69 Background: Immunotherapy (IO) has shown to improve survival in recurrent or metastatic (R/M) squamous cell cancer of the head and neck (SCCHN) with a better toxicity profile than chemotherapy (CT). An increased objective response rate (ORR) to CT has been shown after PD(L)1 blockade in SCCHN and other solid tumors. However, there are no data regarding the safety and efficacy of PD(L)1 rechallenge in SCCHN. Methods: Retrospective study of patients with R/M SCCHN treated with PD-1 inhibitors after an overt clinical and radiological progression to PD(L)1 blockade. Post-IO CT regimens, overall survival (OS), objective response rates (ORR) and percentage of tumor reduction (PTR) with post-IO CT and toxicity of IO rechallenge were recorded. Results: Eight patients treated between October 2016 and October 2018, were included. All patients received the first IO (1st-IO) treatment within clinical trials (anti-PDL1: 7; anti-PD1: 1), and received rescue cetuximab-based CT at progression (PD) (ERBITAX: 7; EXTREME: 1). ORR to post-IO 1st rescue CT (1RCT): 7 partial responses (PR), 1 stable disease (SD). PTR to 1RCT (median): 45% (range: 40-80). All second IO (2nd-IO) treatments consisted of PD1 inhibitors (nivolumab) and 6 received rescue CT (2RCT) at PD (ERBITAX: 1; wkCDDP-Cetuximab: 2; EXTREME: 3). Only 1of 6 evaluable patients responded to 2nd-IO with 5 PD as best response. Median duration of 2nd-IO: 3 months (range: 1-6). ORR to 2RCT (5 evaluable): 4 PR, 1 PD. PTR to 2RCT (median): 30% (range: 30-80). No G3/4 toxicities were detected during 2nd-IO. Conclusions: No new safety signals were encountered during PD-1 blockade in patients with SCCHN previously treated with PD-(L)1 inhibitors. First and second IO treatments associated with increased response rates to subsequent CT compared with historical data. Clinical trials should try to address the optimal treatment sequence in the IO era.