Lurbinectedin

Lurbinectedin: First Approval

Anthony Markham1 © Springer Nature Switzerland AG 2020

Abstract

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 regula- tory 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.

1 Introduction

Lurbinectedin (ZEPZELCA™) is an oncogenic transcrip- tion inhibitor being developed by PharmaMar as treatment for various solid tumours, including small cell lung cancer (SCLC) [1]. The drug covalently binds to the central guanine of various nucleotide triplets in the minor groove of DNA forming adducts that are capable of inducing double-strand breaks, with this DNA damage ultimately leading to apop- totic cell death [2]. It is also thought to induce immunogenic cell death (ICD) and stimulate anti-cancer immunity [3]. Lurbinectedin has also been associated with a significant reduction in tumour-associated macrophages (TAMs) and thus may also have a direct effect on the tumour microen- vironment [4]. Lurbinectedin has been granted orphan drug status for the treatment of SCLC by regulatory authorities in the USA [5], the EU [6] and Australia [7] and was recently approved in the USA (2 months ahead of the PDUFA date) [8] for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy [9]. The US FDA and inter- national regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative [10]. The recommended dose of lurbinectedin is 3.2 mg/m2 as a 1 h IV infusion once every 21 days until disease progression or unacceptable toxicity [9].

1.1 Company Agreements

In quarter three of financial year 2013 PharmaMar and Myriad Genetics entered into a commercial partnership agreement in which Myriad will conduct homologous recombination deficiency (HRD) testing in a phase II study of lurbinectedin. The test assessed the ability of tumours to
repair DNA damage and hence their susceptibility to DNA- damaging drugs [11, 12]. In May 2017 PharmaMar licenced the marketing rights for lurbinectedin to Specialised Therapeutics Asia for the treatment of various oncology indications, including SCLC, in Australia, New Zealand, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Papua New Guinea, Philip- pines, Singapore, Timor-Leste, Thailand and Vietnam [13].

2 Scientific Summary
2.1 Pharmacodynamics

Electrophoretic mobility shift assays showed that lur- binectedin bound to a naked 250 bp polymerase chain In November 2017, PharmaMar licensed lurbinectedin to Boryung Pharmaceutical for commercialisation in South Korea [14]. In April 2019 Luye Pharma Group entered into a licensing agreement with PharmaMar for development and commer- cialisation of lurbinectedin in China, Hong Kong and Macau [15]. In December 2019 PharmaMar agreed to exclusively license the rights to market lurbinectedin in the USA to Jazz Pharmaceuticals [16] and this agreement became effective January in 2020 upon expiry of the Hart–Scott–Rodino Anti- trust Improvements Act of 1976 (HSR) waiting period [17]. In April 2020, PharmaMar signed an agreement with Immedica Pharma AB for the exclusive distribution and marketing, if approved, of lurbinectedin for territories that include the UK, Ireland, the Nordic countries, some coun- tries within Eastern Europe, the Middle East and North Africa. PharmaMar will retain the rights to distribute and market the product in the rest of Europe [18]. In May 2020, PharmaMar signed a licensing agreement with Megapharm reaction product from the human adiponectin gene [2]. A related compound—ET-745—that lacks the carbinolamine (hemiaminal) group of lurbinectedin did not produce any band shifts, indicating that the DNA binding activity of lurbinectedin is dependent on the presence of this moi- ety. A fluorescence-based DNA melting assay revealed the preferred DNA triplets for lurbinectedin binding were adenine–guanine–cytosine (AGC), cytosine–guanine–gua- nine (CGG), adenine–guanine–guanine (AGG) and thy- mine–guanine–guanine (TGG), with the central guanine of each triplet being the site of covalent adduct forma- tion. Fluorescent microscopy of A549 cells treated with lurbinectedin 25 nmol/L for 6 h revealed the formation of g-H2AX foci (a surrogate indicator of double strand DNA breaks) with positive cells carrying multiple foci, indica- tive of several double strand breaks per cell. Exposure of A549 cells to lurbinectedin 150 nmol/L for 24 h induced apoptosis. This was associated with a marked increase in the levels of the apoptosis-related cytokeratin 18 Asp396 epitope, indicating the apoptotic activity of the drug is dependent on caspase activity [2].

In a further study, treatment of lung cancer (A549), Ewing sarcoma (A673), colon (HCT-116), cervix (HeLa), and breast (MDA-MB-231) cancer cell lines with lurbi- nectedin 30 nmol/L was associated with 80% inhibition of RNA synthesis after 2 h. Rapid, time-dependent dis- appearance of hypo-(IIa) and hyper-(IIo) phosphorylated forms of Rpb1 (indicative of degradation of Pol II) was observed in A549 whole cell extracts after treatment with lurbinectedin. Western blot analysis revealed that the car- boxy-terminal domain (CTD) of Rpb1 was phosphorylated indicating that lurbinectedin does not prevent phosphoryla- tion of Pol II, and pretreatment of A549 cells with DRB (an inhibitor of the CDK7 kinase subunit of TFIIH that phosphorylates serine 5 of the CTD of Pol II) prevented lurbinectedin-induced degradation of Rpb1. Further studies indicated that lurbinectedin-induced degradation of Pol II is dependent on the ubiquitin–proteasome system, that Pol II degradation is initiated in actively transcribing genes in the presence of lurbinectedin, and that Pol II degradation is involved in the formation of DNA breaks in cells treated with lurbinectedin [20]. Treatment of TC32 Ewing sarcoma cells with lurbinectedin 5 nmol/L was associated with redistribution of the oncogenic transcription factor EWS- FLI1 within the nucleus to the nucleolus. The drug was also shown to suppress expression of the EWS-FLI1 target gene NR0B1 in TC32, EW8, TC252 and A673 Ewing sar- coma cell lines, but not in control RH30 and RD cell lines, and induced NROB1 mRNA expression in control A2058, MCF7 and U2OS cells [21].

The apoptotic process induced by lurbinectedin is associated with a number of parameters that characterise ICD and with production of an anticancer immune response [3].In several cancer cell lines (human osteosarcoma U2OS; human breast cancer HCC70; human colon carcinoma HT29; and mouse fibrosarcoma MCA205), lurbinectedin (1 nmol/L to 1 μmol/L) evaluated at 4, 8, 16 and 32 h post exposure induced a dose- and time-dependent reduction in cellular viability similar to that of the positive con- trol (mitoxantrone 1 and 3 μmol/L) [3]. Compared with untreated controls, cells exposed to lurbinectedin or mitox- antrone, showed evidence of calcereticulin (CALR) trans- location (a surrogate marker for CALR surface exposure), ATP release (significant reduction in intracellular ATP), release of the non-histone binding protein high mobility group box 1 (HMGB1) and an significant increase in de novo GFP signal intensity (a surrogate for type I inter- feron production. Lurbinectedin activated a dose-depend- ent phosphorylation of the eukaryotic translation initiation factor 2 alfa (eIF2α) and inhibited mRNA transcription, parameters also characteristic of ICD inducers. When syngeneic immunocompetent mice previously injected with lurbinectedin-treated murine fibrosarcoma cells were rechallenged with an injection of live fibrosarcoma cells of the same type, tumour growth was significantly reduced and overall survival was increased. In addition, the anti- cancer effects of lurbinectedin were enhanced when admin- istered in combination with immune checkpoint inhibitors targeting CTLA-4 or PD-1in established mouse fibrosar- coma MCA205 tumours and in an induced hormone/car- cinogen breast cancer model known to be immune-system modulated [3].

Lurbinectedin significantly reduced the viability of human monocytes in vitro in a concentration-dependent manner and strongly activated caspase-8. In lipopolysaccha- ride (LPS)-stimulated monocytes, treatment with lurbinect- edin 5 nmol/L for 1 h was associated with strong inhibition of the chemokines CCL2 and CXCL8, and the angiogenic factor VEGF. In the human myxoid liposarcoma cell line
402.91 under the same experimental conditions lurbinect- edin strongly inhibited CCL2 but had less effect on CXCL8 than in LPS-stimulated cells [4].

In vitro, lurbinectedin had 50% growth inhibition (GI50) values between 0.3 and 9.7 nmol/L against a panel of 23 human tumour cell lines representing prostate, pancreas, ovarian, lung, liver, kidney, stomach, colon and breast can- cers, and leukaemia [2]. In SHP-77 SCLC cells, lurbinect- edin at GI50 was associated with down-regulation of ASCL1, a gene encoding a transcription factor required for the devel- opment of neuronal and pulmonary neuroendocrine cells that is increased in SCLC [22].

In vivo, IV lurbinectedin 0.18 mg·kg−1·day−1 significantly (p < 0.05) inhibited tumour growth compared to vehicle in murine xenograft models of lung (NCI-H460 cell line), ovarian (A2780 cell line), colon (HT29 cell line) and gastric (HGC-27 cell line) cancers [2]. Lurbinectedin was also associated with a significant reduction in the number of tumour-associated macrophages (TAMs) pre- sent in xenografted human pancreatic ductal adenocarci- noma tumours in mice compared to vehicle [16.6 and 82.8 TAMs per μm2 for SW-1990 and MIA PaCa-2 tumours, respectively, with vehicle vs 7.2 and 27.8 TAMs per μm2 with lurbinectedin (both p = 0.002)] [23]. In mice with the syngenic fibrosarcoma MN/MCA1 that were administered lurbinectedin at doses that did not completely halt tumour growth, significant and selective decreases the number of circulating monocytes were observed, in addition to signifi- cant reduction in the number of TAMs and tumour blood vessels. Similar findings were observed in mice with the lurbinectedin-resistant tumour variant RES-MN/ MCA1, suggesting a direct effect of lurbinectedin on the tumour microenvironment [4]. 2.2 Pharmacokinetics Lurbinectedin 3.2 mg/m2 produced geometric mean plasma Cmax and AUC∞ values of 107 μg/L and 551 μg·h/L, respec- tively, with no accumulation observed after repeated once- every-3-weeks administration. The drug had a steady state volume of distribution of 504 L and was ≈ 99% bound to plasma protein [9]. A population-pharmacokinetic and covariate anal- ysis based on data from 443 patients participating in six phase I and three phase II trials found an open three-compartment model with linear distribution and linear elimination from the central compartment most adequately described the pharmacokinetic profile of lur- binectedin in patients with advanced cancer. The popu- lation estimate for total plasma clearance was 11.2 L/h, and apparent volume at steady state was 438 L. Moderate inter-individual variability (20.9–51.2%) was observed for all parameters [24]. The total plasma clearance of lurbinectedin is 11 L/h (50%) with a t ½ of 51 h. 89% and 6% of radioactivity was recovered in faeces and urine, respectively (< 0.2 and 1% unchanged, respectively) after administration of a single radiolabelled dose of lurbinectedin [9]. In the population- pharmacokinetic study, high α-1-acid glycoprotein and C-reactive protein and low albumin were associated with reductions in clearance of 28%, 20%, and 20%, respectively [24]. Age (18–85 years), gender, body weight (39–154 kg), mild to moderate renal impairment (creatinine clearance 30–89 mL/min) or mild hepatic impairment had no clinically relevant effect on the pharmacokinetic profile of lurbinect- edin. However, the effects of severe renal impairment and moderate or severe hepatic impairment on the pharmacoki- netics of the drug have not been studied [9]. In the popula- tion-pharmacokinetic study co-administration of cytochrome P450 3A inhibitors was associated with a 30% reduction in clearance [24]. 2.3 Therapeutic Trials 2.3.1 SCLC Lurbinectedin demonstrated anti-tumour activity in patients with progressive SCLC who had received one previous plat- inum-based chemotherapy-containing line of treatment in a single-arm, open-label, phase II basket trial (NCT02454972) [25]. 105 patients were enrolled and treated with lurbinect- edin 3.2 mg/m2 administered as a 1 h IV infusion once every 3 weeks until disease progression or unacceptable toxicity. Results were analysed in the cohort overall and according to sensitivity to previous chemotherapy [chemotherapy- free interval < 90 days; considered chemotherapy resistant (n = 45) and chemotherapy-free interval ≥ 90 days; consid- ered chemotherapy sensitive (n = 60)]. After a median fol- low-up of 17.1 months the overall response rate was 35.2% (37 patients with partial response); there were no complete responses and 35 patients (33%) had stable disease. Among those patients with partial response 27 were considered chemotherapy sensitive and 10 were considered chemo- therapy resistant. The median duration of response was 5.3 months overall and was 6.2 and 4.7 months in patients considered chemotherapy-sensitive and chemotherapy-resist- ant, respectively. Progression-free survival was achieved by 90 (86%) patients overall and by 49 (82%) and 41 (91%) of those considered chemotherapy-sensitive and chemotherapy- resistant, respectively. Median progression-free survival duration was 3.5 months overall and 4.6 and 2.6 months, respectively, in patients considered chemotherapy-sensitive and chemotherapy-resistant, respectively. Among 39 of 105 patients alive at data cut-off median overall survival was 9.3 months in the overall group, 11.9 months in patients considered chemotherapy-sensitive and 5 months in those considered chemotherapy-resistant [25]. In an expansion cohort of a phase Ib trial, 27 patients with SCLC who had received ≤ 1 prior chemotherapy line were treated with lurbinectedin 2 mg/m2 plus doxorubicin 40 mg/m2 (reduced from the dose used in the primary phase of the study to improve safety). Doxorubicin was stopped after 10 cycles and patients continued with lurbinectedin alone. The confirmed objective response rate was 37%, with 4% of patients achieving complete response. In patients with a chemotherapy-free interval of ≥ 90 days (chemotherapy- sensitive) the overall response rate was 50% with 6% achiev- ing complete response. Overall median progression-free sur- vival was 3.4 months and was 1.9 months in patients with a chemotherapy-free interval of 30–89 days (chemotherapy- resistant) and 5.7 months in patients with a chemotherapy- free interval of ≥ 90 days [26]. 2.3.2 Breast Cancer Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations in a phase II trial in patients with meta- static breast cancer (NCT01525589). Patients were stratified according to germline BRCA1/2 status; those with BRCA1/2 mutations (n = 54) and those with BRCA1/2 wild-type or unknown status (n = 35), and treated with lurbinectedin at a fixed-flat dose of 7 mg IV once every 3 weeks, later modi- fied to 3.5 mg/m2 IV once every 3 weeks in patients with BRCA1/2 mutations. In patients with BRCA1/2 mutations the objective response rate was 41% comprising two com- plete and 20 partial responses. The modification in lurbi- nectedin dose from 7 to 3.5 mg/m2 did not affect efficacy. The median duration of response and progression-free sur- vival were 6.1 and 4.6 months, respectively. Median overall survival was 20 months (median 15.9 and 26.6 months in patients with BRCA1 and BRCA2 mutations, respectively). The BRCA1/2 wild-type or unknown status arm of the study was closed after futility analysis on the first 30 evaluable patients revealed insufficient objective responses to con- tinue. The objective response rate in 34 evaluable patients was 9% comprising three partial responses. The median duration of response and progression-free survival were 5 and 2.5 months, respectively. Median overall survival was 12.5 months [27]. 2.3.3 Malignant Pleural Mesothelioma Lurbinectedin had promising activity in patients with pro- gressive malignant pleural mesothelioma in a phase II study (NCT03213301). Forty two patients who had previ- ously been treated with platinum-pemetrexed chemotherapy with or without immunotherapy were given lurbinectedin 3.2 mg/m2 IV once every three weeks until disease progression or unacceptable toxicity. Progression-free survival at 12 weeks was observed in 22 patients (52.4%, p = 0.015). Median progression free survival was 4.1 months after a median 15.8 months’ follow up. Median overall survival was 11.1 months with a duration of disease control of 6.6 months [28]. 2.3.4 Sarcomas Lurbinectedin in combination with doxorubicin demon- strated potential as a treatment for metastatic soft tissue sarcomas in a phase II study (NCT02448537). Forty two patients, most with leiomyosarcoma (n = 20), were allocated to one of three treatment groups according to treatment history; lurbinectedin 2 mg/m2 plus doxorubicin 50 mg/m2 on day one of a 21 day cycle in anthracycline-naïve patients (group A, n = 20), lurbinectedin 1.6 mg/m2 plus gemcit- abine 800 mg/m2 on day 8 of a 21 day cycle in patients previously treated with anthracycline (group B, n = 10); and lurbinectedin 3.2 mg/m2 alone on day one of a 21 day cycle in patients previously treated with anthracycline or gemcit- abine (group C, n = 12). After 24 weeks’ treatment 7 patients in group A had partial response and one had stable disease. In group B, one patient had a partial response and one had stable disease. No patients in group C responded and one patient had unconfirmed stable disease. The disease control rate (patients with complete or partial response, or stable disease) at 24 weeks was 23.8% overall; 40% in group A, 20% in group B and 0% in group C. Median progression-free survival was 4.2, 1.7 and 1.3 months in groups A, B and C, respectively [29]. The phase II basket trial described above (NCT02454972) enrolled 28 evaluable patients with relapsed Ewing sarcoma who received four (median) cycles of lurbinectedin. Partial response was observed in four patients and 12 had stable dis- ease. The median duration of response and progression-free survival were 2.9 and 2.8 months respectively [30]. 2.3.5 Ovarian Cancer In the phase III CORAIL study (NCT02421588) compar- ing lurbinectedin with pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian can- cer there was no significant difference between treatment groups in terms of median progression-free survival, over- all survival and, objective response rate. Patients were ran- domized to treatment with lurbinectedin 3.2 mg/m2 once every 3 weeks (n = 221) or investigator’s choice of either pegylated liposomal doxorubicin 50 mg/m2 once every 4 weeks or topotecan 1.5 mg/m2/day on days one to 5 once every three weeks (n = 221) until progression or discontinu- ation because of toxicity. Median progression-free survival assessed by independent review committee was 3.5 months in the lurbinectedin group compared to 3.6 months in the control group. The objective response rate assessed by inde- pendent review was 14.0 and 12.2% in the lurbinectedin and control groups, respectively. Interim overall survival was 11.2 and 11.1 months, respectively [31]. Lurbinectedin demonstrated activity against platinum resistant/refractory ovarian cancer in a two-stage controlled phase II trial. Twenty two patients were enrolled in the exploratory first stage of the study and received lurbinect- edin at a fixed-flat dose of 7 mg once every three weeks. In the second stage of the study patients were randomized to lurbinectedin, using the same regimen as the first stage, (n = 30) or topotecan 4.0–2.4 mg/m2 on days one, 8 and 15 of a 4 week cycle (n = 29) or 1.5–0.75 mg/m2 on days one to 5 of a 3 week cycle (n = 8). Seven patients in the first stage and 5 in the second responded to treatment with lur- binectedin including one complete and 11 partial responses (overall response rate 23%), compared to none in the topote- can group. The median duration of response and progres- sion free survival were 4.6 and 4.0 months, respectively, in patients treated with lurbinectedin across the two arms of the study. Median progression free survival in the second stage of the trial was 3.9 months in the lurbinectedin group vs. 2.0 months in the topotecan group (p = 0.0067). Median overall survival was 9.7 vs. 8.5 months [32]. 2.3.6 Gynaecological Tumours The phase II basket trial described above (NCT02454972) enrolled 56 patients with endometrial carcinoma who had received at least one prior chemotherapy line. The overall response rate was 12.5% comprising one complete response (1.8%) and 6 partial responses (10.7%). Twenty three patients (41%) had stable disease [33]. Lurbinectedin in combination with olaparib demonstrated efficacy in a phase I/II trial in patients with advanced gynae- cological tumours (NCT02684318). Sixty three patients with relapsed high-grade serious or endometroid platinum resist- ant ovarian (not refractory), fallopian tube or primary peri- toneal cancer, endometrial cancer or triple negative breast cancer were treated with lurbinectedin 1.5 mg/m2 IV on day one plus oral olaparib 250 mg twice daily on days one to 5 in 21 day cycles. The best response at 12 weeks included one complete and three partial responses and 40 patients with stable disease. The clinical benefit rate (complete plus partial response plus stable disease) was 69.8% overall and 71.05% in patients with ovarian cancer [34]. 2.3.7 Solid Tumours A combination of lurbinectedin and irinotecan had anti- tumour efficacy in patients with SCLC and endometrial carcinoma in a phase Ib/II trial in patients with advanced solid tumours (NCT02611024). Patients with SCLC (n = 13), endometrial cancer (n = 10), soft tissue sarcoma (n = 9) or glioblastoma (n = 13) were treated with escalat- ing doses of lurbinectedin starting at 1 mg/m2 on day one plus a fixed dose of irinotecan 75 mg/m2 on days 1 and 8 once every three weeks plus granulocyte colony stimulat- ing factor (G-CSF) in patients experiencing dose-limiting neutropenia. The overall response rate was 61.5, 30, 0 and 0%, in SCLC, endometrial cancer, soft tissue sarcoma and glioblastoma, respectively, with the recommended dose of lurbinectedin in this regimen established as 2.0 mg/m2 (in conjunction with irinotecan 75 mg/m2 on days 1 and 8 once every 3 weeks + G-CSF), and with most responses observed in patients receiving this dosage. The maximum tolerated dose of lurbinectedin was 2.4 mg/m2 combined with irinote- can 75 mg/m2 and G-CSF [35, 36]. 2.4 Adverse Events Adverse reactions (all grades) with an incidence of ≥ 10%, occurring in patients with SCLC treated with lurbinectedin in the phase II basket trial (NCT02454972) described above [25] (n = 105) included fatigue (77%), pyrexia (13%), chest pain (10%), nausea (37%), constipation (31%), vomiting (22%), diarrhoea (20%), abdominal pain (11%), musculo- skeletal pain (33%), decreased appetite (33%), dyspnoea (31%), cough, (20%), respiratory tract infection (18%), pneu- monia (10%), peripheral neuropathy (11%) and headache (10%). Grade 3 to 4 adverse events included fatigue (12%), diarrhoea (4%), abdominal pain (1%), musculoskeletal pain (4%), decreased appetite (1%), dyspnoea (6%), respiratory tract infection (5%), pneumonia (7%), peripheral neuropathy (1%) and headache (1%). Laboratory abnormalities (≥ 20% change from base- line, all grades) included decreased leukocyte levels (79%), decreased lymphocyte levels (79%), decreased haemo- globin levels (74%), decreased neutrophil levels (71%), decreased platelet levels (37%) increased creatinine levels (69%), increased alanine aminotransferase levels (66%), increased glucose levels (52%), decreased albumin levels (32%), decreased sodium levels (31%), increased aspartate aminotransferase levels (26%) and decreased magnesium levels (22%). Grade 3–4 laboratory abnormalities included decreased leukocyte levels (29%), decreased lympho- cyte levels (43%), decreased haemoglobin levels (10%), decreased neutrophil levels (46%), decreased platelet lev- els (7%), increased alanine aminotransferase levels (4%), increased glucose levels (5%), decreased albumin levels (1%), decreased sodium levels (7%) and increased aspartate aminotransferase levels (2%) [9]. Serious adverse reactions occurred in 34% of patients treated with lurbinectedin. Those occurring in ≥ 3% of patients included pneumonia, febrile neutropenia, neutro- penia, respiratory tract infection, anaemia, dyspnoea, and thrombocytopenia. Two patients (1.9%) permanently dis- continued treatment because of adverse events (peripheral neuropathy and myelosuppression) and 30.5% required dose interruptions because of adverse events, with those occur- ring in ≥ 3% of patients including neutropenia and hypoal- buminemia. Adverse reactions requiring dosage reductions occurred in 25% of patients, with those occurring in ≥ 3% of patients including neutropenia, febrile neutropenia and fatigue [9]. 2.5 Ongoing Clinical Trials Completion of the phase II basket trial described above (NCT02454972) is expected in early 2021 and the phase III ATLANTIS (NCT02566993) trial evaluating the activ- ity of lurbinectedin in combination with doxorubicin as second-line therapy for SCLC is ongoing. A phase I/ II study of lurbinectedin plus atezolizumab in advanced SCLC (NCT04253145) is underway. Other ongoing studies include a phase II trial of lurbinectedin in advanced malig- nant pleural mesothelioma (NCT03213301), a phase II trial of lurbinectedin alone or in combination with chemotherapy metastatic/unresectable sarcoma (NCT02448537) and a phase I/II trial of lurbinectedin plus irinotecan in advanced solid tumours (NCT02611024). The phase I/II LUPER trial (NCT04358237) will evaluate the activity of lurbinectedin combined with pembrolizumab in SCLC. 3 Current Status Lurbinectedin received its first approval on 15 June 2020 in the USA for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy [8]. Acknowledgements During the peer review process, the manufacturer of lurbinectedin was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit. Declarations Authorship and Conflict of interest A. Markham is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content. Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability Not applicable. References 1. PharmaMar. Oncology pipeline. 2020. https://pharmamar.com/ science-and-innovation/oncology-pipeline/?lang=en. Accessed 6 Jul 2020. 2. Leal JF, Martínez-Díez M, García-Hernández V, et al. PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol. 2010;161(5):1099–110. 3. Xie W, Forveille S, Iribarren K, et al. Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immu- nity. Oncoimmunology. 2019;8(11):e1656502. 4. Belgiovine C, Bello E, Liguori M, et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017;117(5):628–38. 5. PharmaMar. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PharmaMar’s lurbinectedin [media release]. 3 Aug 2018. https://www.pharmamar.com. 6. PharmaMar. PharmaMar receives positive opinion from EMA (COMP) for orphan drug designation of Zepsyre(R)(lurbinect- edin) for small-cell lung cancer [media release]. 24 Jan 2019. https ://www.pharmamar.com. 7. PharmaMar. Lurbinectedin receives orphan drug designation from the TGA for small-cell lung cancer in Australia [media release]. 19 Feb 2020. https://www.pharmamar.com. 8. US Food & Drug Administration. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer [media release]. https://www.fda.gov/drugs/drug-approvals-and- databases/fda-grants-accelerated-approval-lurbinectedin-metas tatic-small-cell-lung-cancer. Accessed 15 Jun 2020. 9. PharmaMar. ZEPZELCA® (lurbinectedin): US prescribing infor- mation. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2020/213702s000lbl.pdf. Accessed 1 Jul 2020. 10. Specialised Therapeutics Asia. New small cell lung cancer drug accepted for TGA evaluation under Project Orbis [media release]. 3 Jun 2020. https://www.stbiopharma.com. 11. Myriad Genetics Inc. Myriad Genetics reports third quarter fiscal year 2013 results [media release]. 7 May 2013. https://www.myria d.com. 12. Myriad Genetics Inc. Myriad and PharmaMar announce first com- mercial partnership with Myriad’s new HRD test [media release]. 26 Mar 2013. https://www.myriad.com. 13. PharmaMar. PharmaMar and Specialised Therapeutics Asia sign licensing and marketing agreement for lurbinectedin cover- ing Australia, New Zealand and several Asian countries [media release]. 18 May 2017. https://www.pharmamar.com. 14. PharmaMar. PharmaMar and Boryung Pharm sign a licensing agreement for Zepsyre® (lurbinectedin) in Korea [media release]. 7 Nov 2017. https://www.pharmamar.com. 15. PharmaMar. PharmaMar and Luye Pharma sign license agreement for development and commercialization of lurbinectedin in China territories [media release]. 26 Apr 2019. https://www.pharmamar. com. 16. PharmaMar. PharmaMar and Jazz Pharmaceuticals sign exclusive license agreement for lurbinectedin in the U.S. [media release]. 19 Dec 2019. https://www.pharmamar.com. 17. PharmaMar. PharmaMar and Jazz Pharmaceuticals announce the U.S. License agreement for lurbinectedin is effective with the expiration of the HSR waiting period [media release]. 22 Jan 2020. https://www.pharmamar.com. 18. PharmaMar. PharmaMar signs an agreement with Immedica Pharma to market lurbinectedin in Eastern Europe, the UK, Ire- land, the Nordic countries and some Middle Eastern countries [media release]. 29 Apr 2020. https://www.pharmamar.com. 19. PharmaMar. PharmaMar and Megapharm sign a licensing agree- ment for lurbinectedin in Israel [media release]. 11 May 2020. https://www.pharmamar.com. 20. Santamaria Nunez G, Robles CM, Giraudon C, et al. Lurbinect- edin specifically triggers the degradation of phosphorylated rna polymerase II and the formation of DNA breaks in cancer cells. Mol Cancer Ther. 2016;15(10):2399–412. 21. Harlow ML, Maloney N, Roland J, et al. Lurbinectedin inactivates the Ewing sarcoma oncoprotein EWS-FLI1 by redistributing it within the nucleus. Cancer Res. 2016;76(22):6657–68. 22. Mannarino L, Craparotta I, Mirimao F, et al. Lurbinectedin down- regulates ASCL1 transcription factor in small cell lung cancer (SCLC) [abstract no. LB-B13]. Mol Cancer Ther. 2019;18(12 Suppl). 23. Céspedes MV, Guillén MJ, López-Casas PP, et al. Lurbinect- edin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech. 2016;9(12):1461–71. 24. Fernandez-Teruel C, Gonzalez I, Trocóniz IF, et al. Popula- tion-pharmacokinetic and covariate analysis of lurbinectedin (PM01183), a new RNA polymerase II inhibitor, in pooled phase I/II trials in patients with cancer. Clin Pharmacokinet. 2019;58(3):363–74. 25. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second- line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645–54. 26. Forster M, Moreno V, Calvo E, et al. Overall survival with lur- binectedin plus doxorubicin in relapsed SCLC: results from an expansion cohort of a phase Ib trial [abstract no. P1.12-20 + poster]. J Thorac Oncol. 2018;13(10 Suppl):S581. 27. Cruz C, Llop-Guevara A, Garber JE, et al. Multicenter phase II study of lurbinectedin in BRCA-mutated and unselected meta- static advanced breast cancer and biomarker assessment substudy. J Clin Oncol. 2018;36(31):3134–43. 28. Metaxas Y, Fruh M, Eboulet EI, et al. Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16). Ann Oncol. 2020;31(4):495–500. 29. Cote GM, Choy E, Chen T, et al. A phase II multi-strata study of lurbinectedin as a single agent or in combination with conven- tional chemotherapy in metastatic and/or unresectable sarcomas. Eur J Cancer. 2020;126:21–322. 30. Subbiah V, Sankhala KK, Ratan R, et al. Efficacy and safety of lur- binectedin (PM1183) in Ewing sarcoma: final results from a phase 2 study [abstract no. 11519]. J Clin Oncol. 2018;36(15 Suppl 1). 31. Gaillard S, Oaknin A, Ray-Coquard IL, et al. Phase III trial of lur- binectedin versus PLD or topotecan in platinum-resistant ovarian cancer patients: results of CORAIL trial [abstract no. 9320]. Ann Oncol. 2018;29(Suppl 8):viii332. 32. Poveda A, Del Campo JM, Ray-Coquard I, et al. Phase II rand- omized study of PM01183 versus topotecan in patients with plat- inum-resistant/refractory advanced ovarian cancer. Ann Oncol. 2017;28(6):1280–7. 33. Forster MD, Moreno V, Boni V, et al. Activity of lurbinectedin (PM01183) as single agent and in combination in patients with endometrial cancer [abstract no. 5586]. J Clin Oncol. 2017;35(15 Suppl 1). 34. Andres P, Ana O, Andres R, et al. Phase II study to evaluate the efficacy, tolerability, and biomarkers of PM01183 with olaparib in patients with advanced gynecological tumors [abstract no.]. Int J Gynecol Cancer. 2018;28(Suppl 2):626. 35. Ponce Aix S, Cote GM, Gonzalez AF, et al. Lurbinectedin (LUR) in combination with irinotecan (IRI) in patients (pts) with advanced solid tumors: updated results from a phase Ib-II trial [abstract no. 3514]. J Clin Oncol. 2020;38(15 Suppl):3514. 36. Ponce Aix S, Flor MJ, Falcon A, et al. Lurbinectedin (LUR) in combination with irinotecan (IRI) in patients (pts) with advanced solid tumours [abstract no. 471P]. Ann Oncol. 2019;30(Suppl 5):v178.