Abstract LB-C17: A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations

Background:RET gene aberrations including fusions have been identified across several types of solid malignancies, including lung adenocarcinomas, thyroid, colorectal and invasive breast cancers. Preclinical models has shown that the combination of vandetanib (VAN), a multi tyrosine kinase inhibitor of VEGFR2/EGFR and RET pathways) and everolimus (EV), an mTOR pathway inhibitor, overcomes intrinsic and /or acquired tumor resistance to either agent alone, suggesting a rationale for investigating this combination in cancer patients, including those harboring aberrations in the drug targets. Methods: We designed a dose escalation and expansion trial with “3+3” design to determine the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), dose-limiting toxicities (DLTs) and activity of the combination. During the escalation phase, the study drugs (VAN, EV) were given at the following doses, respectively: level 0 (100 mg, 2.5 mg), level 1 (200mg, 2.5mg), level 2 (200mg, 5mg), level 3 (300 mg, 5mg), and level 4 (300mg, 10mg). Both study drugs are given continuously on a 28 day schedule. Tumor responses are assessed using RECIST v1.1. Tumor molecular aberrations were detected by Next Generation Sequencing (NSG) and/or Fluorescence In Situ Hybridization (FISH). Results: To date, 72 adult patients have been treated. Median age was 56 years (range 18-82 years) and 38 patients (53%) were male. The most common diagnoses were sarcoma (n = 15); renal cell carcinoma (n = 11); thyroid cancer (n = 10; n = 3 medullary) lung cancer (n = 10). Thirty patients (41%) had 3 or more sites of metastases. Nine patients were treated at dose level 0 (VAN 100 mg daily + EV 2.5 mg daily), five at dose level 1 (VAN 200 mg daily + EV 2.5 mg daily), and 6 patients at dose level 4 (highest dose VAN 300 mg daily + EV 10 mg daily). The most common adverse events observed in patients across different dose levels included G1 rash (n = 10), G1-G3 diarrhea (n = 21); G1-G4 thrombocytopenia (n = 9); G1-G2 hypertriglyceridemia/hypercholesterolemia (n = 8); G1-G2 hypertension (n = 6), G1-G2 QTc prolongation (n = 4); G1-G transaminitis (n = 4). Dose escalation has been completed and the expansion phase is currently ongoing in patients with advanced malignancies harboring RET, or P13K, PIK3R1, TSC1/2 and AKT genomic aberrations. The best responses were PR (n = 7), and SD (n = 33). Ten patients with reported SD (30.3%) experienced durable responses (> 6 months). One RET M918T mutant medullary thyroid cancer patient, who developed acquired resistance to VAN, achieved a 25% reduction on this combination. Three NSCLC patients with RET fusions (100%) responded with one reaching 48% decrease per RECIST. In addition there was evidence of blood-brain barrier penetration in 2 patients with RET fusion patients who had brain metastases. Conclusions: The combination of VAN and EV was reasonably well tolerated at the highest doses of each of the drugs. Evidence of response was noted in heavily pre-treated patients with refractory solid tumors and targetable genomic aberrations specifically RET. The combination has CNS penetration in RET fusion NSCLC. Citation Format: Tina Cascone, Kenneth R. Hess, Sarina Piha-Paul, David S. Hong, Michael Roxas, Ishwaria M. Subbiah, Siquing Fu, Aung Naing, Filip Janku, Daniel Karp, Steven I. Sherman, Funda Meric-Bernstam, John V. Heymach, Vivek Subbiah. A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C17.