FDA Approval Sought for Lurbinectedin in Small Cell Lung Cancer

A new drug application (NDA) has been submitted to the FDA seeking an accelerated approval for lurbinectedin for use as a second-line treatment for patients with small cell lung cancer (SCLC), according to PharmaMar, the manufacturer of the investigational agent.

The company reported in a press release that the NDA is based on results from a phase II basket trial in which lurbinectedin reached an overall response rate (ORR) of 35.2% as a second-line treatment SCLC. The ORR consisted of all partial responses, which occurred in 37 of 105 patients. An additional 35 patients had stable disease, for a disease control rate of 68.6% (95% CI, 58.8-77.3). Overall, 65% of patients had a decrease in tumor size and responses occurred in 5 of 8 patients who had failed prior immunotherapy. Twenty-eight patients (26.7%) had progressive disease and 5 patients were not evaluable.

The median duration of response was 5.3 months (95% CI, 4.1-6.4). The response rate was higher in patients with sensitive disease, defined as those with a chemotherapy-free interval (CTFI) ≥90 days. Among these patients, the ORR was 45% compared with 22.2% in patients with resistant disease (CTFI <90 days).

“It is great to finally see some new therapeutic options arriving for small cell lung cancer patients, who represent a major unmet medical need. I have been following the emerging clinical trial data on lurbinectedin, which suggest appealing efficacy and a tolerable safety profile. I believe many treating physicians may welcome lurbinectedin, if approved, as a new standard of care option for their patients with recurrent small cell lung cancer," Charles Rudin, MD, PhD, chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center and principal investigator of the NCI Small Cell Lung Cancer Consortium, said in the press release.

Over the past 20 years, topotecan is the only therapy that the FDA has approved for the second-line treatment of patients with platinum-sensitive SCLC. Historical response rates with the agent in this setting range from 5% to 24%, with a median overall survival (OS) of 6 to 8 months.

In the multicenter, single-arm, phase II basket study (NCT02454972), investigators evaluated the safety and efficacy of lurbinectedin in patients across advanced several solid tumors, including SCLC.

The 105 patients in the SCLC cohort were enrolled between October 2015 and October 2018. The median patient age was 60 years (range, 40-83) and 35.2% of patients were aged ≥65 years. The ECOG performance status was 0 for 36.2% of patients, 1 for 56.2% of patients, and 2 for 7.6% of patients.

The median number of prior therapies was 1 (range, 1-2). Regarding response to prior platinum-based therapy, 8.6% of patients had a complete response and 66.7% of patients had a partial response. Fifty-seven percent (n = 60) of patients had sensitive disease and 43% (n = 45) of patients had resistant disease.

Patients received 3.2 mg/m² of lurbinectedin as a 1-hour IV infusion once every 3 weeks. At the time of the data cutoff, 11 patients remained on treatment, 25 patients had discontinued treatment, 66 patients had died, and 3 were lost to follow-up.

Overall, the median progression-free survival (PFS) was 3.9 months (95% CI, 2.6-4.6) and the 6-month PFS rate was 33.6% (95% CI, 24.0-43.1). In the sensitive subgroup, the median PFS was 4.6 months (95% CI, 3.0-6.5) and the 6-month PFS rate was 44.6% (95% CI, 31.2-57.9). In the resistant population, the median PFS was 2.6 months (95% CI, 1.3-3.9) and the 6-month PFS rate was 18.8 months (95% CI, 6.8-30.9).

At a median follow-up of 17.1 months, the median OS was 9.3 months (95% CI, 6.3-11.8) and the 12-month OS rate was 34.2% (95% CI, 23.2-45.1). The median OS was 11.9 months in sensitive patients versus 5.0 months in resistant patients.

Adverse events (AEs) across all grades occurred in 84.8% of patients, with 34.3% of patients experiencing a grade ≥3 AE. Serious AEs were observed in 10.5% of patients. AE-related discontinuations, dose delays, and dose reductions, occurred in 1.9%, 22.1%, and 26.3% of patients, respectively. There were no AE-related deaths.

The most common grade 1/2 AEs included fatigue (51.4%), nausea (32.4%), decreased appetite (21.0%), vomiting (18.1%), diarrhea (12.4%), constipation (9.5%), and neutropenia (5.7%). Grade 3/4 AEs included neutropenia (22.9%), anemia (6.7%), fatigue (6.7%), thrombocytopenia (4.8%), febrile neutropenia (4.8%), pneumonia (1.9%), increase ALT level (1.9%), skin ulcer (1.0%), and diarrhea (1.0%).

Lurbinectedin inhibits RNA polymerase II, and by blocking trans-activated transcription, it induces apoptosis. Previous research demonstrated strong clinical activity with lurbinectedin when used in combination with doxorubicin in the second-line SCLC setting, particularly for sensitive patients.

Paz-Ares LG, Perez JMT, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial. J Clin Oncol. 2019;37(suppl; abstr 8506).