Activity of trabectedin in germline brca1/2-mutated metastatic breast cancer: results of an international first-in-class phase ii study .S. Delaloge, R. Wolp-Diniz, T. Byrski2 , J. L. Blum, A. Gonçalves , M. Campone, P. Lardelli, C. Kahatt, A. Nieto, M. Cullell-Young and J. Lubinski .
Abstract .
Background :
Breast cancer is a heterogeneous disease defined by both germline and somatic abnormalities. In preclinical models, tumors carrying homologous recombination defects are highly sensitive to trabectedin. This phase II trial evaluated the efficacy and safety of trabectedin in BRCA1/2 germline mutation carriers with pretreated metastatic breast cancer (MBC).
Patients and methods :
Trabectedin 1.3 mg/m2 as a 3-hour intravenous infusion was administered every 3 weeks until progression or intolerance. The primary efficacy endpoint was the objective response rate (ORR) as per RECIST. Secondary efficacy endpoints comprised time-to-event endpoints, and changes in tumor volume and expression of tumor marker CA15.3. Safety was evaluated using the NCI-CTCAE.
Results :
Forty BRCA1/2 germline mutation carriers with MBC were included. Confirmed partial response (PR) occurred in 6 of 35 evaluable patients (ORR=17%; 95% CI: 7%-34%) and lasted 1.4-6.8 months. Median PFS was 3.9 months (95% CI, 1.6-5.5 months). Eight patients (21%) showed changes in tumor volume, and 14 (40%) a clinical benefit. Trabectedin-related adverse events were generally mild/moderate, the most common being fatigue, nausea, constipation and anorexia. Severe laboratory abnormalities (neutropenia, transaminase increases) were mostly transient and non-cumulative, and were managed by dose adjustments.
Conclusion :
With the caveat of the limited patient number, trabectedin monotherapy showed activity and was well tolerated in heavily pretreated metastatic breast cancer patients selected for germline BRCA mutation.
These results prompt further evaluation of trabectedin alone or combined with other specific drugs in this indication .