Abstract A095: Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer
Authors: Hassan Raffit , Wang Ding , Wrangle John , Thomas Anish , Byars Angus , Asschert Lianne , Atienza Rolando , Rajagopalan Prabhu , Walter Annette , Zhang Jun , Sarapa Nenad , Kindler Hedy 
Published: August 2018

Abstract
Background: Phase I study with the antibody-drug conjugate anetumab ravtansine demonstrated promising safety and efficacy as monotherapy in mesothelin-expressing tumors, and in particular for patients with advanced metastatic malignant pleural mesothelioma. Pemetrexed in combination with cisplatin is standard for first-line treatment of patients with metastatic mesothelioma and NSCLC. We therefore conducted a phase Ib study to determine the safety, tolerability, and maximum tolerated dose (MTD) of anetumab ravtansine in combination with pemetrexed/cisplatin (Pem/Cis) in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous NSCLC. Methods: Patients with histologically confirmed, unresectable, locally advanced or metastatic, mesothelin-expressing predominantly epithelial pleural or peritoneal mesothelioma or nonsquamous NSCLC, who previously failed ≤3 prior lines of chemotherapy, were eligible. Patients were prescreened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. Anetumab ravtansine was administered by 1-hour IV infusion on day 1 of every 21-day treatment cycle (Q3W). Pem (500 mg/m2) and Cis (75 mg/m2) were administered as IV infusions Q3W. Serial plasma samples were collected and analyzed for anetumab ravtansine and its components, pemetrexed, total and free platinum. Response to therapy was assessed by RECIST 1.1 and modified RECIST criteria for mesothelioma. Results: As of June 12, 2017, 17 patients had been treated and had received ≥2 cycles of treatment, including 7 patients with pleural mesothelioma, 9 with peritoneal mesothelioma, and 1 with NSCLC. Three patients were treated with anetumab ravtansine 5.5 mg/kg in combination with Pem/Cis with no dose-limiting toxicity (DLT). Six patients were then treated with anetumab ravtansine 6.5 mg/kg in combination with Pem/Cis, again without DLTs. This dose in combination was deemed as the MTD. An additional 8 patients were enrolled in an MTD expansion cohort. Anetumab ravtansine-related adverse events were mainly grade (G)1 and G2. G1/G2 eye toxicities were possibly more frequent with the combination than in historical data. There was one G3 corneal microcystic event and one G3 hypertension. There was a 50% overall response rate (all partial responses) from 16 evaluable patients. Of 13 patients treated at the 6.5 mg/kg MTD dose of anetumab ravtansine in combination with Pem/Cis, the overall response rate was 46%. Based on comparisons to historical data and within-subject comparisons in small number of subjects, clinically relevant PK interaction was not observed. Conclusions: Anetumab ravtansine at 6.5 mg/kg dosed Q3W in combination with standard dosing of Pem/Cis had a manageable toxicity profile without evidence of PK interaction and with early signs of clinical efficacy. Anetumab ravtansine at 6.5 mg/kg in combination with Pem 500 mg/m2 and Cis 75 mg/m2, all administered in a Q3W regimen, is thus feasible and the recommended dose for future study.
Citation Format: Raffit Hassan, Ding Wang, John Wrangle, Anish Thomas, Angus Byars, Lianne Asschert, Rolando Atienza, Prabhu Rajagopalan, Annette Walter, Jun Zhang, Nenad Sarapa, Hedy Kindler. Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A095.