Trabectedin (T) as second line treatment option for patients with epithelioid malignant pleural mesothelioma (MPM) in progression following pemetrexed/platin-derivates chemotherapy: ATREUS trial.

Abstract

8513 Background: Systemic chemotherapy in MPM is inevitably followed by relapse, and response rates to second line treatment are limited. T is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment with demonstrated activity against a range of tumors. We aimed to study the activity and safety of T in advanced MPM. Methods: ATREUS, an Italian multicenter single arm phase II trial, assessed the activity T in MPM evaluating the proportion of patients responding to treatment and achieving progression free survival for 12 weeks (PFS12w). Pre-treated epithelioid and naive or pre-treated biphasic/sarcomatoid pts were treated until progression or unacceptable toxicity. Initial dose was 1.3 mg/m2, over 3 hours every 21 days, later reduced to 1.1 mg/m2to improve tolerability. In the epithelioid cohort, sample size was based on a Simon's Optimal Two-Stage Design. The study was set to reject, at an alpha error of 10% the hypothesis that PFS12w was ≤25% and to demonstrate, with a power of 85% the hypothesis that PFS12w was ≥40%. At least 20 out of 62 pts with assessed disease, no major protocol violations, either receiving ≥12 weeks of treatment or interrupting before for progression or death (per protocol – PP analysis) were to reach PFS12w in order to consider T effective. Results: 71 pts were enrolled and evaluable. Average age was 65.8 ± 8.75 years. 71.8% were male and 82.5% presented stage III or IV disease. 42.4% (25/59) of pts included in the PP analysis obtained PFS12w (95% CI: 29.6% - 55.9%). In a second, more conservative analysis, including pts withdrawn prematurely for toxicity or intercurrent illness as failures, PFS12w rate reached 38.5% (25/65 pts). The most frequent grade ≥3 treatment-related toxicities werehepatic toxicity (60.5%), non-febrile neutropenia (21.1%), and fatigue (6.6%). Five pts (7%) interrupted treatment for toxicities (2 liver, 1 multi-organ failure, 1 thrombocytopenia, 1 T intolerance). Conclusions: In pts with advanced epithelioid MPM, second line treatment with T showed an elevated rate of disease stabilization. Safety data is promising but require further evaluation. Clinical trial information: NCT02194231.

Congress Report ASCO 2017

“…A phase II basket trial explored the antibody-drug conjugate ado-trastuzumab, also known as T-DM1, in patients with HER2-amplified and HER2-mutant advanced solid cancers, at 3.6 mg/kg every 3 weeks until disease progression [6]. T-DM1 consists of trastuzumab and the cytotoxic agent emtansine, and it has already been approved for the treatment of HER2-positive breast cancer.…”

“…Based on the AURA3 data, Mok et al presented the first comparative evidence of osimertinib activity in CNS metastases from a randomised phase III study [6]. Patients with stable asymptomatic brain lesions were eligible for AURA3.…”

“…However, patients invariably relapse on crizotinib treatment, with the central nervous system (CNS) being one of the most common and challenging sites of relapse. The second-generation ALK inhibitor alectinib is more potent than crizotinib [1,2] and shows clinical activity in crizotinib-resistant NSCLC [3][4][5][6]. Notably, trial data have indicated significant CNS activity.…”

“…Indeed, as demonstrated by a retrospective analysis of 23 patients from the phase I AURA trial, MET amplifi cations represent a major resistance mechanism to osimertinib treatment [6]. All patients underwent tissue biopsy and/ or analysis for plasma circulating tumour DNA at the time of progression on osimertinib.…”

“…In EGFRmutant NSCLC, the receptor tyrosine kinase MET is expressed in approximately 25 % to 75 % of cases and represents a mechanism of acquired resistance to EGFR inhibition. The bivalent MET antibody emibetuzumab was tested in a phase II study that evaluated addition of emibetuzumab to first-line erlotinib, with the purpose being to delay acquired resistance to erlotinib in EGFR-mutant, metastatic NSCLC patients [6]. Only patients who showed disease control after an 8-week erlotinib lead-in were randomised to either emibetuzumab plus erlotinib (n = 71) or erlotinib alone (n = 70).…”