Abstract 114P
Background
T cell-derived acetylcholine (Ach) induces vasodilation and increases T cell migration to infected tissues in response to viral infection. We previously reported that an increase from baseline in Ch (a stable Ach precursor) at week 7 after pembrolizumab was associated with improved PFS (NCT02644369; Watson et al, ASCO 2020). Our aim is to validate these findings in an independent cohort.
Methods
Serial blood samples were collected from pts with advanced cancer treated with IO agents in early phase trials from Dec/17 to Mar/20. Pts with available baseline and on-treatment blood samples collected at 3-4 weeks (pre-cycle 2) were selected. Serum Ch was analyzed with a high-performance liquid chromatography tandem mass spectrometry assay. Delta choline (DCh) was defined as the change in serum Ch levels between baseline and pre-cycle 2. Kaplan-Meier curves and log-rank tests were used to assess the impact of Ch and DCh on PFS and OS and Fisher’s exact test for the association with objective response rate (ORR).
Results
Of 102 pts enrolled, 80 had blood samples at both timepoints. Median age was 56 years, 25 tumor types were included (most common were sarcoma 11%, colorectal 10%, breast 9%). Most pts received IO agents targeting immune checkpoints (94%), including PD-1 inhibitors (inh) alone (5%) or combined with other checkpoint inh (21%), costimulatory molecules (8%) and other immunomodulatory drugs (30%). After a median follow-up of 10.2 months (m), ORR was 10%, median PFS and OS were 1.9 m and 10.2 m. Neither baseline nor pre-cycle 2 serum Ch levels correlated with PFS, OS and ORR in the entire cohort or in the subgroup of 51 pts treated with PD-1 inh. A trend to improved 3-, 6-, and 12-m PFS with increased versus decreased DCh (29.3% vs 23.1%, 19.5% vs 15.4% and 14.6% vs 5.1%, p=0.56) was observed. The difference for PFS at 3-, 6-, and 12-m was greater in pts treated with PD-1 inh (37.5% vs 25.9%, 29.2% vs 18.5%, and 20.8% vs 7.4%, p=0.25). There were no differences in ORR or OS based on DCh.
Conclusions
Although DCh was not shown to be a predictor of IO treatment outcomes in this heterogeneous cohort there was a numerical signal for improved PFS in pts with increased DCh, consistent with our prior findings that warrants further evaluation.
Clinical trial identification
NCT03702309.
Editorial acknowledgement
Legal entity responsible for the study
University Health Network - Princess Margaret Cancer Centre.
Funding
BMO Chair in Precision Medicine.
Disclosure
A.R. Abdul Razak: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Adaptaimmune; Financial Interests, Personal, Advisory Role: Bayer; Non-Financial Interests, Personal and Institutional, Principal Investigator: Deciphera; Non-Financial Interests, Personal and Institutional, Principal Investigator: Karyopharma Therapeutics; Non-Financial Interests, Personal and Institutional, Principal Investigator: Pfizer; Non-Financial Interests, Personal and Institutional, Principal Investigator: Roche/Genentech; Non-Financial Interests, Personal and Institutional, Principal Investigator: Bristol Myers Squibb; Non-Financial Interests, Personal and Institutional, Principal Investigator: MedImmune; Non-Financial Interests, Personal and Institutional, Principal Investigator: Amgen; Non-Financial Interests, Personal and Institutional, Principal Investigator: GlaxoSmithKline; Non-Financial Interests, Personal and Institutional, Principal Investigator: Blueprint Medicines; Non-Financial Interests, Personal and Institutional, Principal Investigator: Merck; Non-Financial Interests, Personal and Institutional, Principal Investigator: AbbVie; Non-Financial Interests, Personal and Institutional, Principal Investigator: Adaptimmune; Non-Financial Interests, Personal and Institutional, Principal Investigator: Iterion Therapeutics. A.R. Hansen: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Institutional, Principal Investigator: Karyopharm Therapeutics; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Roche/Genentech; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: AstraZeneca/MedImmune; Financial Interests, Institutional, Principal Investigator: Astellas Pharma; Financial Interests, Institutional, Principal Investigator: Macrogenics. A. Spreafico: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Oncorus; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Merck; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Idera; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Bayer; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Janssen Oncology; Financial Interests, Personal, Other, Travel, Acommodation, Expenses: Roche; Financial Interests, Personal, Other, Honoraria: Janssen Oncology; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: AstraZeneca/MedImmune; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: Surface Oncology; Financial Interests, Institutional, Principal Investigator: Janssen Oncology; Financial Interests, Institutional, Principal Investigator: Northern Biologics; Financial Interests, Institutional, Principal Investigator: Replimune; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Alkermes; Financial Interests, Institutional, Principal Investigator: Array BioPharma; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline. E. Chen: Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: Roche Canada; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Principal Investigator: AstraZeneca/MedImmune; Financial Interests, Personal, Principal Investigator: Bristol Myers Squibb; Financial Interests, Personal, Principal Investigator: Novartis; Financial Interests, Personal, Principal Investigator: Boston Biomedical; Financial Interests, Personal, Principal Investigator: Mirati Therapeutics; Financial Interests, Personal, Principal Investigator: Merck Serono. L.L. Siu: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune; Financial Interests, Personal, Advisory Role: MorphoSys; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Loxo; Financial Interests, Personal, Advisory Role: Voronoi; Financial Interests, Personal, Advisory Role: Oncorus; Financial Interests, Personal, Advisory Role: Symphogen; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Treadwell Therapeutics; Financial Interests, Personal, Advisory Role: Arvinas; Financial Interests, Personal, Advisory Role: Navire; Financial Interests, Personal, Advisory Role: Janpix; Financial Interests, Personal, Advisory Role: Relay Therapeutics; Financial Interests, Personal, Member of the Board of Directors, An immediate Family Member: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, An immediate Family Member: Agios; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Genentech/Roche; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: MedImmune; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: Astellas Pharma; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: Avid Radiopharmaceuticals; Financial Interests, Institutional, Principal Investigator: Mirati Therapeutics; Financial Interests, Institutional, Principal Investigator: Intensity Therapeutics; Financial Interests, Institutional, Principal Investigator: Karyopharm Therapeutics. P. Bedard: Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Sanofi; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Genentech/Roche; Financial Interests, Institutional, Principal Investigator: Servier; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: PTC Therapeutics; Financial Interests, Institutional, Principal Investigator: Nektar; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Seattle Genetics; Financial Interests, Institutional, Principal Investigator: Mersana; Financial Interests, Institutional, Principal Investigator: Immunomedics; Financial Interests, Institutional, Principal Investigator: Lilly; Financial Interests, Institutional, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: Bicara Therapeutics. All other authors have declared no conflicts of interest.