Abstract B014: Plasma metabolites as biomarkers of survival in head and neck cancer patients undergoing pembrolizumab and cabozantinib

Abstract Purpose: The combination of pembrolizumab (a PD-1 inhibitor) and cabozantinib (a VEGF inhibitor) has shown promising disease control in recurrent or metastatic head and neck cancer (rmHNC). Building on previous research linking plasma metabolites to weight loss, clinical outcomes, and survival in HNC patients on standard therapy, this study evaluates pre- and post-treatment plasma metabolites as indicators of therapeutic response and survival in patients treated with this combination therapy. Methods: In a phase II single-arm trial of rmHNC patients, blood plasma was collected before and 9 weeks after the initial cycle of combination therapy. We performed ultra high-resolution liquid chromatography-mass spectrometry and extracted 171 extracted 171 laboratory-authenticated metabolites. The identified metabolites were 4 amines, 50 amino acid derivatives, 11 carbohydrates, 21 cholines/betaines/carnitines, 28 lipids, 7 nucleotides, 34 simple organic acids, 6 cofactors, and 10 others, encompassing a wide breadth of human metabolism. Metabolites were z-standardized and analyzed using repeated measures ANOVA to assess treatment response per RECIST v1.1, with significant metabolites (P<0.05) further examined in survival analyses via adjusted Cox models. Results: Of the 14 patients, 11 were male and nine were white, with a median age of 59 years. Seven had human papillomavirus (HPV)-positive rmHNC and nine had a combined positive score (CPS) ≥20. Six patients responded to the therapy, with one experiencing progression. Conversely, among the eight non-responders, six either progressed or died. The plasma metabolome showed remarkable stability post-therapy, with lysine (P=0.006) as the only metabolite that significantly differed before and after treatment, exhibiting increased levels in both responders and non-responders. Notably, of the 22 metabolites that differed significantly between responders and non-responders, 14 were amino acids(*) or their derivatives (χ2 P=0.0002), with increased levels observed in responders. Six of those metabolites—phenylalanine* (P=0.02), guanidinoacetic acid* (P=0.02), methionine* (P=0.03), leucine* (P=0.03), propionylcarnitine (P=0.04), and 2-deoxyglucose (P=0.04)—were positively associated with longer progression-free survival. Higher levels of the first three were also associated with longer overall survival. Importantly, these associations emerged exclusively from post-treatment blood draws, indicating their potential as biomarkers for monitoring patient response to treatment. The associations were independent of age, HPV status and PD-L1 CPS, underscoring their robustness as prognostic markers. Conclusions: Elevated levels of these plasma amino acids in responders and survivors after therapy highlight their potential role as key determinants of sensitivity to the combination therapy in rmHNC, suggesting their utility in patient monitoring. This is new finding in HNC but the amino acid profiles aligns with findings in non-small cell lung cancer and underscores the role of amino acid catabolism in immune suppression. Citation Format: Ronald C Eldridge, Allyson Anderson, Ritu Chaudhary, Kelly Magliocca, Qiuying Shi, Mihir R Patel, James E Bates, Kedar Kirtane, Nicole C Schmitt, Conor E Steuer, Dong M Shin, Yuan Liu, Yong Teng, Christine H Chung, Nabil F Saba. Plasma metabolites as biomarkers of survival in head and neck cancer patients undergoing pembrolizumab and cabozantinib [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B014.