Abstract
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.
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