903P - AL101 therapy in patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC): Final ACCURACY trial results and meta-analysis of clinical outcomes

Background

Approved therapies for R/M ACC are lacking. Notch mutations (Notch^mut) are found in ∼20% of ACC and are linked to aggressive disease and poor prognosis. AL101 is a gamma-secretase inhibitor that blocks Notch signaling, which is being prospectively studied in this biomarker driven high-risk population.

Methods

ACCURACY is a phase 2, multicenter, open-label study of AL101 (4 or 6 mg IV QW) in patients (pts) with R/M ACC and Notch1-4^mut with evidence of disease progression. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST v1.1 (or modified MDACC bone criteria). A benchmark for the ACCURACY results was developed from a meta-analysis of outcomes among R/M ACC pts (regardless of Notch status) treated in other clinical trials.

Results

ACCURACY enrolled 87 pts with median age 50 and 59 years in the 4 mg and 6 mg arms, respectively. Prior systemic therapy was used in 60% of 4 mg and 51% of 6 mg pts. As of the data cutoff of 27 Oct 2022, among 77 evaluable pts, ORRs of 14.6% for 4 mg and 8.3% for 6 mg compared favorably with ORRs from the meta-analysis (Table). The most common treatment-related adverse events (TRAE) for pooled doses were diarrhea (70%), fatigue (51%), nausea (47%), hypophosphatemia (38%), vomiting (28%), and cough (25%). Grade 3 and 4 TRAE occurred in 35 (40%) and 2 (2%) pts, respectively. TRAE led to discontinuation of AL101 in 6 (7%) pts (3 on 4 mg and 3 on 6 mg) and 2 (2%) deaths (pneumonia and acute respiratory syndrome). Table: 903P

Tumor response rates in ACCURACY trial and meta-analysis of other clinical trials.

*Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD

Conclusions

AL101 showed acceptable safety and tolerability in ACC pts with Notch^mut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.

Clinical trial identification

NCT03691207, EudraCT 2019-000309-64.

Editorial acknowledgement

Medical writing support provided by Laurie LaRusso, MS, ELS, of Chestnut Medical Communications, paid for by Ayala Pharmaceuticals.

Legal entity responsible for the study

Ayala Pharmaceuticals, Inc.

Funding

Ayala Pharmaceuticals, Inc.

Disclosure

R. Ferrarotto: Financial Interests, Personal, Advisory Board: Regeneron-Sanofi, Ayala Pharmaceuticals, Bicara Therapeutics, Prelude Therapeutics, Guidepoint, Elevar Therapeutics, G1 Therapeutics, ExpertConnect, Remix; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Coordinating PI: Merck, Gennentech, Pfizer, Ayala, EMD Serono; Financial Interests, Institutional, Other, Co-PI: Rakuten, Nanobiotix; Financial Interests, Institutional, Local PI: Prelude, ISA Therapeutics; Non-Financial Interests, Advisory Role: Cellestia. P. Bobbili: Financial Interests, Institutional, Research Funding, Employee of Analysis Group, which received research funding from Ayala for this study: Ayala Pharmaceuticals. D.W. Bowles: Financial Interests, Institutional, Advisory Board: Exelixis; Financial Interests, Institutional, Local PI: Elevar, Ayala. C. Even: Financial Interests, Personal, Advisory Board: BMS, MSD, Innate Pharma, Merck Serono; Financial Interests, Institutional, Advisory Board: F Star Therapeutics, Novartis, Elevar; Financial Interests, Institutional, Local PI: BMS, AstraZeneca, ISA pharmaceutics, MSD, Debiopharma, Ayala, Gilead; Financial Interests, Institutional, Coordinating PI: BMS, Novartis, sanofi. G. Gordon: Financial Interests, Personal, Advisory Role: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmaceuticals. A. Gutierrez: Financial Interests, Personal, Full or part-time Employment: Ayala Pharmaceuticals. R. Metcalf: Financial Interests, Personal, Advisory Board: Ayala, Bayer, Aptus Clinical, PCI Biotech, Oxsonics, Roche, Achilles Therapeutics; Financial Interests, Personal, Other, Honoraria: BMS, MSD, Sanofi. C. Nguyen: Financial Interests, Institutional, Research Funding, Employee of Analysis Group, which received research funding from Ayala for this study: Ayala Pharmaceuticals. M. Oliva: Financial Interests, Personal, Invited Speaker: BMS, Merck, MSD; Financial Interests, Personal, Other, Teaching activities: Merck, MSD; Financial Interests, Personal, Writing Engagement: MSD; Financial Interests, Personal, Advisory Board: Merck, MSD; Financial Interests, Personal, Other, IDMC: Transgene; Non-Financial Interests, Institutional, Local PI: AbbVie, ALX Oncology, Ayala, Bayer, Boehringer Ingelheim, Debiopharm, Gilead, ISA, Merck, MSD, Roche, Seagen; Non-Financial Interests, Personal and Institutional, Funding: Roche, GSK; Non-Financial Interests, Institutional, Product Samples: Roche. C.A. Perez: Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hyamab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals, Artios Pharma. C. Rodriguez: Financial Interests, Personal, Advisory Board: Vaccitech, Coherus, CUE biopharma; Financial Interests, Institutional, Local PI: Ayala, Merck, Sanofi, Kura, CUE Biopharma, Prelude; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb. S.R. Sendhil: Financial Interests, Institutional, Research Funding, Employee of Analysis Group, which received research funding from Ayala for this study.: Ayala Pharmaceuticals. E. Winquist: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Eisai, Ipsen, Merck, Roche; Financial Interests, Institutional, Local PI: Ayala, Eisai, Merck, Pfizer, Roche/Genetech. L.J. Wirth: Financial Interests, Personal, Advisory Board: Bayer, Coherus, Eli Lilly, Eisai, Exelixis; Financial Interests, Personal, Other, Consultant: Curie Therapeutics, Morphic Therapeutics, Tome Biosciences; Financial Interests, Personal, Other, DMSC: PDS Biotherapeutics; Financial Interests, Institutional, Steering Committee Member: Novartis, Eli Lilly. B. Xia: Financial Interests, Personal, Full or part-time Employment: Janssen. J. Yovell: Financial Interests, Personal, Full or part-time Employment, VP clinical Development at Ayala Pharmaceuticals: Ayala Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Ayala Pharmacutical; Non-Financial Interests, Project Lead: Ayala Pharmacuticals; Non-Financial Interests, Member: ASCO. A.L. Ho: Financial Interests, Personal, Invited Speaker, discussed head and neck cancer therapies: Chinese American Hematologist and Oncologist Network; Financial Interests, Personal, Invited Speaker, Discussed salivary cancer therapies: Lurie Cancer Center (Northwestern); Financial Interests, Personal, Invited Speaker, discussed thyroid cancer therapies: Physician Education Resource; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapies: Endocrine Society; Financial Interests, Personal, Invited Speaker, Discussed head and neck cancer therapies: University of Pittsburgh Medical Center; Financial Interests, Personal, Invited Speaker, Discussed thyroid cancer therapeutics: New York University; Financial Interests, Personal, Advisory Board, Serve on DSMC: Affyimmune; Financial Interests, Personal, Other, Serve on the NCI Head and Neck Steering Committee: National Cancer Institute; Financial Interests, Personal, Advisory Board, Member of advisory board: Exelixis, Remix Therapeutics, Elevar Therapeutics, Prelude Therapeutics, Eisai, Ayala, Kura Oncology; Financial Interests, Personal, Other, Member of Safety Monitoring Committee: Kura Oncology; Financial Interests, Personal, Advisory Board, Member of advisory board.: Merck; Financial Interests, Personal, Other, Consultant: ExpertConnect; Financial Interests, Personal, Advisory Board, Member of advisory board and consulting.: Rgenta; Financial Interests, Personal, Full or part-time Employment: Memorial Sloan Kettering Cancer Center; Financial Interests, Personal, Stocks/Shares, options: Rgenta Therapeutics; Financial Interests, Institutional, Other, Listed as inventor for: Memorial Sloan Kettering Cancer Center; Financial Interests, Institutional, Coordinating PI, Serve as PI. also served on paid advisory board: Ayala; Financial Interests, Institutional, Coordinating PI, Serve as trial PI, also serve on paid SMC/advisory board: Kura Oncology; Financial Interests, Institutional, Local PI, Trial PI and served on an advisory board: Elevar Therapuetics; Financial Interests, Institutional, Coordinating PI, PI of IIT: Novartis, Merck, Bristol Meyer Squibb; Financial Interests, Institutional, Coordinating PI, PI of several IIT trials: Bayer; Financial Interests, Institutional, Coordinating PI, PI of trial: Bioatla, TILT Biotherapeutics, Genentech Roche, Astellas, Celldex; Financial Interests, Institutional, Local PI, PI of trial: OncC4; Financial Interests, Institutional, Coordinating PI, PI of several IITs: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of trial and was part of paid advisory board: Eisai; Financial Interests, Institutional, Local PI, co-PI of trial: Poseida Therapuetics; Financial Interests, Institutional, Local PI: Hookipa; Non-Financial Interests, Advisory Role: Cellestia, Inxmed; Non-Financial Interests, Member of Board of Directors: International Thyroid Oncology Group; Non-Financial Interests, Leadership Role: International Rare Cancer Initiative; Non-Financial Interests, Leadership Role, for the head and neck working group: Alliance for Clinical Trials in Oncology. All other authors have declared no conflicts of interest.