Abstract P3-13-01: Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial
Authors: Balmaña Judit , Cruz Cristina , Garber Judy , Perez Fidalgo Jose A , Lluch Ana , Tung Nadine , Antolin Silvia , Fernandez Cristian , Kahatt Carmen , Szyldergemajn Sergio , Soto Matos Arturo , Extremera Sonia , Baselga Jose , Isakoff Steven J 
Published: May 2015

Abstract
Background: Metastatic breast cancer (MBC) is a clinically heterogeneous disease in which selective approaches are needed to identify patients (pts) who will benefit the most from available therapies and avoid unnecessary toxicities.
Lurbinectedin (PM01183) is a new anticancer drug that binds to the DNA minor groove inducing double-strand breaks and blocking transcription. It has significant in vitro and in vivo antitumor activity, particularly in breast cancer models. PM01183 is more active against homologous recombination-deficient cell lines. Hence, MBC pts with deleterious germline BRCA mutations might be more sensitive to PM01183 than those with sporadic tumors.
PM1183 activity was shown in different tumor types in clinical trials, especially in pts with platinum-resistant ovarian cancer (objective response rate [ORR]: 30%).
Methods: MBC pts &lt; 75-years-old with ductal or lobular carcinoma pretreated with ≤ 3 chemotherapy regimens for MBC, measurable disease per RECIST v1.1, performance status (PS) ≤1 and adequate major organ function are being treated with PM01183 7.0 mg flat dose i.v. every 3 weeks.
The primary aim is to evaluate the clinical efficacy of PM01183 in two cohorts of MBC pts: cohort A: BRCA+ (known germline BRCA1/2 mutation) and cohort B: unselected (BRCA1/2 wild type or unknown mutation status).
The primary endpoint is confirmed ORR by RECIST v1.1. A futility analysis was planned when 20 and 30 pts were recruited in cohort A and B, respectively. If at least 4 pts in cohort A and 3 pts in cohort B, achieve a response, recruitment in that cohort will continue up to 53 and 64 total pts, respectively.
Results: As of June 2014, 56 pts had been enrolled. Cohort A/B (n: 21/35): Median age 40/52-years-old; Cohort A(%)/B(%): PS 0: 48/66; &gt;2 metastatic sites: 58/40; most common sites of metastasis: lymph node 79/33, liver 48/60 and bone 42/48; triple negative: 57/46; hormonal receptor +: 38/49; prior anthracyclines: 95/91, taxanes: 100/94, platinum: 52/26, PARPi: 29/0; cohort A: BRCA 1/2 (%): 52/48.
Cohort A-BRCA 1/2+ (n=21)Cohort B-unselected (n=35)Median cycles (range)4 (1-20)3 (1-14)Best overall response(n= 17 evaluable)(n= 34 evaluable)CR1 (6%)0PR6 (35%)3 (9%)SD6 (35%)16 (47%)PD4 (24%)15 (44%)ORR (95%CI)41% (18-67%)9% (1.9-23.7%)Median duration of response Monts (95%CI)5.0 (0.1-12.8)3.3 (1.4-5.1)
In an exploratory analysis, ORR in cohort A was higher in PARPi naïve pts: 64% (7/11 pts).
Grade (G) 3-4 related adverse events occurred in &gt;5% pts were myelosuppression (neutropenia 69%, febrile neutropenia 7%, thrombocytopenia 14%); G3 fatigue 7%, transient transaminase increase 19% (G4: 2%), nausea 6% and dyspnea 6% (3 pts, 2 of them due to pneumonitis). One patient with massive liver involvement and impaired function died on C1D4 due to multiorgan failure possibly related to the study drug.
Conclusions: PM01183 has promising activity in pretreated MBC pts with BRCA mutation. Safety profile appears to be mostly predictable and with non-cumulative toxicity. Treatment-related neutropenia was manageable with G-CSF and/or dose reduction.
After futility analysis, targeted activity has been met in cohort A (BRCA+), and recruitment will continue up to 53 evaluable BRCA+ pts.
Citation Format: Judit Balmaña, Cristina Cruz, Judy Garber, Jose A Perez Fidalgo, Ana Lluch, Nadine Tung, Silvia Antolin, Cristian Fernandez, Carmen Kahatt, Sergio Szyldergemajn, Arturo Soto Matos, Sonia Extremera, Jose Baselga, Steven J Isakoff. Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-01.