Lurbinectedin NDA Anticipated in Small Cell Lung Cancer

A new drug application (NDA) will be submitted to the FDA under accelerated approval status for lurbinectedin monotherapy for the second-line treatment of patients with small cell lung cancer (SCLC), according to PharmaMar, the developer of the marine-derived agent.

The NDA will be based on findings from a SCLC cohort of the phase II basket trial (NCT02454972) evaluating single-agent lurbinectedin, which demonstrated an overall response rate (ORR) of 35.2% in this patient population. The application will likely be filed in the fourth quarter of 2020, the company stated in a press release.

Lurbinectedin inhibits RNA polymerase II, and by blocking transactivated transcription, it induces apoptosis.

In the multicenter, single-arm, phase II basket study, investigators evaluated the safety and efficacy of lurbinectedin in patients across advanced solid tumors, including SCLC, head and neck cancer, neuroendocrine tumors, biliary tract cancer, endometrial cancer, BRCA1/2-mutant metastatic breast cancer, carcinoma of unknown primary site, germ cell tumors, and Ewing’s family of tumors.

There were 105 patients in the SCLC cohort, who 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 (PR). Fifty-seven percent (n = 60) of patients had sensitive disease and 43% (n = 45) of patients had resistant disease.

Lurbinectedin was administered at 3.2 mg/m² as a 1-hour intravenous 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.

The ORR consisted of all PRs, 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).

Results also showed that 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.

Regarding safety, adverse events (AEs) across all grades were reported 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 alanine aminotransferase level (1.9%), skin ulcer (1.0%), and diarrhea (1.0%).

Lurbinectedin inhibits RNA polymerase II, and by blocking transactivated 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.

The accelerated approval program allows for the submission of the registration dossier for evaluation based on phase II data from the investigational agent for serious conditions that also satisfy an unmet medical need.

In August 2018, the FDA granted lurbinectedin an orphan drug designation for the treatment of patients with SCLC. The designation facilitates the development and review of therapies in areas of high unmet medical need.

References

1. PhamaMar will submit NDA for lurbinectedin under accelerated approval in SCLC in the USA. PharmaMar. Published August 19, 2019. https://bit.ly/2KIxMbF. Accessed August 19, 2019.
2. 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).