ESMO 2016: Antitumour Activity Demonstrated With Lurbinectedin in Patients With Metastatic Breast Cancer and BRCA Mutations

Lurbinectedin proceeds to phase III trial evaluation

Lurbinectedin shows promising clinical benefit in pretreated patients with metastatic breast cancer and BRCA1 or BRCA2 mutations, including patients previously treated with platinum.

Lurbinectedin (PM01183) blocks trans-activated transcription by binding to the minor groove of DNA. Activity has been demonstrated in patients with diverse tumour types, and in those that are resistant to platinum-based chemotherapy. Observations that lurbinectedin was active against homologous-recombination-deficient cell lines led investigators to test it in patients with metastatic breast cancer having deleterious germline BRCA mutations.

Lead investigator Judith Balmaña, Department of Medical Oncology, Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology in Barcelona, Spain, presented findings from a phase II trial at the ESMO 2016 Congress in Copenhagen, Denmark on 8 October.

This phase II trial enrolled patients with BRCA mutation positive, measurable metastatic breast cancer per RECIST v1.1, with performance status ≤ 1. Patients were required to have adequate major organ function. Lurbinectedin was initially to be administered to all patients at 7 mg fixed dose by i.v. every 3 weeks but the dose was changed by protocol amendment to 3.5 mg/m2 for improved safety. In all, 35 patients received 7 mg of lurbinectedin and 19 patients were treated with 3.5 mg/m2. The primary endpoint of the trial was confirmed overall response rate (ORR) by RECIST v1.1.

The patients’ median age was 43 years. Thirty patients were performance status 0 and 33 patients had more than 2 metastatic sites. The patients had a median of one prior chemotherapy treatment for advanced disease; additionally, 45 patients had received prior anthracyclines, 47 received taxanes, 27 received platinum, and 9 had been treated with PARP inhibitors. BRCA1 mutations were documented in 30 patients and 31 patients had triple negative breast cancer.

Lurbinectedin trial met the primary endpoint

Lurbinectedin has been administered to 54 patients as of May 2016, with patients receiving a median of 6 (range: 1 to 24) treatment cycles.

Of 54 patients with evaluable data, the ORR was 39% (95% CI   26, 54) in patients receiving the fixed dose, and 44% in patients dosed at 3.5 mg/m2, with an overall response rate of 40.7% (95% CI 27, 55). The best overall response with lurbinectedin included complete response in one (2%) patient, partial response in 21 (39%) patients, and stable disease in 23 (43%) patients. Just 9 (17%) patients with advanced metastatic breast cancer experienced progressive disease. The median duration of response was 6.7 months (95% CI 3.0, 11.3) and progression-free survival was 4.1+ months (95% CI 2.8, 5.9).

Platinum pre-treated patients demonstrated an ORR of 26% (95% CI  11, 26).

Antitumour Activity Demonstrated With Lurbinectedin in Patients With Metastatic Breast Cancer and BRCA Mutations

Waterfall of sum of target lesions. © Judith Balmaña

Efficacy maintained with fewer adverse events at lower dose

In patients receiving the fixed dose of lurbinectedin, the most commonly reported grades 3/4 adverse events (AEs) included neutropenia in 71% of patients and grade 4 neutropenia, which was seen in 51%. Febrile neutropenia occurred in 29%, thrombocytopenia, and transaminase increase were each seen in 26% of patients. Grade 4 throbocytopenia, and transaminase increase occured in 20%, and 3% of patients respectively. Grade 3 fatigue and nausea occured in 17% and 9% of patients, respectively.

Conclusions

At the reduced dose, AEs incuded neutropenia in 50% of patients, febrile neutropenia and thrombocytopenia in 6% each, transaminase increase occurred in 11%, and grade 3 fatigue and nausea occurred in 17% and 6%, respectively. Grade 4 neutropenia was seen in 5% of patients but no other grade 4 AEs occurred in this cohort.

The investigators concluded that the trial met the primary endpoint and lurbinectedin showed activity in primary BRCA positive metastatic breast cancer, including patients that had previously received platinum therapy.

They noted that tolerance to lurbinectedin improved at the 3.5 mg/m2 dose without compromising efficacy.

Based on these results and on predefined criteria of 17 or more confirmed responses in the cohort of evaluable patients, the investigators concluded that further development of lurbinectedin in patients with BRCA mutation and metastatic breast cancer is warranted.

Reference

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Anti-tumor activity of PM01183 (lurbinectedin) in BRCA1/2-associated metastatic breast cancer patients: Results of a single-agent phase II trial

J. Balmaña, C. Cruz, B.K. Arun, M. Telli, J. Garber, S. Domchek, C.M. Fernandez, C. Kahatt, S. Szyldergemajn, A. Soto-Matos, A. Perez de la Haza, J.A. Perez Fidalgo, A. Lluch-Hernandez, S. Antolin, N.M. Tung, L.T. Vahdat, R. Lopez, S.J.J. Isakoff

This trial was funded by PharmaMar S.A.