Cercek, Andrea

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the United States. Aberrant activation of the Wnt signaling pathway is associated with CRC progression. Ring finger protein 43 (RNF43) is a single-pass type 1 transmembrane protein and a key feedback regulator of Wnt. SC-006 is a RNF43 targeted antibody drug conjugate, linked to a pyrrolobenzodiazepine dimer DNA crosslinking agent. Budigalimab (ABBV-181) is a PD-1 targeting, humanized, recombinant immunoglobulin G1 monoclonal antibody with Fc mutations (L234A, L235A) shown to reduce Fc receptor interactions and limit effector function. This open-label, Phase 1 clinical trial assessed the safety and efficacy of SC-006 as monotherapy and in combination with budigalimab in patients with CRC (NCT03035279). Methods: Evaluable patients had histologically or cytologically confirmed advanced metastatic or unresectable CRC. The trial consisted of 2 parts: part A (SC-006-monotherapy, 2 to 12 µg/kg, IV) and part B (SC-006 in combination with budigalimab at a fixed dose of 375 mg/kg IV every 3 weeks [Q3W]). Efficacy was assessed per RECIST 1.1 by radiographic assessments. Results: As of April 2019, 29 patients were enrolled (n=20 in part A and n=9 in part B). All patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs (>20% of patients) are summarized in Table 1. Two patients (7%) had dose-limiting toxicities of grade 4 thrombocytopenia. All 29 patients discontinued from the study, with study drug being discontinued for 76% of patients due to progressive disease. One death occurred in part A due to gastrointestinal hemorrhage with possible relation to SC-006. Serious TEAEs occurred in 8 patients (28%); these included thrombocytopenia and malignant neoplasm progression in 2 patients (7%) each. Progressive disease occurred in 18 patients (62%), stable disease was reported in 10 patients (34%) and the response for 1 patient was not reported. Conclusion: SC-006 dose escalation was limited by thrombocytopenia observed below the predicted efficacious dose, leading to study termination. Table 1.Summary of the Most Common Treatment-Emergent Adverse EventsPart A: SC-006-monotherapyPart B: SC-006+budigalimabTEAEs (>20% patients), n (%)2 ug/kg4 ug/kg8 ug/kg4 ug/kg8 ug/kg12 ug/kg4 ug/kg Q6W+budigalimab8 ug/kg Q6W+budigalimabOverallQ3WQ3WQ3WQ6WQ6WQ6W(N=1)(N=3)(N=1)(N=2)(N=10)(N=3)(N=4)(N=5)(N=29)Thrombocytopenia01 (33)1 (100)1 (50)4 (40)3 (100)1 (25)4 (80)15 (52)Fatigue0001 (50)3 (30)2 (67)3 (75)3 (60)12 (41)Nausea0001 (50)5 (50)1 (33)2 (50)2 (40)11 (38)Edema peripheral01 (33)01 (50)4 (40)02 (50)1 (20)9 (31)Decreased appetite01 (33)01 (50)4 (40)002 (40)8 (28)Dyspnea00004 (40)3 (100)01 (20)8 (28)Vomiting0001 (50)3 (30)1 (33)2 (50)1 (20)8 (28)Constipation0001 (50)3 (30)01 (25)2 (40)7 (24) Citation Format: Katrina S. Pedersen, Amit Mahipal, Andrea Cercek, Susanna Ulahannan, Michael Rossi, Abraham Fong, Daniel Brickman, Johanna Bendell. First-in-human clinical trial of SC-006, a RNF43 targeted antibody-drug conjugate, as a monotherapy and in combination with budigalimab in patients with advanced colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT167.

TPS3624 Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.