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Introduction: Platinum rechallenge is recommended for patients with small cell lung cancer (SCLC) who relapse ≥90 days after completing first-line chemotherapy, although it may not always be the most suitable option., Areas Covered: Articles for review were identified via PubMed and ClinicalTrials.gov searches, supplemented with non-indexed publications (e.g. conference abstracts) known to the manufacturer. We examined evidence for platinum re-exposure in patients with sensitive relapsed SCLC, and present lurbinectedin as a potential alternative. The complementary mechanisms of action of lurbinectedin and platinum, owing to opposite sensitivity of SCLC cells, may resensitize tumor cells to platinum. As efficacy outcomes with lurbinectedin are equivalent or better than those with platinum rechallenge and its hematological safety profile is more favorable, achieving maximum dose intensity is more likely. The simpler dosing schedule of lurbinectedin (1 vs 3 days) and lack of need for granulocyte colony-stimulating factor primary prophylaxis lessens treatment burden., Expert Opinion: Incorporation of lurbinectedin into therapeutic algorithms for relapsed SCLC has challenged long-established treatment paradigms. Initial evidence indicates that using lurbinectedin after failure of first-line platinum may prolong the platinum-free interval and reserve platinum for later use. Current evidence supports lurbinectedin as a second-line option in patients with sensitive relapsed SCLC.

Objectives: This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland., Materials and Methods: Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients)., Results: Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan., Conclusion: With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Solange Peters received education grants,provided consultation, attended advisory boards and/or provided lecturesfor the following organizations, from whom she received honoraria (all fees to institution): consultation/advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen,Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, MJH Life Sciences, Nykode Therapeutics, Novartis, Novocure, OncologyEducation, Pharma Mar, Promontory Therapeutics, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda; Board of Director position: Galenica; Talk in a company’s organized public event: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, Merck Sharp and Dohme, Mirati, MJH Life Sciences, Novartis, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Taked; receipt of grants/research supports: Principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, Arcus, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics. Dr. José Trigo participated on data monitoring and safety board for this study. Dr. Alejandro Navarro received consulting fees from Boehringher Ingelheim,Takeda, Bristol Myers Squibb Foundation, Adium Pharma, Pfizer, Eczacibasi and Amgen; received payment for speaker’s bureau from Roche and AstraZeneca Spain; received payment for expert testimony from Oryzon Genomics, Medsir and Hengenix; and had support for attending meetings and/or travel from Boehringer Ingelheim, Pfizer and Roche. Dr. Luis Paz-Ares had grants or contracts from MSD, Astrazeneca, Pfize and BMS; received consulting fees from Lilly, MSD, Roche, Pharmamar, Merck, Astrazeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda and Daichii Sankyo; and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astrazeneca, Janssen, Merck and Mirati. Dr. Christian Gohé received consulting fees from Boehringher, AstraZeneca, Novartis, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Boehringher and AstraZeneca; payment for expert testimony from AstraZeneca; and had support for attending meetings and/or travel from Daichi. Drs. José Antonio López-Vilariño, Cristian Fernandez, Carmen Kahatt, Vicente Alfaro, Antonio Nieto and Ali Zeaiter received personal fees for salary as full time employees and stock ownership from Pharma Mar. Dr. Vivek Subbiah participated in Advisory Boards of Jazz Pharmaceuticals, Loxo Oncology/Eli Lilly, Regeneron, Relay Therapeutics, Pfizer, Roche, ABBVIE, Novartis, Bayer, Aadi Biosciences, Illumina, and Labcorp; and received payment for educational events from Clinical Care Options, LLC. Other authors declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: 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 2 every 3 weeks) was acceptable and manageable in 105 adult SCLC patients from a phase II basket trial. This study analyses safety data from several solid tumours treated at the lurbinectedin-approved dose., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of Competing Interest Vivek Subbiah reports research funding from Pharma Mar and Jazz Pharma to conduct clinical trials; other grant support for clinical trials from AbbVie; Agensys, Inc; Alfasigma; Altum; Amgen; Bayer; BERG Health; Blueprint Medicines Corporation; Boston Biomedical, Inc; Boston Pharmaceuticals; Celgene Corporation; D3 Bio, Inc; Dragonfly Therapeutics, Inc; Exelixis; Fujifilm; GlaxoSmithKline; Idera Pharmaceuticals, Inc; Incyte Corporation; Inhibrx; Loxo Oncology/ Eli Lilly; MedImmune; MultiVir, Inc; Novartis; NanoCarrier, Co; National Comprehensive Cancer Network; NCI-CTEP; Novartis; PharmaMar; Pfizer; Relay Therapeutics; Roche/Genentech; Takeda; Turning Point Therapeutics; UT MD Anderson Cancer Center; and Vegenics Pty Ltd; travel support from ASCO, ESMO, Helsinn Healthcare, Incyte Corporation, Novartis and PharmaMar; consultancy or advisory board participation for Helsinn Healthcare, Incyte Corporation, Loxo Oncology/Eli Lilly, MedImmune, Novartis, QED Therapeutics, Relay Therapeutics, Daiichi-Sankyo and R-Pharm US; and other relationship with Medscape. Cristian Fernandez, Carmen Kahatt, Antonio Nieto and Ali Zeaiter are full-time employees of and own stock from Pharma Mar. Martin Cullell-Young is a full-time employee of Pharma Mar. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m 2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC., Methods: In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m 2 plus doxorubicin 40·0 mg/m 2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m 2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m 2 , doxorubicin 45·0 mg/m 2 , and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete., Findings: Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group)., Interpretation: Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control., Funding: PharmaMar., Competing Interests: Declaration of interests SPA has received honoraria from Roche and Bristol Myers Squibb; has received support for attending meetings or travel from Roche; and has a patent for lurbinectedin plus atezolizumab. TEC reports consultant or advisory fees from Astellas Pharma, Janssen, Bristol Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme, Sanofi, Novartis, Servier, and A&D Pharma; and travel support from Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, A&D Pharma, AstraZeneca, Genentech, Bristol Myers Squibb, Merck Sharp & Dohme Oncology, Eli Lilly, Janssen, Novartis, and Astellas Pharma. LB reports payment or honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and participation on a data safety monitoring board or advisory board for AstraZeneca and Roche. EFS reports consulting fees paid to his institution from Merck and Eli Lilly; payment or honoraria to his institution from Boehringer Ingelheim, AstraZeneca, and Daiichi Sankyo; and participation on a data safety monitoring board or advisory board for Merck, AstraZeneca, and Merck Sharp & Dohme. AC reports payment or honoraria from Genentech, Takeda, Blueprint Medicines, and Amgen; participation on a data safety monitoring board or advisory board for Ipsen, Odonate Therapeutics, Jazz Pharmaceuticals, Aileron Therapeutics, Janssen, AstraZeneca, and Sanofi; and holds stock or stock options in Merck. IH reports personal payments and payments to her institution from Syneos Health UK. AFF reports a consultancy or advisory role with AstraZeneca, Syros, OncLive, Clinical Care Oncology, Bayer, H3 Biomedicine, Pfizer, Medscape, PeerView, Genentech, Merck, Bristol Myers Squibb, and Boehringer Ingelheim; research funding to her institution from Bayer, Genentech, and AstraZeneca; was an employee and held stock or stock options in Novartis; and received support for this manuscript from PharmaMar. JAL-V, ANi, NV, JG, CK, and AZ are employees of PharmaMar and report stock or stock options in PharmaMar. MC-Y is an employee of PharmaMar. KS reports personal consulting fees from Roche, Bristol Myers Squibb, and Merck Sharp & Dohme; and consulting fees paid to his institution from Amgen. IB reports payment or honoraria from AstraZeneca, Amgen, Takeda, Bristol Myers Squibb, and Pfizer. CFW reports consulting fees from Viatris, Roche, and Alvotech; honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; meeting or travel support from Bristol Myers Squibb; and honoraria for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme. OJ-V reports consulting fees from Boehringer Ingelheim, Merck Sharp & Dohme, AstraZeneca, Eli Lilly, and Takeda; payment or honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, and Takeda; and meeting or travel support from Merck Sharp & Dohme and Roche. NR reports payment or honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Eli Lilly, Merck Sharp & Dohme, Merck, Pfizer, and Takeda; and meeting or travel support from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, and Takeda. MD reports payment or honoraria for lectures and advisory boards from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Sanofi, and Roche. LP-A reports honoraria for scientific advice and speaker fees from Eli Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Mirati, GlaxoSmithKline, Janssen, and Takeda; participates as external member of the board of Genómica; is a founder and board member of Altum sequencing; and has received institutional support for contracted research from Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m 2 ) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m 2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m 2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer., (© 2022. The Author(s).)

Background A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m 2 and lurbinectedin 2.0 mg/m 2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registration www.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013., (© 2021. The Author(s).)

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.

Introduction: 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 2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days., Material and Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: 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 and Methods: 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)., Results: 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., Conclusion: 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., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)