LBA91 - TOMAS2: A randomized phase II study from the Italian Sarcoma Group (ISG) of trabectedin plus olaparib (T+O) or trabectedin (T) in advanced, metastatic, or unresectable soft tissue sarcomas (STS) after failure of standard treatments

Background

Advanced STS represent an unmet medical need. We previously reported feasibility and preliminary activity data of T+O in advanced STS failing standard treatments.

Methods

In this investigator-initiated, open-label, phase 2 randomized trial, adult patients (pts) with advanced STS progressing after ≥1 treatment(s) were randomized in a 1:1 ratio to T 1.1 mg/m2 q21d i.v. plus O tablets 150 mg BID, or T 1.5 mg/m2 q21d i.v. Randomization stratified pts for histology (L-sarcoma vs non-L-sarcoma) and number of prior lines (1 vs ≥2). Primary endpoint: progression-free survival (PFS) rate at 6-month (PFS6m) by RECIST 1.1. Main secondary endpoints: PFS, overall survival (OS), RECIST 1.1 overall response rate (ORR), duration of response (DOR), safety. Exploratory endpoints: correlation of clinical characteristics and molecular biomarkers with outcomes.

Results

Between May-2020 and Nov-2022, 130 pts were enrolled (M/F 49/81; L-/Non-L-sarcoma 67/63; prior lines 1/≥2 93/37) at 13 ISG sites. With a median (m-)follow-up of 10.2 mos, estimated PFS6m and m-PFS per intention-to-treat were 32% (95%CI 22-46%) and 4.0 mos (2.9-5.4) in T+O arm; 28.5% (19.3-42.1) and 2.9 mos (2.2-4.5) in T arm. PFS12m was 20% (12-33) with T+O and 2% (0-14) with T. Best response in 122 evaluable pts was: 6 PR, 25 SD, 31 PD in T+O arm, and 4 PR, 21 SD, 35 PD in T arm, for an ORR of 10 and 7%, respectively. m-DOR was 14.5 mos with T+O and 4.5 with T. OS events were not mature but did not differ between the two arms. Most common grade ≥3 adverse events were neutropenia (58%) thrombocytopenia (20%) and anemia (18.5%) with T+O, and neutropenia (31%), ALT increase (26%) and thrombocytopenia (8%) with T. 5 pts in T+O (8%) and 2 in T (3%) discontinued treatment due to toxicity. No toxic death was reported. Data on available exploratory endpoints will be presented at the meeting.

Conclusions

This is the first randomized trial prospectively testing T+O and T in advanced STS pts. PFS6m with T+O was slightly below the prespecified threshold of 40%. Notably, 20% of pts in T+O were treated for >1 year and deepening into biomarkers of these long responders would improve selection of pts for T+O.

Clinical trial identification

NCT03838744; EudraCT 2018-004497-10.

Editorial acknowledgement

Legal entity responsible for the study

Italian Sarcoma Group.

Funding

The Italian Sarcoma Group sponsored the study. PharmaMar and AstraZeneca provided the drugs free of charge. PharmaMar provided an unrestricted grant to Italian Sarcoma Group.

Disclosure

L. D'Ambrosio: Other, Personal, Advisory Board: PSI CRO Italy, GSK, AstraZeneca, Boehringer Ingelheim; Other, Personal, Other, Meeting participation: PharmaMar, AstraZeneca. A. Brunello: Financial Interests, Personal, Advisory Board: PharmaMar, Boehringer Ingelheim, Deciphera; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Institutional, Local PI: Roche, Deciphera, Boehringer Ingelheim, Rain Therapeutics. B. Vincenzi: Other, Personal, Advisory Board: Abbot, GSK, Lilly; Other, Personal, Speaker’s Bureau: PharmaMar; Other, Institutional, Funding: BD Bard. R. Sanfilippo: Other, Personal, Advisory Board: Boehringer Ingelheim, PharmaMar, Rain Therapeutics. G.G. Baldi: Other, Personal, Advisory Board: Boehringer Ingelheim, Aboutevents srl, Eisai, Lilly, MSD. C. Marchiò: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Bayer, Daiichi Sankyo; Non-Financial Interests, Member, Participation to the ESMO precision Medicine and Translational Research Working Group: ESMO. A..P. Dei Tos: Financial Interests, Personal, Advisory Board: Bayer, Roche; Financial Interests, Personal, Invited Speaker: PharmaMar, Novartis. S. Stacchiotti: Financial Interests, Personal, Advisory Board: Bayer, Bavarian Nordic, Daiichi, Novartis, Ikena, Astex Pharmaceuticals, Rain Therapeutics; Financial Interests, Personal, Invited Speaker: GSK, PharmaMar, Aadi; Financial Interests, Personal, Advisory Board, Advisory board meeting: Agenus; Financial Interests, Personal, Advisory Board, Advisory board meetings: Boehringer; Financial Interests, Personal, Invited Speaker, Lectures: Gentili; Financial Interests, Personal, Advisory Board, Advisory board: Servier; Financial Interests, Institutional, Local PI: Advenchen, Deciphera, Epizyme, Daiichi, GSK, Karyopharm, PharmaMar, SpringWorks, Hutchison MediPharma International Inc, Inhibrix; Financial Interests, Institutional, Coordinating PI: Bayer; Financial Interests, Institutional, Funding: Blueprint, Novartis; Non-Financial Interests, Member of Board of Directors, Secretary: Connective Tissue Oncology; Non-Financial Interests, Advisory Role: Chordoma Foundation, Epithelioid HaemangiondotheliomaFoundation, DesmoidFoundation, Epithelioid Hemangioendothelioma (EHE) Rare Cancer Charity (UK); Non-Financial Interests, Other, Secretary: EORTC soft tissue and bone sarcoma group; Non-Financial Interests, Leadership Role, President: Italian Sarcoma Group. G. Grignani: Other, Personal, Advisory Board: Bayer, Lilly, Boehringer Ingelheim, PharmaMar. All other authors have declared no conflicts of interest.