FDA Grants Lurbinectedin Orphan Drug Status for SCLC

Luis Mora Capitan

The FDA has granted lurbinectedin (PM1183) an orphan drug designation for the treatment of patients with small cell lung cancer (SCLC), according to PharmaMar, the manufacturer of the marine-derived treatment.

The Orphan Drug program is intended to facilitate the development and review of novel therapies for the treatment of patients with rare diseases or conditions that affect fewer than 200,000 people in the United States.

Data were presented at the 2018 ASCO Annual meeting for an SCLC cohort from a phase II multicenter basket trial examining lurbinectedin across various solid tumors. The overall response rate (ORR) was 39.3% in the SCLC cohort.

“We are delighted to receive this orphan drug designation as it underscores the great need for innovative, effective treatments for this cancer, and recognizes the potential benefits that lurbinectedin may provide for patients with small cell lung cancer,” Luis Mora Capitán, Managing Director of the Oncology Business Unit of PharmaMar, said in a statement.

“Receiving orphan drug designation for the treatment of small cell lung cancer is a significant regulatory milestone in the development of lurbinectedin,” Capitán added.

Among 68 enrolled patients, the median age was 60.5 years (range, 40-83), 43 were male, and 25 were female. The ECOG performance status was 0 (n = 21), 1 (n = 43), or 2 (n = 4). The median number of sites of disease involvement was 3 (range, 1-5).

Forty-six (68%) patients had bulky disease and 1 patient had known CNS metastases at baseline. The median number of prior lines of therapy was 1 (range, 1-2). Forty-two (62%) patients had a complete (CR) or partial response (PR) as their best response to their last chemotherapy, with 12 (17%) patients having a best response of stable disease.

Patients received lurbinectedin at 3.2 mg/m² as a 1-hour IV infusion once every 3 weeks. The primary outcome measure was ORR, with secondary endpoints including duration of response, progression-free survival (PFS), overall survival (OS), and safety.

The 39.3% (95% CI, 27.1-52.7) ORR was determined from 24 responses among 61 evaluable patients. An additional 7 patients had stable disease ≥4 months, for a clinical benefit rate of 50.8% (n = 31; 95% CI, 37.7-63.9), and another 14 patients had stable disease <4 months, for a disease control rate of 73.8% (n = 45; 95% CI, 60.9-84.2). The median duration of response was 6.2 months.

The median PFS was 4.1 months (95% CI, 2.6-5.7). The PFS rate was 51.1% (95% CI, 38.0-64.2) at 4 months and 36.3% (95% CI, 23.2-49.5) at 6 months. The median OS was 11.8 months (95% CI, 9.6-15.9). The OS rate was 79.3% (95% CI, 67.6-91.0) at 6 months and 43.1% (95% CI, 22.5-63.7) at 12 months.

Safety data were reported for 66 patients with SCLC who received lurbinectedin. The most common grade 1/2 adverse events (AEs) were anemia (86.4%), ALT increase (58.5%), fatigue (51.5%), AST increase (36.9%), neutropenia (31.8%), thrombocytopenia (31.8%), nausea (31.8%), AP increase (24.6%), vomiting (18.2%), anorexia (16.7%), constipation (10.6%), bilirubin increase (9.4%), and diarrhea (9.1%).

The most frequently reported grade 3 AEs were neutropenia (16.7%), anemia (6.1%), ALT increase (4.6%), fatigue (4.5%), febrile neutropenia (3.0%), and thrombocytopenia (3.0%). Grade 4 AEs included neutropenia (22.7%), febrile neutropenia (6.1%), and thrombocytopenia (4.5%).

Neutropenia caused a dose delay in 8 patients and led to dose reductions in 10 patients. Eleven patients received G-CSF.

Lurbinectedin inhibits RNA polymerase II, an enzyme essential for the transcription process that is overactivated in certain tumors. By blocking trans-activated transcription, lurbinectedin induces a cascade of events promoting apoptosis. The drug may also modulate the tumor microenvironment to promote an antitumor response. The drug, which is administered intravenously, is a synthetic compound that is structurally related to trabectedin (Yondelis), a marine-derived agent that is FDA-approved for patients with metastatic liposarcoma or leiomyosarcoma.

Lurbinectedin is currently being studied in the global, randomized, phase III ATLANTIS study with doxorubicin versus investigator’s choice of either cyclophosphamide, doxorubicin and vincristine or topotecan (NCT02566993). ATLANTIS is actively recruiting for patients with SCLC who have failed 1 prior platinum-containing line of therapy.

Perez JMT, Leary A, Besse B, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): Results from a phase 2 study. J Clin Oncol. 2018;36 (suppl; abstr 8570).