCLC, first-line treatment needs to be used. The most appropriate treatment option for the patient is selected; however, it is possible for the cancer to continue to get worse, even over a brief period of time. The patient will then be given another treatment; however, studies on the effectiveness of classical second-line drugs are scarce. For this reason, new therapies for SCLC are in development. One of these treatments is a marine-derived drug called lurbinectedin, which shows promising activity in some solid tumors, such as extensive SCLC, after failure of first-line treatment. Here the authors present the results of the main trials related to the activity of lurbinectedin either alone or in combination with other drugs for this type of cancer.

Topics: Carbolines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Prognosis; Small Cell Lung Carcinoma

Small cell lung cancer (SCLC) is a rapidly progressive, aggressive metastatic and lethal subtype of lung cancer. Unfortunately, there has been little progress regarding the development of novel treatments for SCLC. However, lurbinectedin, a transcriptional inhibitor, has emerged as a potential novel treatment for cancer. It produces antitumor efficacy by inhibiting oncogenic transcription activity, inducing the accumulation of DNA double-strand breaks and modulating the tumor microenvironment (TME). Data from phase I/II trials indicates that lurbinectedin has significant antitumor efficacy and tolerable adverse effects in SCLC patients. Furthermore, lurbinectedin is efficacious in platinum-sensitive and platinum-resistant SCLC patients and in those with SCLC relapse after second-line treatment. In 2020, the U.S. Food and Drug Administration (FDA) approved lurbinectedin for the treatment of adult patients with metastatic SCLC or for patients that have received platinum-based chemotherapy. In this review, we discuss the molecular profile and the preclinical and clinical studies of lurbinectedin in the treatment of SCLC patients.

Topics: Adult; Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Tumor Microenvironment

The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.

Topics: Adult; Australia; Carbolines; Clinical Trials as Topic; Disease Progression; Drug Administration Schedule; Drug Approval; Drug Development; Heterocyclic Compounds, 4 or More Rings; History, 21st Century; Humans; Infusions, Intravenous; Lung Neoplasms; Orphan Drug Production; Small Cell Lung Carcinoma; United States; United States Food and Drug Administration

SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints. Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy. This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

Topics: Aurora Kinases; Azepines; Benzimidazoles; Carbolines; Cell Cycle Checkpoints; Cell Proliferation; Cytotoxins; DNA Damage; DNA Repair; Etoposide; Genomic Instability; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Molecular Targeted Therapy; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Pyrimidines; Rad51 Recombinase; Small Cell Lung Carcinoma

Based on findings from a single-arm, phase 2 basket trial (NCT02454972), lurbinectedin may be an effective treatment for individuals with small cell lung cancer (SCLC) who progressed on or after platinum-based chemotherapy.. To estimate the comparative effectiveness of lurbinectedin versus the historical standard of care for relapsed SCLC in Canada.. A synthetic control arm (SCA) analysis was conducted using real-world data. Population-level data were obtained from real-world databases in Alberta, Canada. Individuals diagnosed with SCLC who initiated post-platinum systemic therapy and met approximated eligibility criteria from the lurbinectedin trial were included in the SCA. Median overall survival (OS) in the SCA was estimated after adjusting for chemotherapy-free interval (CTFI; < 90 versus ≥ 90 days) and stage at initial diagnosis (extensive versus limited). The CTFI-adjusted hazard ratio was estimated using a Cox proportional hazards model.. One hundred seventy-four individuals were included in the SCA and 105 in the lurbinectedin trial. The adjusted median OS in the SCA was 6.1 months (95% CI 5.4-7.7 months; unadjusted: 6.7 months, 95% CI 6.0-7.7 months) versus 9.3 months (95% CI 6.3-11.8 months) in the lurbinectedin trial. The adjusted hazard ratio comparing lurbinectedin with the historical standard of care (referent group) was 0.61 (95% CI 0.45-0.82; unadjusted HR: 0.72; 95% CI 0.54-0.97). The hazard ratio was more pronounced among individuals with CTFI ≥ 90 days (HR: 0.49, 95% CI 0.33-0.73).. These findings suggest improved OS with lurbinectedin monotherapy versus the historical standard of care in Alberta, Canada.

Topics: Canada; Carbolines; Humans; Lung Neoplasms; Small Cell Lung Carcinoma

The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m. Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1.. ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported.. Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma

Lurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).. Patients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days).. Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease.. Doxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carbolines; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Doxorubicin; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local

Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients, and the overall survival (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response.. We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and Western blot analysis.. Lurbinectedin markedly reduced cell viability in the majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial-mesenchymal transition, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo, and transformed SCLC models.. Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.

Topics: Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Signal Transduction; Small Cell Lung Carcinoma

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Topics: Ataxia Telangiectasia Mutated Proteins; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma

Lurbinectedin was approved by FDA and other health regulatory agencies for treating adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Safety profile at approved dose (3.2 mg/m. Data were pooled from 554 patients: 335 from all nine tumour-specific cohorts of the phase II basket trial and 219 from a randomised phase III trial (CORAIL) in platinum-resistant ovarian cancer. Events and laboratory abnormalities were graded using NCI-CTCAE v.4.. Most common tumours were ovarian (n = 219, 40%), SCLC (n = 105, 19%) and endometrial (n = 73, 13%). Transient haematological laboratory abnormalities were the most frequent grade 3 or more events: neutropenia (41%), leukopenia (30%), anaemia (17%) and thrombocytopenia (10%). Most common treatment-emergent non-haematological events (any grade) were transient transaminase increases (alanine aminotransferase [66%], aspartate aminotransferase [53%]), fatigue (63%), nausea (57%), constipation (32%), vomiting (30%) and decreased appetite (25%). Dose reductions were mostly due to haematological toxicities, but most patients (79%) remained on full lurbinectedin dose. Serious events mostly consisted of haematological disorders. Eighteen treatment discontinuations (3%) and seven deaths (1%) were due to treatment-related events.. This analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.

Topics: Adult; BRCA1 Protein; BRCA2 Protein; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Neutropenia; Ovarian Neoplasms; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma

Lurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients.. A retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events.. Lurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported.. This real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.

Topics: Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Retrospective Studies; Small Cell Lung Carcinoma

Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rats, nonhuman primates (NHP), and humans was determined as 23.4%, 29.8%, and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, and human), albumin, and

Topics: Animals; Carbolines; Feces; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Rats; Small Cell Lung Carcinoma

Small-Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2, INSM1, MYC, and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles's heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor.

Topics: Basic Helix-Loop-Helix Transcription Factors; Carbolines; Cell Line, Tumor; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Promoter Regions, Genetic; Repressor Proteins; Small Cell Lung Carcinoma

Small cell lung cancer (SCLC) is a progressive disease with a poor prognosis. Recently, a method to classify SCLC by the expression status of four transcription factors, ASCL1, NEUROD1, POU2F3, and YAP1, was proposed. Here, we investigated the potential relationships between expression of these four transcription factors and the effect of lurbinectedin.. mRNA and protein expression of ASCL1, NEUROD1, POU2F3, and YAP1 were quantified in eight SCLC cell lines and analyzed for potential correlations with drug sensitivity. In addition, ASCL1, NEUROD1, POU2F3, and YAP1 expression were evaluated in 105 resected cases of high-grade neuroendocrine carcinoma of the lung, including 59 resected cases of SCLC.. Based on the results of qRT-PCR and western blot analyses, the eight SCLC cell lines examined were classified into NEUROD1, POU2F3, and YAP1 subtypes, as well as five ASCL1 subtypes. There were no correlations between cell line subtype classification and drug sensitivity to cisplatin, etoposide, or lurbinectedin. Next, we compared relative mRNA expression levels of each transcription factor with drug sensitivity and found that the higher the mRNA expression level of POU2F3, the lower the IC. In our experiments, high mRNA expression of POU2F3 in SCLC cell lines correlated with the effect of lurbinectedin.

Topics: Carbolines; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Octamer Transcription Factors; RNA, Messenger; Small Cell Lung Carcinoma; Transcription Factors

Lurbinectedin is an alkylating agent approved for the second-line treatment of small cell lung cancer. Although initial studies showed no association between body surface area (BSA) and drug clearance, the recommended dose is 3.2 mg/m

Topics: Anemia; Body Surface Area; Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Thrombocytopenia

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

Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined.. To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy.. We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m. Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia.. Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbolines; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Neutropenia; Retrospective Studies; Small Cell Lung Carcinoma

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

Topics: Databases, Factual; Humans; Lung Neoplasms; Rhabdomyolysis; Tumor Lysis Syndrome; United States; United States Food and Drug Administration

Topics: Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms

In the ATLANTIS study, second-line lurbinectedin/doxorubicin did not improve overall survival (OS), however patients with a chemotherapy-free interval (CTFI) of ≥180 days had an improved progression free survival (PFS). The objective of this retrospective study was to identify the proportion of real-world small cell lung cancer (SCLC) patients who are suitable for lurbinectedin-based therapy based on these criteria.. A retrospective study of all SCLC referred to BC Cancer between 2012 and 2017 was conducted. Patient demographics, staging, treatment, and survival data were collected retrospectively. Baseline characteristics were compared using descriptive statistics. OS was calculated using Kaplan-Meier curves. Statistically significant. A total of 1048 patients were identified. Baseline characteristics: median age 68 years, 47% male, 61% current smoking status, 68% extensive disease. Best supportive care was received by 22%. First-line systemic therapy was platinum doublet for 71% of the population. Second-line systemic therapy was delivered to 22%. Of the 219 patients who received second-line systemic therapy after platinum doublet, 183 patients had a CTFI of ≥90 days and 107 patients had a CTFI of ≥180 days. Patients originally treated as limited stage disease, received platinum doublet as second line, received thoracic radiation (RT) or prophylactic cranial irradiation (PCI) were more likely to have a CTFI of ≥90 and ≥180 days.. In our real-world SCLC population, only 21% of the SCLC population received second-line therapy after platinum doublet with 17% achieving CTFI of ≥90 days and 10% CTFI of ≥180 days. Based on this retrospective review, only a small fraction of platinum-treated patients would be preferentially offered lurbinectedin in the second-line setting.

Topics: Aged; Female; Humans; Lung Neoplasms; Male; Patient Acceptance of Health Care; Platinum; Retrospective Studies; Small Cell Lung Carcinoma

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26-45], with a median DOR of 5.3 (95% CI: 4.1-6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbolines; Combined Modality Therapy; Disease Management; Drug Approval; Drug Evaluation, Preclinical; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Retreatment; Small Cell Lung Carcinoma; Treatment Outcome; United States; United States Food and Drug Administration

To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC).. PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms. English-language clinical trials of lurbinectedin were evaluated.. Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin.. Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration.. With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Neoplasm Recurrence, Local

BACKGROUND Lurbinectedin (Lurbi) was first approved in June 2020 for metastatic small cell lung cancer (SCLC) patients with progression following platinum-based chemotherapy. Extrapulmonary small cell neuroendocrine cancers (SCNECs) are treated with regimens used for SCLCs. Tumor lysis syndrome (TLS) in solid SCLCs and SCNECs following Lurbi use has not been reported in the literature so far. CASE REPORT We report a case of Lurbi-induced TLS in a patient with metastatic SCNEC of the cecum following a single intravenous dose of Lurbi 3.2 mg/m2. She presented to the hospital with abdominal pain, anuria, and grade 4 TLS. She required emergent hemodialysis due to acute renal failure. Our patient had a high Ki-67 proliferation index (95%), harbored a huge disease burden, and had bilateral renal metastasis, thus making her more susceptible to develop TLS. CONCLUSIONS Although data regarding the occurrence of TLS due to Lurbi in solid tumors are scarce, it remains a potential complication of Lurbi in neuroendocrine tumors with high proliferation index and large tumor burden.

Topics: Carbolines; Carcinoma, Neuroendocrine; Cecum; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Tumor Lysis Syndrome

Topics: Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma

Lurbinectedin is a DNA-binding inhibitor of transcription that potently induces immunogenic cell death (ICD). In June 2020, the Federal Drug Administration (FDA) approved lurbinectedin for the salvage treatment of small-cell lung cancer that has relapsed from platinum compound-based first-line chemotherapy. Thus, the clinical activity of lurbinectedin may originate, at least in part, from the induction of ICD.

Topics: Carbolines; Heterocyclic Compounds, 4 or More Rings; Humans; Immunogenic Cell Death; Lung Neoplasms; Small Cell Lung Carcinoma

Topics: Antineoplastic Agents; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Labeling; Heterocyclic Compounds, 4 or More Rings; Humans; Infusions, Intravenous; Lung Neoplasms; Small Cell Lung Carcinoma

Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify lurbinectedin in human plasma and urine. Plasma samples were pre-treated with 1 M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns. Lurbinectedin was eluted from the columns using tert-butyl methyl ether (TBME). Urine was first diluted in plasma and lurbinectedin was extracted from this matrix by liquid-liquid extraction using TBME. Samples were measured by LC-MS/MS in the positive electron ion spray mode. The method was linear over 0.1-100 ng/mL and 1-1000 ng/mL in plasma and urine, respectively, with accuracies and precisions within ±15% (20% for LLOQ) and below 15% (20% for LLOQ), respectively. The method was developed to support a mass balance study in which patients received a dose of 5 mg lurbinectedin.

Topics: Antineoplastic Agents; Carbolines; Chromatography, High Pressure Liquid; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 4 or More Rings; Humans; Limit of Detection; Liquid-Liquid Extraction; Lung Neoplasms; Reproducibility of Results; RNA Polymerase II; Sensitivity and Specificity; Small Cell Lung Carcinoma; Tandem Mass Spectrometry; Time Factors

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