Matteo Duca

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.

Pitfalls in oncology: a unique case of thoracic splenosis mimicking malignancy in a patient with resected breast cancer

Thoracic splenosis (TS) is a condition of autotransplantation of splenic tissue into the pleural cavity after thoraco-abdominal trauma, with diaphragmatic and spleen injury. It is usually asymptomatic and discovered as an incidental finding at imaging performed for other reasons. Its differential diagnosis regards different benign and malignant conditions and should be discerned avoiding invasive procedures. We report a case of thoracic mass associated with pleural nodules mimicking malignancy in a patient with resected breast cancer for whom a diagnosis of TS was made early by using non-invasive methods. Briefly, we review the literature data on TS, comment concisely the possible implications of using invasive procedures and describe the current non-invasive techniques available. Furthermore, we highlight the importance of an accurate medical history collection, the role of the multidisciplinary board and their impact on treatment decision making. Finally, we conclude that clinical information and imaging would be the discriminating factors to avoid unnecessary invasive procedures.

Abstract 3943: Baseline LDH serum level as predictive value of activity in patients treated with anti PD-1 and PDL-1 monoclonal antibodies

BACKGROUND: Lactate dehydrogenase (LDH) is a key enzyme in the glycolytic metabolism, especially in anaerobic condition. High serum levels at baseline seem to be a negative prognostic marker in many tumor types, as well a negative predictive marker for response to treatment with anti CTL4 antibodies(Ipilimumab)in Malignant Melanoma. Recently, the treatment of several advanced tumors with anti PD-1 or PDL-1 monoclonal antibodies (mAbs) showed better outcome in comparison to Ipilimumab. However, biomarkers for a proper selection of responding patients is not yet available. The aim of this study is to correlate LDH serum level at baseline with clinical outcome in patients (pts) with advanced solid tumors treated with anti PDL-1 and anti PD-1 mAbs. MATERIAL AND METHODS: We evaluated baseline LDH serum level in 145 pts affected by advanced solid tumors, treated at our Institute with anti PDL-1 and anti PD-1 mAbs. The rate of clinical responses and progression free survival (PFS) were related to normal or elevated baseline LDH serum level. We stratified the pts in 4 groups: normal value (group A),up to 1.5 x ULN (group B); 1.5 x ULN (Group C); > 2 x ULN (Group D). We defined as disease control (DC) any complete (CR) and partial response (PR) or stable disease (SD) lasting > 3 months. Correlation between LDH serum levels and DC was assessed by Fisher9s exact test; PFS was estimated using the Kaplan-Meier method. RESULTS: We evaluated a heterogeneous population of 145 patients: 73 pts with lung cancer (50.3%; 67 NSCLC, 6 SCLC); 32 pts with Melanoma (22%) and 40 pts (27.6%) with other solid tumors (8 urothelial, 7 biliary tract, 6 mesothelioma, 4 head and neck, 4 sarcoma, 3 gastric, 3 colon, 2 RCC, 1 thyroid, 1 ovarian, 1 HCC). 79 pts (54.5%) were treated by anti PD-1 and 66 (45.5%) by anti PDL-1 agents. Overall as “best response”, 79 pts (54.5%) achieved DC (1 CR, 26 PR, 52 SD) and 66 pts (45.5%) had progressive disease (PD). DC was achieved in 41/79 (52%) pts treated by anti PD-1 and 38/66 (58%) pts treated by anti PDL-1: only 2/41 (5%) and 5/38 (13%) of them had high LDH levels at baseline, respectively. Among 107 pts in Group A, 72 (67.3%) achieved DC as compared to 7/38 pts (18.4%) with high levels of LDH (Group B-D) (p: 0.0001). In the latter groups, PD occurred in 17/23 (74%), 5/6 (83%) and 9/9 (100%) patients in the B, C and D group respectively. CONCLUSIONS: According to this preliminary analysis high baseline LDH serum levels seems to predict a greater likelihood of obtaining worse clinical outcome in terms of response and PFS also in patients treated by anti PD-1 and anti PDL-1 mAbs. In order to confirm this interesting result, we are evaluating a greater number of patients treated with anti PD-1 and anti PDL-1 mAbs at our Institution. Citation Format: Maria Silvia Cona, Valter Torri, Massimo Di Nicola, Marina Garassino, Michele Del Vecchio, Sara Cresta, Diego Signorelli, Silvia Damian, Matteo Duca, Alice Indini, Monica Niger, Filippo de Braud. Baseline LDH serum level as predictive value of activity in patients treated with anti PD-1 and PDL-1 monoclonal antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3943.

Abstract LB-A08: ALK and ROS-1 status: A retrospective analysis in solid tumors

Background: Tyrosine kinase receptors are important regulators of cellular signal transduction pathways that play a crucial role in development of cancer. Among them, Anaplastic Lymphoma Kinase (ALK) and C-Ros Oncogene-1 (ROS-1) are activated by rearrangement in several tumors. Tailored therapies have been developed according to the status of ALK and ROS-1, successfully used in NSCLC and potentially useful in other solid tumors harboring ALK and ROS-1 aberrations. Material and methods:ALK and ROS-1 status was evaluated in 666 and 441 patients with solid tumors, respectively, since 2014 at the Pathology Department. ALK and ROS-1 rearrangement and gene copy number variation (CNV) were assayed by fluorescence in situ hybridization (FISH). Gene copy number gain was defined by 3 to 5 fusion signals on average in ≥10% of cells, with amplification being highlighted by the clusters or 10 to 15 fusion signals in 10% or more tumor cells. Results:ALK status was assessed in 650/666 (97%) cases, while ROS-1 status was evaluable in 426/441 (96%). We identified 15/650 (2.3%) cases with ALK rearrangment, including 13 lung adenocarcinomas (4.1%), 1 colon cancer (0.5%) and 1 myoepithelioma (0.5%). CNV for ALK was documented in 53% lung adenocarcinoma, 50% pancreatic, 41% biliary and 37% colon carcinoma patients. We found 7/426 (1.6%) tumors with ROS-1 rearrangement, corresponding to 5 lung (2.7%) and 2 colon (1.3%) adenocarcinomas. CNV for ROS-1 was more frequent in melanoma (77%), neuroendocrine tumors (39%) and NSCLC (32%, 3/4 cases of ROS-1 amplification were squamous carcinoma). Eight out of the 22 rearranged cases (5 ALK and 3 ROS-1) were tested for both genes: these aberrations were mutually exclusive. Three out of 5 (60%) ALK rearranged tumors showed ROS-1 deletion. No ALK and ROS-1 alterations were documented in 30 pancreatic, 25 HN 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A08.