FDA Accelerates Approval of Lurbinectedin in Metastatic SCLC

The FDA had granted accelerated approval to the anti-cancer agent lurbinectedin (Zepzelca) for the treatment of adult patients with metastatic small cell lung cancer (SCLC) whose disease has progressed on or after platinum-based chemotherapy. The accelerated approval was granted in light of the positive overall response rate (ORR) and duration of response (DOR) observed with the drug, PharmaMar and Jazz Pharmaceuticals announced.¹

“It is great to see a new therapeutic agent available for patients with relapsed small cell lung cancer. Lurbinectedin is the first new drug approved for second-line treatment since 1996. Small cell lung cancer remains a major unmet medical need. Many of us in the oncology community will welcome lurbinectedin as a new standard option for patients with recurrent small cell lung cancer,” said Charles Rudin, MD, chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center and principal investigator of the NCI Small Cell Lung Cancer Consortium, in a statement.

The data that led to the FDA action were from a phase 2 open-label, multicenter, single-arm basket trial of lurbinectedin monotherapy administered to 105 adult patients with platinum-sensitive or platinum-resistant relapsed SCLC. The results recently published in the Lancet Oncology showed that lurbinectedin is an active treatment for second-line SCLC.²

Median follow-up in the study was 17.1 months (interquartile range, 6.5-25.3). Overall responses were observed in 37 treated patients, resulting in an ORR of 35.2% (95% CI, 26.2%-45.2%). All responses in the study were partial responses (PRs). Responses lasted for a median duration of 5.3 months (95% CI, 4.1-6.4).

Reduction in target lesions occurred in 64 patients (65%) and of this group, 19 individuals had a chemotherapy-free interval of fewer than 90 days and 45 had a chemotherapy-free interval of 90 days or more. The study included a pre-planned analysis of overall response by chemotherapy-free interval of more (considered sensitive disease) or less than (considered resistant disease) 90 days. This analysis showed overall responses in 27 patients (45.0%; 95% CI, 32.1%-58.4%) among the 60 patients who had a chemotherapy-free interval of 90 days or longer with a median DOR of 6.2 months (95% CI, 3.5-7.3). For the 45 patients who had a chemotherapy-free interval of less than 90 days, overall responses were achieved in 10 (22.2%; 95% CI, 11.2%-37.1%) with a median DOR of 4.7 months (95% CI, 2.6-5.6).

A post-hoc analysis was conducted to assess a subgroup of 8 patients who received first- or second-line immunotherapy. Two patients had received immunotherapy in the frontline setting and 6 received immunotherapy second line. Sixty-three percent of this subpopulation had a durable response to treatment with lurbinectedin, per investigator assessment.

There were 98 patients who were evaluable for response by Independent Review Committee (ICR), and of those patients, objective responses were observed in 32 (32.7%, 95% CI, 23.5%-42.9%) with a median DOR of 5.1 months (95% CI, 4.9-6.4). The ICR assessment also showed reduction in target lesions, which included 20 (19%) patients with a chemotherapy-free interval of 90 days or less and 41 (81%) of those with a chemotherapy-free interval of 90 days or more. The overall response rate among patients with the higher chemotherapy-free interval was 44.8% (95% CI, 31.7%-58.5%) with a median DOR of 5.3 months (95% CI, 4.9-7.0). Those with the lower chemotherapy-free interval had an overall response of 15.0% (95% CI, 5.7-29.8). The median DOR in the lower chemotherapy-free interval population was 4.8 months (95% CI, 2.4-5.3).

Per investigator assessment, the median progression-free survival (PFS) in the overall population was 3.5 months (95% CI, 2.6-4.3). Among patients with a chemotherapy-free interval of fewer than 90 days, the median PFS was 4.6 months (95% CI, 2.8-6.5) and among those with a chemotherapy-free interval of 90 days or longer, the median PFS was 2.6 months (95% CI, 1.3-3.9).

A total of 94 patients discontinued treatment with lurbinectedin. Of the patients who discontinued therapy, patients (9%) had central nervous system metastases. As a result, the investigators did not observe an increase in CNS metastases in the study.

At data cutoff, 39 out of 105 patients were still alive, leading to an overall survival (OS) rate of 37.1%. The median OS was 9.3 months (95% CI, 6.3-11.8) overall. In the subgroup of patients with a chemotherapy-free interval of 90 days or longer, the median OS was 11.9 months (95% CI, 9.7-16.2) and was 5.0 months (95% CI, 4.1-6.3) in patients with a chemotherapy-free interval of less than 90 days.

A post-hoc analysis evaluated OS among patients who achieved an objective response at 1 year, and notably, the median OS exceeded 1 year in the overall population at 12.6 months (95% CI, 10.8-15.8). Among patients with sensitive disease, the median OS was 15.8 months (95% CI, 10.2-not reached [NR]). In patients with platinum-resistant disease, the median OS was 10.9 months (95% CI, 6.3-14.0).

Following treatment with lurbinectedin, 47 (45%) patients were given further antitumor therapy consisting of either carboplatin, etoposide, paclitaxel, or topotecan, most commonly. Seven percent of patients received further immunotherapy, which resulted in a median OS of 14.9 months (95% CI, 3.2-NR), according to a post-hoc analysis. This OS was superior to that observed in patients who did not receive further immunotherapy, which was 9.3 months (95% CI, 6.3-11.8 months).

In terms of safety, all 105 patients were evaluable. The most common grade 3/4 adverse events (AEs) and laboratory abnormalities (≥2% of patients) were hematological disorders, like neutropenia (46%), leucopenia (29%), anemia (9%), thrombocytopenia (7%), and febrile neutropenia (5%). The only AE considered to be treatment-related was febrile neutropenia.

Serious AEs were observed in 10% of patients, with the most common being neutropenia and febrile neutropenia, which each occurred in 5% of patients.

Overall, only 2% of patients discontinued treatment with lurbinectedin due to treatment-related AEs. There were no treatment-related AEs that led to death, but overall 66 patients in the study died as a result of disease progression.

In this study, lurbinectedin 3.2 mg/m² was administered intravenously over the course of one hour, repeated every 21 days until disease progression or unacceptable toxicity. The primary end points for the SCLC cohort were ORR and DOR per investigator assessment.

The study is also evaluating patients with head and neck carcinoma, neuroendocrine tumors, biliary tract carcinoma, endometrial carcinoma, BRCA 1/2-associated metastatic breast carcinoma, carcinoma of unknown primary site, germ cell tumors, and Ewing's family of tumors.

“We are pleased to bring a new treatment choice to relapsed SCLC patients,” said José María Fernández, PhD, president of PharmaMar, in a statement. “The US FDA accelerated approval of lurbinectedin underscores its potential to fill an unmet need in the SCLC community.”

Lurbinectedin is under further investigation in combination with doxorubicin as second-line SCLC therapy is currently being investigated in a randomized, phase 3 ATLANTIS trial (NCT02566993).

_References:

_{PharmaMar announces the U.S. FDA approval of lurbinectedin (Zepzelca) for the treatment of metastatic small cell lung cancer. News release. PharmaMar and Jazz Pharmaceuticals. June 15, 2020. Accessed June 15, 2020.}

_{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):645-654. doi:10.1016/S1470-2045(20)30068-1}