FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer

Singh, Sonia; Jaigirdar, Adnan A.; Mulkey, Flora; Cheng, Joyce; Hamed, Salaheldin S.; Li, Yangbing; Liu, Jiang; Zhao, Hong; Goheer, Anwar; Helms, Whitney S.; Wang, Xing; Agarwal, Rajiv; Pragani, Rajan; Korsah, Kwadwo Ameyaw; Tang, Shenghui; Leighton, John K.; Rahman, Atiqur; Beaver, Julia A.; Pazdur, Richard; Theoret, Marc R.; Singh, Harpreet

doi:10.1158/1078-0432.ccr-20-3901

Cited by 55 publications

(47 citation statements)

References 5 publications

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“…Moreover, the lack of effective molecular therapies as well as the immune-evasive tumor microenvironment makes the treatment of MPM particularly challenging [ 5 , 6 , 7 , 8 , 9 , 10 , 42 ]. Because MPM currently lacks peculiar oncogenic drivers, we have explored the potential therapeutic efficacy of lurbinectedin, an alkylating agent which recently received FDA-conditional approval for the treatment of metastatic small cell lung cancer patients relapsing after chemotherapy [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lurbinectedin (PM01183) is a marine-derived anticancer drug that exerts a potent antitumor activity in different cancer cell lines and xenografts models and is currently under clinical evaluation in several tumor types [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Recently, the FDA has released a conditional approval for lurbinectedin for the treatment of second-line metastatic small cell lung cancer patients [ 36 ] while promising antitumor activity has been reported in MPM patients in second- and third-line [ 37 ]. However, there are no data available on the role of lurbinectedin as monotherapy or in combination in the first-line treatment of MPM.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Anobile

Bironzo²,

Picca

et al. 2021

Cancers

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Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Anobile

Bironzo²,

Picca

et al. 2021

Cancers

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“…In June 2020, the United States Food and Drug Administration (FDA) granted accelerated approval to lurbinectedin for adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. 5 Lurbinectedin plus doxorubicin showed synergistic antitumor effect in small cell lung cancer xenografted tumors. Improved activity with this combination and activity observed for lurbinectedin Original research in a study of humans 6 prompted a phase I trial to evaluate this combination in advanced solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study

Kristeleit

Moreno

Boni³

et al. 2021

Int J Gynecol Cancer

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ObjectiveSecond-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.MethodsThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0–5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.ResultsMedian age (range) was 65 (51–78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.ConclusionsIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.

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“…In particular, SCLC is characterized by early and widespread metastatic dissemination and a remarkable response to chemotherapy that is almost invariably followed by the development of drug resistance 4 . The first-line therapy for patients with SCLC has not changed for several decades; however, studies have recently shown that lurbinectedin could be an effective second-line therapy 5 . Although it has been shown that SCLC has a high frequency of TP53 and RB1 mutations, these gene mutations are not effective drug targets 3 , 6 .…”

Section: Introductionmentioning

confidence: 99%

De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small-cell lung carcinoma

Maruyama

Sato

Nakayama

et al. 2021

Sci Rep

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Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Although ribonucleotide reductase (RNR) is known to catalyze the rate-limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small-cell lung carcinoma (SCLC) remains unclear. In this study, we established siRNA-transfected SCLC cell lines to investigate the anticancer effect of silencing RRM1 gene expression. We found that RRM1 is required for the full growth of SCLC cells both in vitro and in vivo. In particular, the deletion of RRM1 induced a DNA damage response in SCLC cells and decreased the number of cells with S phase cell cycle arrest. We also elucidated the overall changes in the metabolic profile of SCLC cells caused by RRM1 deletion. Together, our findings reveal a relationship between the deoxyribonucleotide biosynthesis axis and key metabolic changes in SCLC, which may indicate a possible link between tumor growth and the regulation of deoxyribonucleotide metabolism in SCLC.

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FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer

Cited by 55 publications

References 5 publications

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study

De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small-cell lung carcinoma

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