Results of ACCURACY: A phase 2 trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notch <sup>mut</sup> ).
Authors: Renata Ferrarotto, Robert Metcalf, Cristina P. Rodriguez, Jameel Muzaffar, Caroline Even, Cesar Augusto Perez, Carla M.L.- Van Herpen, Marc Oliva, Bing Xia, Daniel W. Bowles, Aharon Popovtzer, Eric Winquist, Lori J. Wirth, Desiree Hao, Hyunseok Kang, Sebastien J. Hotte, Salomon M. Stemmer, Ranee Mehra, Francis P. Worden, Alan Loh Ho
Journal: Journal of Clinical Oncology (2022)

6046 Background: Notch signaling plays a key role in ACC tumorigenesis. Notch mut are found in ̃20% of ACC tumors, which are aggressive with a poor prognosis. Approved or standard therapies for relapsed/metastatic ACC are lacking, regardless of Notch status. Investigational drug AL101, a γ-secretase inhibitor, blocks Notch signaling and inhibits tumor growth in Notch mut patient-derived ACC xenografts. AL101 has clinical activity at 4 mg once weekly (QW) with a disease control rate (DCR) of 68% (15% partial response, (PR)) and appears to be well tolerated. An additional cohort of 42 patients was enrolled at 6 mg QW, and here we update the final results of the trial. Methods: ACCURACY is an open-label, multicenter phase 2 study of AL101 (4 and 6 mg intravenous QW) in subjects with R/M ACC with Notch1-4 mut (ASCO ‘19, Abstr TPS6098). Subjects required evidence of disease progression within 6 months of entry or newly diagnosed metastatic disease and an ECOG performance status of 0-1. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (or modified MD Anderson bone criteria), as assessed by investigators. Secondary endpoints were ORR by central review, duration of response, and safety. The study provided ≥80% power to detect an increase of the ORR from 8% to 25% using a type I error of 5%. Results: A total of 82 subjects were enrolled in the study. The data cutoff date used was Oct 25, 2021. Most common (≥20%) treatment-related adverse events of all grades in the study were diarrhea (78%; grade 3 (gr3) 10%), fatigue (67%; gr3 6%), nausea (60%; gr3 7%). Pharmacokinetics (PK) and blood pharmacodynamics (PD) both displayed a dose dependent change in AL101 plasma concentration and modulation of Notch target gene expression (Hes1 and Hes4), respectively. Of the 77 evaluable subjects, there were 9 PRs (12%) and 44 SDs (57%) for a disease control rate of 69%. Conclusions: Investigational drug AL101 at both 4 and 6 mg QW appears to be well tolerable in Notch mut R/M ACC. Additional efficacy and PK/PD data will be presented Clinical trial information: NCT03691207. Disposition and baseline characteristics of subjects treated with AL101 a . 4 mg QW 6 mg QW Treated, n 45 37 Gender, n (%)MaleFemale 20 (44)25 (56) 24 (57)18 (43) Median age, years 50 59 Race, n (%)WhiteBlackAsianOther/not reported 31 (69)4 (9)2 (4)8 (18) 33(79)2 (5)1 (2)6 (14) Prior systemic therapy, n (%) 27 (60) 19 (51) Disease status at screening, n (%) b MetastaticLocal recurrenceTreatment naïve and metastatic 42 (93)15 (33)4 (9) 36 (86)11 (28)6 (14) Most common sites of metastases, n (%) b LungBoneLiver 22 (49)13 (29)8 (18) 22 (52)15 (36)13 (31) QW=once weekly. a Data cutoff Oct 25, 2021. b Subjects may select more than 1 category.