Background: Immune checkpoint inhibitors (ICI) are currently approved in the treatment of patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will progress on ICI. Little is known regarding the best treatment approach for this patient population. We previously showed that the combination of weekly carboplatin, paclitaxel and cetuximab was associated with reduced risk of grade 3/4 toxicities, which makes it an ideal regimen in this setting. Here; we report the outcomes of pts with R/M HNSCC who were treated with chemotherapy alone vs weekly chemotherapy plus cetuximab after progression on ICI. Methods: Between January 15th 2016 and April 9th 2020, 154 pts who progressed on ICI were analyzed. Among these pts, 64 had received subsequent systemic therapy and met the inclusion criteria. Progression Free Survival (PFS) was defined as the time elapsed between initiation of subsequent chemotherapy and tumor progression or death. Overall Survival (OS) was defined as the time elapsed between initiation of subsequent chemotherapy to death. Descriptive statistics and Cox regression were used to explore study variables. Results: 64 pts received subsequent chemotherapy after progression on ICI. 28 pts (44%) received a combination of weekly chemotherapy plus cetuximab. This regimen included carboplatin AUC 1.5, paclitaxel 45 mg/m², and cetuximab loading dose of 400mg/m² followed by weekly dose of 250 mg/m². 36 pts (56%) received chemotherapy alone without cetuximab. These regimens included capecitabine, afatinib, and gemcitabine, among others. Sex: 51 males (80%), 13 females (20%), age (median): 61 (IQR: 53-66), tumor site: oropharynx 32 (50%), oral cavity 11 (17%), larynx 8 (12%), other sites 13 (21%). P16 status: negative 36 (56%), positive 28 (44%). Prior ICI drug: pembrolizumab 34 (53%), nivolumab 26 (41%), ipilimumab + nivolumab 4 (6%). Median follow up: 9 months (IQR: 5-13). Overall response rate: weekly chemotherapy plus cetuximab 32%, chemotherapy alone 22% (p = 0.4). Pts who received chemotherapy alone had a median PFS of 3.2 months (CI: 2-5) vs 5.6 months (CI: 4.3-10.1) in the weekly chemotherapy plus cetuximab group. After adjusting for p16 status and prior ICI drug, PFS was improved in the group that received weekly chemotherapy plus cetuximab vs. chemotherapy alone (HR: 0.52; CI: 0.28-0.98; p = 0.042). Median OS was 10 months (CI: 8.5-NR) in the weekly chemotherapy plus cetuximab group vs 8.7 months (CI: 5.7-13.8) in the chemotherapy alone group (HR: 0.84; CI: 0.4-1.8; p = 0.8). Conclusions: Pts with R/M HNSCC who progressed on ICI experience longer PFS with the addition of cetuximab to weekly chemotherapy. Further investigation in a larger cohort of pts is needed to fully assess the impact on survival for this treatment combination.