Abstract 331P
Background
FOLFIRINOX and gemcitabine (G) in combination with nab-paclitaxel (nP) are the standard first-line treatment for patients (Pt) with advanced pancreatic cancer (aPC) but the impact on outcomes is limited. The hedgehog (Hh) pathway plays an important role in developmental biology. In preclinical cancer models, Hh inhibitors disrupt the tumor microenvironment, increasing the delivery and efficacy of chemotherapy and immunotherapy. NLM-001 is an oral investigational small molecule inhibitor of the Hh pathway.
Methods
Phase Ib/IIa, open label, single arm study in adults with aPC previously untreated and ECOG PS 0-1. Pt received standard treatment with G+nP. NLM-001 was administered at a dose of 800 mg/day p.o. days -4 to -1 and 10-13 before G+nP treatment in cycles 1-3, 6-8, 11-13 and so on (3 cycles followed by 2 rest cycles). Anti CTLA-4 inhibitor, zalifrelimab (Z), was administered on day 15 of cycle 1 and every 6 weeks thereafter. Disease burden was assessed monthly by a tumor-informed ctDNA test and bi-monthly by CT-Scan. Tumor biopsies were collected at baseline and at day 21.
Results
Twenty-two pt were included, median age 60 years, 59% were male and 91% had liver metastases. Treatment was well tolerated. Most frequent grade 3-4 AEs were neutropenia (41%), asthenia (27%) and neurotoxicity (14%). No pt discontinued study treatment due to toxicity. ORR was 50 % and disease control rate was 95%. At a median follow-up of 8.5 months (m), median PFS is 7.1 m and 1-year PFS is 32%. 70 % of pt had > 75 % reduction in CA19-9. Disease monitoring by serial analysis of ctDNA showed molecular responses in 14 of 20 pt. Pt who achieved ctDNA clearance at cycle 5 had a significant better PFS (7 vs 11.5 months; p<0.005). In four paired biopsies analyzed so far, we observed reduced hypoxia and cancer cell contents in all pt and reduction in CAF, Tregs and macrophages in one pt.
Conclusions
Safety profile of study treatment is as expected for G+nP standard regimen. No new safety signals were observed for the NLM-001 + G+nP+Z treatment. Preliminary efficacy results are promising. Updated results will be presented during the congress.
Clinical trial identification
EudraCT: 2020-004932-52; NCT04827953.
Editorial acknowledgement
The authors would like to thank Juan Luis Sanz for his editorial assistance.
Legal entity responsible for the study
Nelum Corp.
Funding
Nelum Corp.
Disclosure
T. Macarulla Mercade: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd., Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dohme, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZeneca, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-La Roche, FibroGen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, MedImmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Pfizer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO; Other, Editorial Board: GI Annals of Oncology. R.A. Pazo Cid: Financial Interests, Personal, Advisory Board: Roche, BMS, Servier, Ipsen; Financial Interests, Personal, Invited Speaker: Servier, BMS, Roche, Eisai; Financial Interests, Personal, Expert Testimony: Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, Support for manuscript presentation (funding, provision of study materials, medical writing, article processing charges): Ipsen, Astellas. L. Medina Rodríguez: Financial Interests, Personal, Invited Speaker: Novartis, Servier. F. Rivera Herrero: Financial Interests, Personal, Invited Speaker: Roche, MSD, BMS, Servier, Astellas, Amgen, Merck; Financial Interests, Personal, Advisory Board: MSD, BMS, Servier, Astellas, Amgen, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, Novartis, Seagen, OBT, Inspirna. V. Varela Pose: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, BioNTech and Regeneron, Ipsen Pharma, Nelum corp. A. Martín-Muñoz: Financial Interests, Personal, Full or part-time Employment, Industrial PhD candidate and employee: Altum Sequencing S.L. Y. Ruiz-Heredia: Financial Interests, Personal, Member of Board of Directors, CEO: Altum Sequencing S.L. R. Kalluri: Financial Interests, Personal and Institutional, Advisory Board: PranaX; Financial Interests, Personal, Advisory Board: Xsome Biotech. M. Hidalgo: Financial Interests, Personal, Member of Board of Directors: BMS; Financial Interests, Personal, Ownership Interest: Nelum, Champions; Financial Interests, Personal, Advisory Board: MiNK, InxMed, Oncomatrix, Peaches; Non-Financial Interests, Personal, Principal Investigator: Agenus. All other authors have declared no conflicts of interest.