Lurbinectedin (Zepzelca)

Number: 0978

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses lurbinectedin (Zepzelca) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of lurbinectedin (Zepzelca) is required of all Aetna participating providers and members in applicable plan designs. For precertification of lurbinectedin (Zepzelca), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Small cell lung cancer

   Aetna considers lurbinectedin (Zepzelca) medically necessary for subsequent treatment of small cell lung cancer as a single agent in any of the following settings:

   1. Relapse following complete or partial response or stable disease with initial treatment; or
   2. Primary progressive disease; or
   3. Metastatic disease following disease progression on or after platinum-based chemotherapy.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of lurbinectedin (Zepzelca) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Lurbinectedin (Zepzelca) is supplied as 4 mg lyophilized powder in a single-dose vial for intravenous infusion.

The recommended dosing is as follows:

Small Cell Lung Cancer

Zepzelca is administered as 3.2 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Source: Jazz Pharmaceuticals, 2020

Experimental, Investigational, or Unproven

Aetna considers lurbinectedin experimental, investigational, or unproven for all other indications including the following (not an all-inclusive list):

• Breast cancer
• Endometrial cancer
• Macular edema
• Neuroendocrine carcinoma
• Non-small cell lung cancer
• Ovarian cancer.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
96415	Chemotherapy administration, intravenous infusion technique; each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9223	Injection, lurbinectedin, 0.1 mg
Other HCPCS codes related to the CPB:
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [small cell lung cancer (SCLC)][not covered for non-small cell lung cancer]
ICD-10 codes not covered for indications listed in the CPB:
C50.011 - C50.929	Malignant neoplasm of breast
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C56.1 - C56.9	Malignant neoplasm of ovary
C7A.00 - C7A.098	Malignant neuroendocrine tumors
H35.81	Retinal edema

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Background

U.S. Food and Drug Administration (FDA)-Approved Indication

• Zepzelca is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Compendial Uses

• Relapsed small cell lung cancer
• Primary progressive small cell lung cancer

Small cell lung cancer (SCLC) represents 15 percent of all lung cancers and occurs almost exclusively in smokers. It is distinguished from non-small cell lung cancer by its rapid doubling time, high growth fraction, and the early development of widespread metastases. Although considered highly responsive to chemotherapy and radiotherapy, SCLC usually recurs within 14 to 15 months for patients with limited-stage SCLC and five to six months for patients with extensive-stage SCLC. The median survival of patients with relapsed SCLC ranges from two to six months. The most important factors affecting prognosis are performance status, tumor extent (i.e., limited versus extensive), and time to relapse after first-line therapy. Similarly, the likelihood of an objective response to second-line therapy depends upon the time from last therapy to relapse, the response to initial treatment, and the performance status.

On June 15, 2020, the Food and Drug Administration granted accelerated approval to lurbinectedin (Zepzelca), a selective inhibitor of oncogenic transcription, for adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. The FDA approval was based on results from PM1183-B-005-14 (Study B-005; NCT02454972; Trigo 2020), a multicenter, open-label, multi-cohort basket trial evaluating Zepzelca as a single agent in patients with advanced or metastatic solid tumors. A basket trial is a type of clinical trial that tests how well a new drug or other substance works in patients who have different types of cancer that all have the same mutation or biomarker. Patients received a median of 4 cycles of Zepzelca (range 1 to 24 cycles). Patients were recruited from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. The trial excluded patients with central nervous system (CNS) involvement, grade ≥3 dyspnea, daily intermittent oxygen requirement, hepatitis or cirrhosis, and immunocompromised patients. Tumor assessments were conducted every 6 weeks for the first 18 weeks and every 9 weeks thereafter. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR). Additional efficacy outcome measures included duration of response (DoR), and an Independent Review Committee. A cohort of patients with small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy received Zepzelca 3.2 mg/m² administered as a 1-h intravenous infusion every 3 weeks (one cycle) until disease progression or unacceptable toxicity. All treated patients were analysed for activity and safety. 

Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. The median age was 60 years (range: 40 to 83) with 65% of patients < 65 years and 35% of patients greater than or equal to 65 years, and 60% were male. The majority (75%) of the patients were White, 1% were Asian, 1% were Black and 23% were not reported. Baseline ECOG performance status was 0 or 1 in 92% of patients, and 92% were former/current smokers. All patients received at least one line of platinum-based chemotherapy (range 1-2 lines), and prior radiotherapy had been administered to 71% of patients. Eight patients (8%) had prior immunotherapy in addition to platinum-based chemotherapy. Sixty patients (57%) had platinum-sensitive SCLC, defined as recurrence or progression ≥ 90 days after the last dose of platinum-containing therapy (chemotherapy free interval [CTFI] ≥ 90 days). The remaining 45 patients had platinum-resistant SCLC, defined as recurrence or progression < 90 days after the last dose of platinum-containing therapy (CTFI < 90 days). Median follow-up was 17·1 months (IQR 6·5-25·3).

The main efficacy outcome measures were confirmed overall response rate (ORR) determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was seen in 37 patients (35%; 95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30% (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. The authors concluded that lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomized phase 3 trial.

Other Solid Tumors (e.g., Breast Cancer, Desmoplastic Small Round Cell Tumor, Endometrial Cancer, Ewing Sarcoma, Neuroendocrine Tumors, Non-Small Cell Lung Cancer, Ovarian Cancer, and Pleural Mesothelioma)

Kristeleit et al (2021) noted that 2nd-line treatment of endometrial cancer is an unmet medical need.  In a phase-I clinical trial, these researchers examined the safety and effectiveness of combined lurbinectedin and doxorubicin administered intravenously every 3 weeks in patients with endometrial cancer.  A total of 34 patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0 to 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 1 to 2 prior lines of chemotherapy for advanced disease.  Anti-tumor activity was evaluated every 2 cycles according to the RECIST version 1.1.  Adverse events (AEs) were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.  Median age (range) was 65 (51 to 78) years.  Eastern Cooperative Oncology Group performance status (ECOG PS) was up to 1 in 97 % of patients.  In the escalation phase, 4 (26.7 %) of 15 patients had confirmed response: 2 complete responses (CRs) and 2 partial responses (PRs) (95 % CI: 7.8 % to 55.1 %).  Median duration of response (DoR) was 19.5 months.  Median progression-free survival (PFS) was 7.3 (2.5 to 10.1) months.  In the expansion cohort, confirmed PR was reported in 8 (42.1 %) of 19 patients (95 % CI: 20.3 % to 66.5 %).  Median DoR was 7.5 (6.4 to not reached) months, median PFS was 7.7 (2.0 to 16.7) months, and median OS 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.  The authors concluded that in patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42 %) and DoR (7.5 months) were favorable.  Moreover, these researchers stated that further evaluation of doxorubicin and lurbinectedin is needed in this patient population.

Dumoulin et al (2022) stated that lurbinectedin is a promising new drug being examined in pre-treated patients with SCLC or malignant pleural mesothelioma (MPM).  Its clinical activity in the real-world setting has not been examined 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 carried out on screening and treating peripheral blood samples.  A total of 95 patients (43 SCLC and 52 MPM) were treated, mostly as greater than or equal to 3-line of therapy.  In the SCLC cohort, a median progression-free survival (mPFS) was 1.5 months (95 % confidence interval [CI]: 1.4 to 3.0), and median overall survival (OS) was 7.0 months (95 % CI: 4.7 to not reached).  Objective radiological response and disease control rate (DCR) after 12 weeks were 16 % and 28 %, respectively.  In the MPM cohort, median PFS was 2.8 months (95 % CI: 1.4 to 4.2), and median OS was 7.2 months (95 % CI: 5.9 to not reached); DCR after 12 weeks was 29 %, whereas no partial responses (PRs) 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+ and CD8+ T cells (SCLC) and natural killer and natural killer T-cells (SCLC and MPM) and altered co-stimulatory and co-inhibitory receptor expression on circulating lymphocytes.  The authors concluded that lurbinectedin had a manageable safety profile and showed clinical activity in pre-treated patients with SCLC and MPM.  Its immune-modulatory functions made lurbinectedin a potential platform for immunotherapy combinations.

Longo-Munoz et al (2022) noted that patients with neuroendocrine tumors (NETs) need alternative therapies after failure of 1st-line therapy.  In a phase-II clinical trial, these researchers examined the effectiveness of lurbinectedin (3.2 mg/m2 as a 1-hour intravenous [IV] infusion every 3 weeks) in 32 NETs patients treated in the 2nd- or 3rd-line setting.  The primary effectiveness endpoint was ORR according to RECIST v1.1 assessed by the investigators.  Secondary endpoints included DoR, PFS, OS and safety.  2 of 31 evaluable patients had confirmed PRs (ORR = 6.5 %; 95 % CI: 0.8 % to 21.4 %).  Median DoR was 4.7 months (95 % CI: 4.0 to 5.4 months), median PFS was 1.4 months (95 % CI: 1.2 to 3.0 months) and median OS was 7.4 months (95 % CI: 3.4 to 16.2 months).  Lurbinectedin showed an acceptable, predictable and manageable safety profile.  The most common grade-3/4 toxicity was neutropenia (40.6 %; grade-4, 12.4 %; febrile neutropenia, 3.1 %).  The authors concluded that considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of anti-tumor activity observed (2 confirmed PRs and 7 long disease stabilizations), further development of lurbinectedin is needed in a more selected NETs population.

Gedminas et al (2022) stated that desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor OS.  This tumor is dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor.  Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1.  These researchers demonstrated that that lurbinectedin inhibited EWS-WT1 by re-distributing the protein within the nucleus to the nucleolus.  This nucleolar re-distribution interfered with the activity of EWS-WT1 to reverse the expression of over 70 % of the transcriptome.  Furthermore, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type.  The effects occurred at concentrations that are easily achievable in the clinic and translated to the in-vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT.  More importantly, this mechanism of nucleolar re-distribution was also observed with wild-type EWSR1 and the related fusion protein EWS-FLI1.  The authors concluded that this study provided evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins.  More importantly, the data established lurbinectedin as a promising clinical candidate for the treatment of patients with DSRCT.

Subbiah et al (2022) noted that lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through re-localization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts.  In an open-label, single-arm, phase-II clinical trial, these researchers examined the effectiveness of lurbinectedin in patients with relapsed Ewing sarcoma.  This study included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per RECIST v.1.1, ECOG PS of 2 or less, adequate organ function, no CNS metastasis, and pre-treated with 2 or less chemotherapy lines for metastatic/recurrent disease.  Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks.  Primary endpoint was ORR as per RECIST v.1.1; and secondary endpoints included time-to-event parameters and safety profile.  The ORR was 14.3 % [95 % CI: 4.0 % to 32.7 %], with median DoR of 4.2 months (95 % CI: 2.9 to 5.5 months).  Median PFS was 2.7 months (95 % CI: 1.4 to 4.3 months), clinical benefit rate was 39.3 %, and DCR was 57.1 %.  With 39 % censoring, median OS was 12.0 months (95 % CI: 8.5 to 18.5 months).  Most common grade-3/4 AEs were neutropenia (57 %), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14 % each).  No deaths or discontinuations were due to toxicity.  The authors concluded that lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile.  These researchers stated that this trial had the limitation of not including patients aged of less than 18 years, a population with a high incidence of Ewing sarcoma.  Nevertheless, the response rate of 14.3 % observed for single-agent lurbinectedin warrants further development of the drug in the treatment of relapsed Ewing sarcoma.  Combination of lurbinectedin with irinotecan or temozolomide might improve the anti-tumor activity of single-agent lurbinectedin in relapsed Ewing sarcoma.  An ongoing phase-Ib/II clinical trial is currently examining lurbinectedin in combination with irinotecan in advanced solid tumors, including Ewing sarcoma.

Poveda et al (2022) hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage; therefore, increasing its effectiveness.  The POLA Trial (a phase-I clinical trial) established the recommended phase-II dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 hours (days 1 to 5) for a 21-day cycle.  In the phase-II trial, these researchers examined the effectiveness of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters.  A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib.  Most patients (62 %) received 3 or more lines of prior therapy.  The ORR and DCR were 9.6 % and 72.6 %, respectively.  The PFS was 4.54 months (95 % CI: 3.0 to 5.2); 12 (16.4 %) patients were considered long-term responders (LTR), with a median PFS of 13.3 months.  No clinical benefit was observed for cases with HRR gene mutation.  In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055).  Globally, the total number of LOHs might be associated with the ORR (p = 0.074).  The most common grade 3/4 toxicities were anemia and thrombocytopenia, in 6 (8.2 %) and 3 (4.1 %) patients, respectively.  The authors concluded that the POLA Trial provided evidence that the administration of lurbinectedin and olaparib was feasible and tolerable, with a DCR of 72.6 %; different GI parameters showed associations with better responses.

Calvo et al (2022) noted that lurbinectedin and paclitaxel showed synergism in pre-clinical studies and exhibited non-completely overlapping toxicity profiles.  In a phase-I clinical trial, these researchers examined a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors.  This study was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0 to 5.0 mg flat dose (FD) or 2.2 mg/m2) 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).  A total of 67 patients (A, n = 55; B, n = 12) were treated.  The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 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.  A total of 25 confirmed responses were observed: 20/51 evaluable patients in Group A (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 were feasible combinations.  Further development is needed of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.

Boni et al (2022) stated that lurbinectedin has demonstrated pre-clinical anti-tumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.  In a multi-tumor, phase-II clinical trial, these researchers examined lurbinectedin 3.2 mg/m2 1-hour intravenous (IV) infusion every 3 weeks in a cohort of 21 patients with pre-treated germline BRCA1/2 breast cancer.  Patients with any hormone receptor and human epidermal growth factor receptor (EGFR) 2 status were enrolled.  The primary effectiveness endpoint was ORR according to RECIST v1.1.  Secondary endpoints included DoR, PFS, OS and safety.  Confirmed partial response (PR) was observed in 6 patients [ORR = 28.6 %; 95 % CI: 11.3 % to 52.2 %] who had received a median of 2 prior advanced chemotherapy lines.  Lurbinectedin was active in both BRCA mutations: 4 PRs in 11 patients (36.4 %) with BRCA2 and 2 PRs in 10 patients (20.0 %) with BRCA1.  Median DoR was 8.6 months, median PFS was 4.1 months, and median OS was 16.1 months.  Stable disease (SD) was observed in 10 patients (47.6 %), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9 % (95 % CI: 21.8 % to 66.0 %)].  Clinical benefit rate (PR + SD of 4 months or longer) was 76.2 % (95 % CI: 52.8 % to 91.8 %).  No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors.  The most common treatment-related AEs (TRAEs) were nausea (61.9 %), fatigue (38.1 %) and vomiting (23.8 %).  These AEs were mostly grade-1 to grade-2.  The most common grade-3 to grade-4 toxicity was neutropenia (42.9 %: grade-4, 23.8 %: with no febrile neutropenia).  The authors concluded that this phase-II clinical trial met its primary endpoint and demonstrated activity of lurbinectedin in germline BRCA1/2 breast cancer.  Lurbinectedin showed a predictable and manageable safety profile.  Considering the exploratory objective of this study as well as previous results in other phase-II clinical trials, further investigation of lurbinectedin in this indication is needed.

The authors stated that some drawbacks of this trial were the small size (n = 21) of the cohort evaluated, the absence of a central laboratory to confirm BRCA status, and the lack of sampling during the trial to carry out pharmacodynamic studies.  Moreover, these researchers stated that pharmacogenomic and molecular analysis may aid in selecting the patient population that could obtain a higher benefit with lurbinectedin treatment. 

Awada et al (2022) noted that pre-clinical studies showed a synergistic effect for 5-fluorouracil (5-FU) and lurbinectedin against solid tumors.  In a phase-I clinical trial, these researchers examined combined capecitabine plus lurbinectedin in patients with selected advanced solid tumors.  Results in patients with relapsed metastatic breast cancer (MBC) were described.  Patients received capecitabine daily on day (D)1 to D14 combined with lurbinectedin on D1, D8 or D1 every 3 weeks (q3w) intravenously, following a standard 3 + 3 escalation design and expansion at the recommended dose (RD).  Of the 81 enrolled patients, 28 had relapsed MBC: 20 with hormone receptor (HR)-positive tumors and 8 with triple-negative tumors; 3 were treated in the D1, D8 schedule and 25 in the D1 schedule.  The RD was capecitabine 1,650 mg/m2 daily on D1 to D14 plus lurbinectedin 2.2 mg/m2 on D1 q3w.  A total of 16 confirmed responses and 2 prolonged disease stabilizations (6 months or longer) were observed (ORR/clinical benefit rate (CBR) = 57 %/64 % at all dose levels; 47 %/60 % at the RD); 12 responses and both prolonged stabilizations occurred in HR-positive tumors (ORR/CBR = 60 %/70 % at all dose levels, 56 %/78 % at the RD); 4 responses were found in triple-negative tumors (ORR and CBR = 50 % at all dose levels; 33 % at the RD).  Myelotoxicity was reversible and manageable at the RD; most non-hematological toxicities were mild/moderate.  No episodes of febrile neutropenia or severe palmar-plantar erythron-dysesthesia syndrome occurred.  No major pharmacokinetic drug-drug interaction was found between lurbinectedin, capecitabine or capecitabine metabolites.  The authors concluded that capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors.  Toxicity was manageable at the RD.  Moreover, these researchers stated that further investigation is needed to examine combined lurbinectedin and capecitabine in the treatment of patients with relapsed MBC.

Gadducci and Cosio (2022) stated that the ecteinascidins trabectedin and lurbinectedin are very interesting anti-neoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action.  These drugs form adducts in the minor groove of DNA, which produce single-strand breaks (SSBs) and double-strand breaks (DSBs) and trigger a series of events resulting in cell cycle arrest and apoptosis.  Moreover, the ecteinascidins interact with the tumor micro-environment, reduce the number of tumor-associated macrophages, and inhibit the secretion of cytokines and chemokines.  Trabectedin has been approved by the FDA for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-based regimen.  Moreover, trabectedin in combination with pegylated liposomal doxorubicin (PLD) has been approved in the European Union for the treatment of platinum-sensitive recurrent ovarian cancer.  Lurbinectedin has been approved by the FDA for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.  These researchers examined in-vitro and in-vivo experimental studies on the anti-neoplastic effects of both ecteinascidins as well as the clinical trials on the activity of trabectedin in uterine sarcoma and ovarian carcinoma and of lurbinectedin in ovarian carcinoma and endometrial carcinoma.  Moreover, these researchers stated that since in-vitro and in-vivo experimental studies suggested that both trabectedin and lurbinectedin are active against ovarian clear cell carcinoma, these ecteinascidins should be tested in clinical trials including patients with this histological type that is poorly sensitive to platinum-based chemotherapy.  They noted that a phase-III clinical trial on heavily pre-treated patients with platinum-resistant ovarian cancer showed that lurbinectedin had similar anti-tumor activity and a favorable safety profile compared to the control arm consisting of pegylated liposomal doxorubicin or topotecan.  These investigators stated that additional biological and clinical research is needed to detect biomarkers predictive of response to lurbinectedin and to evaluate the combination of lurbinectedin with other anti-neoplastic agents.

National Comprehensive Cancer Network’s clinical practice guidelines on “Neuroendocrine and adrenal tumors” (Version 1.2023) and “Non-small cell lung cancer” (Version 3.2023) do not mention lurbinectedin as a therapeutic option.

Macular Edema

Simona et al (2022) examined the response to lurbinectedin in a case of macular edema (ME), secondary to central retinal vein occlusion (CRVO).  Serial spectral domain optical coherence tomography (SD-OCT) scans were taken in a 70-year-old man with a 24-month history of ME secondary to CRVO in the right eye.  The patient underwent 5 cycles of chemotherapy with lurbinectedin between October 2018 and May 2019.  Central macular thickness (CMT) before and after each chemotherapy cycle was measured together with progression analysis using the CIRRUS Zeiss software.  SD-OCT demonstrated alternating recurrence and resolution of macular edema closely related to the chemotherapy administrations; CMT oscillated between 496 and 284 μm during the follow-up.  The macular edema decreased as soon as 4 days following chemotherapy.  The authors concluded that the findings of this case study suggested a new possible beneficial anti-edematous effect of lurbinectedin on ME associated with CRVO.  Moreover, these researchers stated that further studies are needed to identify the most promising candidates and to examine the effect of lurbinectedin in this cohort of patients.

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References