Lurbinectedin shows activity in patients with platinum-resistant/refractory ovarian cancer

Lurbinectedin is now being evaluated against comparator therapy with topotecan

Lubrinectedin has shown activity in ovarian cancer cell lines, including several that display platinum-resistance, prompting investigators to test it in patients with advanced platinum-resistant or refractory ovarian cancer. Preliminary results from a randomised phase II trial of this novel agent are reported at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

Lubrinectedin binds the minor groove of DNA and is associated with inhibition of tumour growth resulting from reduced cell proliferation due to apoptosis of cells that undergo aberrations during mitosis. It has shown activity in in vitro/in vivo in broad panel of tumours and most importantly in orthotopic primary grafts. The results in ovarian cancer cell lines, including several that display platinum-resistance, prompted investigators to test lubrinectedin in 22 patients with advanced platinum-resistant or refractory ovarian cancer. The primary endpoint of the study was response rate.

For inclusion in the exploratory part of the trial, patients must have had fewer than 3 prior chemotherapies, adequate major organ function and performance status between ECOG 0-2. One prior chemotherapy had been received by 15 (68%) patients and 7 (32%) patients received 2 previous lines of chemotherapy for advanced disease. Six patients showed no response to the last platinum-containing chemotherapy (platinum resistant) and 16 were platinum-resistant, defined as having a platinum-free interval < 6 months.

Patient age ranged from 35 to 77 years with a median of 59 years. Of the 22 patients evaluated for efficacy, 6 responded (two by Rustin and four by RECIST criteria) for an overall response rate of 27% and one patient had a radiological complete response. Progression was seen in 6 (27%) patients at the first evaluation, yielding an overall disease control rate of 73%.

Having demonstrated a minimum of two confirmed response rate, the trial was allowed to proceed to the second stage in April  2012 and enrolled 60 additional patients who were randomised to either lubrinectedin or comparator treatment with topotecan. The preliminary toxicity profile showed myelosuppression, nausea/vomiting despite adequate prophylaxis, and fatigue to be the most common drug-related toxicity.

The results of the first stage of the study were reported at proffered papers session of the Gynaecological cancers programme track by Dr D. Berton-Rigaud. The randomised second stage of the trial is on-going with a goal to confirm the finding from the stage one. Pharmacogenomic analysis is performed to identify potential biomarkers.

In conclusion, lurbinectedin showed promise in patients with platinum-resistant/refractory ovarian cancer and is now being evaluated against comparator therapy with topotecan. According to Dr. Cristiana Sessa next steps in the clinical development of this drug would be testing of combination with chemotherapy (platinum). The results merit further investigation in ovarian cancer and pancreatic adenocarcinoma. Until then additional data are needed, especially comparison with trabectedin with or without cisplatin in ovarian xenografts, confirmation of pre-clinical results in resistant epithelial ovarian cancer and evaluation in pharmacokinetic differences with trabectedin.