Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab.

Background: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.
Methods: Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNA _C3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor.
Results: A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (Δcholine _C3 ) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNA _C3 and Δcholine _C3 was prognostic for both OS and PFS. Multivariable analyses show Δcholine _C3 was a prognostic factor for PFS independent of ΔctDNA _C3 , cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.
Conclusions: This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and Δcholine _C3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.
Trial Registration Number: NCT03702309.
Competing Interests: Competing interests: ESG, W-JZ, ZAL, SCY, SL, SK, HB, SG, WX have no disclosures. GAW received travel grants from Bristol Myers Squibb and Abbvie, and honoraria from Pfizer. BW has received honoraria from AstraZeneca and Tessa Therapeutics. PLB: consulting/advisory (uncompensated) with Bristol-Myers Squibb, Seattle Genetics, Gilead, Merck, Pfizer, Amgen, Lilly; and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Amgen, Zymeworks, Seattle Genetics, Nektar Therapeutics, Lilly, and Bicara Therapeutics. MOB Ad boards: Merck, BMS, Novartis, Adaptimmune, GSK, Sanofi, LaRoche Possey, Sun Pharma, Instil Bio, IOVANCE, Pfizer. Grant funding: Merck, Takara Bio, Novartis. Safety Review Committee: Adaptimmune, GSK. Honoraria for talks: BMS, Novartis, Merck, Sanofi, Pfizer. SL is principal investigator and co-investigators of different industry-sponsor or investigated initiated trials. I received honoraria from AZ, GSK, Roche, Merck, Eisai and Shattuck labs. DC: Consulting/Advisory Boards: AstraZeneca, Dynamo Therapeutics, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer and Roche. Research funding to institution: GlaxoSmithKline, Inivata, Merck, Pfizer, and Roche. Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. ARH reports institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Astellas and Bayer; and compensated consulting/advisory boards for AstraZeneca, Merck and GlaxoSmithKline. AAR has received research funding from Roche, Genentech, Eli Lilly, Merck, Boehringer Ingelheim, Novartis, AbbVie, Deciphera, Karyopharm, Astra Zeneca, Medimmune, Blueprint, Bristol Myers Squibb, GSK, Entremed/Casi Pharmaceuticals, Adaptimmune and BetaCat. He also has also served the advisory board for Eli Lilly, Merck, Adaptimmune, Boehringer Ingelheim. AS has served as an advisory board consultant for Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). She has also received research funding from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma, GSK. TWM Cofounder Treadwell Therapeutics. Stock ownership Agios Therapeutics Stock, Agios, Treadwell LS: consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, Avid. EC: honoria from Bayer and Taiho; institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Roche, AstraZeneca, Merck, 1Globe, Mirati Therapetuics, Zymeworks and Amgen.
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