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

Compendial Uses

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

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.

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 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.

The recommended lurbinectedin dose is 3.2 mg/m

every 21 days.

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

of the following settings:

Aetna considers all other indications as experimental and investigational.

Continuation of Therapy

Aetna considers continuation of lurbinectedin (Zepzelca) therapy medically necessary 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/m

by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Source: Jazz Pharmaceuticals, 2020