Background: There have been reports of higher than expected objective response rate (ORR) to platinum-based combinations following immunotherapy failure in a number of metastatic solid and hematological malignancies. In light of these intriguing results and the fact that the optimal second line regimen for R/M HNSCC after immunotherapy remains unclear, we conducted a prospective cohort study of patients with R/M HNSCC treated with platinum-based chemotherapy plus paclitaxel after anti-PD-1 monotherapy to investigate survival outcomes. Methods: This is a single institutional prospective cohort study which has a total of 12 patients with R/M HNSCC. Within 2 weeks after confirmation of progression from anti-PD-1 monotherapy (pembrolizumab or nivolumab), platinum-based chemotherapy (cisplatin 80mg/m² or carboplatin AUC=5) plus paclitaxel 175mg/m² every 21 day cycle were initiated and continued for a total of 3-9 cycles. The best overall response (BOR) was assessed by RECIST v1.1. ORR was determined based on binomial distribution theory and Wilson’s method. Progressive-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. The association between ORR and HPV status, PD-L1 score were determined by the chi-square test. Blood samples were collected prior to the start of chemotherapy and also at the time of restaging scans (every 3 cycles of chemotherapy) for RNA sequencing. Results: Patients were treated from May 2021 to June 2023. There were 10 men and 2 women, median age of 63 years (range, 51-73) and ECOG 0-1. Oropharynx (9, 75%) was the most common primary site (oral cavity: 1, larynx: 1). Eleven (92%) had distant metastatic disease. 45% of patients (5 out of 11) had PD-L1 CPS <50. 58% of patients (7 out of 12) had HPV positive HNSCC. The median follow up of the study was 15.6 (range: 4.9-23.9) months. The ORR was 75% with 95% CI: 0.47- 0.91. The median OS was 17.9 months and median PFS was 6.74 months. The median OS for PDL1 >= 50 is longer than 23.9 months vs 15 months in patients with PD-L1 CPS <50. Compared to HPV negative patients, HPV positive patients had a superior median PFS (8.75 vs 3.9 months, p= 0.069). The ORR by HPV status was higher in HPV positive than HPV negative patients (85.7% vs 60%, p=0.311), and the ORR by PDL1 score was higher in PDL1 ≥ 50 than PDL1 <50 (100% vs 66.7%, p=0.154), but neither ORR by HPV status nor PDL1 was significant. Conclusions: Platinum-based chemotherapy plus paclitaxel after anti-PD-1 monotherapy showed dramatically higher ORR and more favorable median OS compared to the historical data from the pre-anti PD-1 era (ORR: 75% vs 26%, median OS: 17.9 vs 8.1 months), which warrants a larger prospective study for validation. Our ongoing analysis of RNA sequencing may reveal mechanism for immunotherapy induced chemosensitization effect.