Alexia Tellier

PURPOSE: Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. PATIENTS AND METHODS: Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. RESULTS: Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti-vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. CONCLUSION: Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.

2511 Background: SAR566658 (SAR) is a maytansinoid-loaded ADC targeting CA6, a sialoglycotope of MUC-1 over-expressed in solid tumors and rarely in normal tissues. Methods: Phase I dose escalation and expansion study to evaluate SAR intravenous administration as single agent every 3 weeks (q3w) and 2 weeks (q2w). Primary objective included dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives were PK, PD and preliminary efficacy assessment (RECIST1.1). Results: One hundred and fourteen patients (Pts) with heavily pretreated solid tumors expressing CA6 in ≥ 30% tumor cells with an intensity 2/3+ by immunohistochemistry were enrolled. SAR was administered across 11 dose levels (DLs) (10 to 240 mg/m² q3w and 120 mg/m² q2w). DLTs [1 grade (Gr) 3 diarrhea and 2 Gr3 keratitis] were observed at 240 mg/m². Initial RD was 190 mg/m² however a high incidence of keratopathy was seen mainly at cycle 2. PK/safety simulation, preserving drug exposure and limiting keratopathy incidence, proposed two alternative schedules: 90 mg/m² D1,D8 q3w and 120 mg/m² q2w. Most common adverse event (AE) was reversible Gr2/3 keratopathy in 41/114 (36%) (Gr3 in 9 Pts). Among these 41 Pts, 15/23 (65%) received 190 mg/m², 12/33 (36%) 150 mg/m², 6/8 (75%) 240 mg/m², 6/17 (35%) 90 mg/m² D1,D8 and 2/16 (13%) 120 mg/m² q2w. Prophylaxis with vasoconstrictor and steroids eye drops implemented in 8 patients in alternative schedules prevented keratopathy. Other AEs were fatigue (32.6%), peripheral neuropathy (31.6%), GI disorders [(nausea (29%), abdominal pain (26%), diarrhea (25%)] and neutropenia (2.6%). Low grade liver and renal abnormalities were noted.Tumor regression was noted in about 60% Pts at 190 and 90 mg/m² D1,D8 and 35% Pts at 150 and 120 mg/m² q2w. One complete response (ovary), 8 partial responses (3 breast, 2 ovary, 1 NSCLC, 1 cervix and 1 bladder) and 39% stable disease were noted. Highest overall response rate (ORR) was observed in 2/15 at 90 mg/m² D1,D8 and 3/23 at 190 mg/m². Conclusions: SAR 90 mg/m² D1,D8 q3w provided a favorable safety profile and encouraging antitumor activity and is selected as the RD for further clinical development. Clinical trial information: NCT01156870.

Abstract Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface–specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization. It recognizes CA6, a Mucin-1 (MUC1)-associated sialoglycotope that is highly detected in breast, ovarian, lung, and bladder carcinomas. SAR566658 antibody–drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative drug, DM4. SAR566658 binds to tumor cells with subnanomolar affinity, allowing good ADC internalization and intracellular delivery of DM4, resulting in tumor cell death (IC50 from 1 to 7.3 nmol/L). SAR566658 showed in vivo antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary tumor xenografts and against three breast patient-derived xenografts. Tumor regression was observed in all tumor models with minimal effective dose correlating with CA6 expression. SAR566658 displayed better efficacy than standard-of-care nontargeted tubulin binders. These data support the development of SAR566658 in patients with CA6-expressing tumors.

Abstract SAR566658 antibody drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative DM4 that has been evaluated in the clinical setting. The purpose of our work was; 1) characterize the epitope targeted by anti DS6 on mucin1, 2) determine the prevalence of antigen expression in a patient population and 3) further explore preclinical activities of the ADC. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization of immunocompetent mice. It specifically recognizes a MUC-1 tandem repeat domain in the context of cancer associated glycosylation. CA6-positive MUC-1 carries mucin-type O-linked glycans with α2,3-sialylated and β1,4-galactosylated termini, and antibody binding was abrogated by treating MUC-1 with specific glycosidases that remove either one of these glycan structures. However, the antibody did not bind to synthetic glycans modeled according to the major O-glycans of MUC-1. Our characterization of the peptide-glycotope leads us to conclude that tumor associated glycosylation is essential for the formation of the epitope on the peptide sequence of the MUC-1 tandem repeat domain. CA6 expression was evaluated by immunohistochemistry in paraffin embedded tumor tissue samples: 35.2% of breast cancer patients, 70,1% of ovarian cancer patients and 58,5% of bladder cancer patients have at least 30% of CA6 positive cells with an intensity of 2+/3+ in a multinational population-based study. In pre-clinical in vivo models, SAR566658 induced anti-tumor activity against CA6 positive tumor models of human pancreas, cervix and bladder cancer as well as and 3 Breast Patient-Derived Xenografts (PDX). Efficacy was correlated with MUC1-CA6 expression levels. In 3 additional models, SAR566658 showed anti-tumor activity that was more potent when compared to 3 conventional tubulin cytotoxic agents, docetaxel, vinorelbine and vinblastine. Citation Format: Marc Trombe, Anne Caron, Alexia Tellier, Chantal Carrez, Stephane Guérif, Severine Clavier, Nathalie Karst, Juhani Saarinen, Tero Satomaa, Virve Pitkänen, Olli Aitio, Annamari Heiskanen, Matteo Fassan, Jan Pinkas, Raffaele Baffa, Veronique Blanc, Celine Nicolazzi. Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 235.

SAR566658 antibody drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative DM4 that has been evaluated in the clinical setting. The purpose of our work was; 1) characterize the epitope targeted by anti DS6 on mucin1, 2) determine the prevalence of antigen expression in a patient population and 3) further explore preclinical activities of the ADC. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization of immunocompetent mice. It specifically recognizes a MUC-1 tandem repeat domain in the context of cancer associated glycosylation. CA6-positive MUC-1 carries mucin-type O-linked glycans with α2,3-sialylated and β1,4-galactosylated termini, and antibody binding was abrogated by treating MUC-1 with specific glycosidases that remove either one of these glycan structures. However, the antibody did not bind to synthetic glycans modeled according to the major O-glycans of MUC-1. Our characterization of the peptide-glycotope leads us to conclude that tumor associated glycosylation is essential for the formation of the epitope on the peptide sequence of the MUC-1 tandem repeat domain. CA6 expression was evaluated by immunohistochemistry in paraffin embedded tumor tissue samples: 35.2% of breast cancer patients, 70,1% of ovarian cancer patients and 58,5% of bladder cancer patients have at least 30% of CA6 positive cells with an intensity of 2+/3+ in a multinational population-based study. In pre-clinical in vivo models, SAR566658 induced anti-tumor activity against CA6 positive tumor models of human pancreas, cervix and bladder cancer as well as and 3 Breast Patient-Derived Xenografts (PDX). Efficacy was correlated with MUC1-CA6 expression levels. In 3 additional models, SAR566658 showed anti-tumor activity that was more potent when compared to 3 conventional tubulin cytotoxic agents, docetaxel, vinorelbine and vinblastine.Citation Format: Marc Trombe, Anne Caron, Alexia Tellier, Chantal Carrez, Stephane Guérif, Severine Clavier, Nathalie Karst, Juhani Saarinen, Tero Satomaa, Virve Pitkänen, Olli Aitio, Annamari Heiskanen, Matteo Fassan, Jan Pinkas, Raffaele Baffa, Veronique Blanc, Celine Nicolazzi. Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 235.