Abstract CT141: mRNA-4157 (V940) individualized neoantigen therapy (INT) + pembrolizumab (pembro) in advanced unresectable HPV- head & neck carcinoma (HNSCC): Clinical & translational analysis

Abstract Introduction: In HPV- HNSCC, limited durable clinical responses to PD1/PD-L1 blockade may be due to diminished effector cytolytic activity and clonal diversity.1-4 mRNA-4157 is a novel mRNA-based INT that encodes up to 34 neoantigens inducing specific antitumor T-cell activation; durable clinical responses with pembro have been shown in melanoma.5 We assessed INT + pembro in unresectable, metastatic HPV- HNSCC in the Phase 1 mRNA-4157-P101/KEYNOTE-603 study (NCT03313778). Methods: Part C of this study enrolled ≥18-year-old patients (pts) with CPI-naïve, recurrent/metastatic HPV- HNSCC. Eligible pts received 200 mg pembro Q3W IV during a 6-week lead-in, then combined with 1 mg INT ≤9 doses Q3W IM, and until disease progression, unacceptable toxicity, or ≤35 total cycles of pembro. Objectives included safety, tolerability and preliminary clinical activity. Peripheral blood was collected longitudinally for both immunogenicity via IFN-γ ELISpot and ctDNA analyses. Next generation sequencing was performed on baseline tumor biopsies. Results: A total of 28 enrolled pts received pembro; 22 received INT + pembro. Most adverse events (AEs) related to INT were grade 1-2; most common were influenza-like illness, injection site pain, and pyrexia. No grade 4/5 AEs were related to INT. Three pts had grade 3 events (pyrexia, increased lipase, and decreased lymphocyte count) attributed to both INT and pembro. Six pts discontinued prior to INT (death/disease progression/deterioration). Response rate for INT + pembro was 27.3% (6/22; 95% CI, 10.7-50.2); disease control rate was 63.6% (14/22; 95% CI, 40.7-82.8) per RECIST V1.1 with best overall response of 2 (9.1%) complete, 4 (18.2%) partial response, and 8 (36.4%) stable disease at data cut-off (May 2023); with median follow-up of 38.4 weeks (range, 7.7-198.3). Median (95% CI) PFS and OS were 15.0 weeks (11.6-38.6) and 107.1 weeks (42.7-NE), respectively. Sustained de novo T-cell induction to targeted neoantigens was observed in 5/5 pts with available samples. A decrease in ctDNA levels post-baseline was observed in 3/4 responders (8 available samples). Differential gene expression from pretreatment tumor samples suggests increased inflamed T-cell-associated gene expression (Benjamini-Hochberg-adjusted descriptive p<0.05, for hallmark inflammatory response) in INT + pembro responders. Conclusions: INT + pembro had a manageable safety profile, showed evidence for activation of immune responses, and induced preliminary clinical responses in pts with HPV- HNSCC. Further testing of INT + pembro in a randomized setting may be warranted. References: 1. Lechner A, et al. Oncotarget 2017;8:44418-33. 2. Wang J, et al. Sci Rep 2019;9:13404. 3. Tosi A, et al. J Exp Clin Cancer Res. 2022;41:279. 4. Xu K, et al Br J Cancer 2020;123:932-41. 5. Weber JS, et al. Lancet 2024;S0140-6736(23)02268-7. Citation Format: Julie E. Bauman, Ricklie A. Julian, Jessica L. Geiger, Janice M. Mehnert, Jeffrey M. Clarke, Manish R. Patel, Martin Gutierrez, Justin F. Gainor, Shyam Srivats, Zhaojie Zhang, Anjali Rao, Vasudha Sehgal, Peijie Hou, Manju Morrissey, Igor Feldman, Lakshmi Srinivasan, Praveen Aanur, Michelle Brown, Robert S. Meehan. mRNA-4157 (V940) individualized neoantigen therapy (INT) + pembrolizumab (pembro) in advanced unresectable HPV- head & neck carcinoma (HNSCC): Clinical & translational analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT141.