Second-line cetuximab plus immune checkpoint inhibitor (ICI) versus cetuximab plus carboplatin and paclitaxel following ICI-containing regimen in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

6046 Background: ICI-containing regimens are the standard first-line therapies for R/M HNSCC. However, the optimal therapeutic regimen after progression on ICI-containing therapies remains uncertain. This study compares outcomes among patients (pts) who received either second-line cetuximab plus ICI (CICI) or cetuximab plus weekly carboplatin and paclitaxel (CPT). Methods: We performed a retrospective analysis of R/M HNSCC pts treated at our institution between 2018 and 2025 who received cetuximab combination therapy after progressing on first-line ICI alone or ICI with chemotherapy. Pts with ECOG 0-2 were included. All pts received cetuximab 400 mg/m 2 followed by 250 mg/m 2 weekly as tolerated, concurrently with either pembrolizumab (200 mg every 3 weeks) or chemotherapy (carboplatin AUC 1.5 and paclitaxel 45 mg/m 2 weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate (DCR; SD+PR+CR), objective response rate (ORR; CR+PR), and rate of treatment modification. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests and Cox proportional hazards models. Fisher’s exact test was used to compare binary outcomes. Results were deemed significant when p<0.05. Subgroup analyses were considered exploratory. Results: Out of 100 pts included, 31 received CICI, and 69 received CPT. Median age at the start of cetuximab was 65 years (range 34-93), 79% were male, 95% were Caucasian, and 38% had HPV-related disease. Primary tumor sites included oropharynx (47%), oral cavity (26%), and larynx (19%). 9% had CPS 0, 30% had CPS 1-19, and 43% had CPS ≥ 20. For first-line treatment, 41% had received an ICI alone, and 59% had received an ICI with chemotherapy. Median follow-up was 7.6 months (range 3.8-13.4) with CICI and 38.8 months (range 4.3-71.5) with CPT. DCR was 77.4% with CICI and 60.6% with CPT (p=0.12). ORR was 51.6% versus 34.8%, respectively (p=0.13). Median PFS was 7.6 months (95% CI 4.1-NR) with CICI and 2.7 months (95% CI 2.0-4.4) with CPT (HR 0.48, 95% CI 0.29-0.82, p<0.01). Median OS was 11.3 months (95% CI 9.1-NA) with CICI and 9.4 months (95% CI 8.2-10.5) with CPT (HR 0.78, p=0.10). Subgroup analyses showed favorable PFS with CICI in select groups: age ≤ 65 (p=0.037), male sex (p=0.009), ECOG 0-1 (p=0.024), and prior ICI plus chemotherapy (p<0.001). No clear differences were found within subgroups with CPS 1-19 or CPS ≥ 20. There was no difference in the rates of treatment modification (p=1.00). Conclusions: In this retrospective cohort of R/M HNSCC pts, CICI was associated with a longer PFS than CPT. This effect remained significant in pts who previously received first-line ICI plus chemotherapy. A longer follow-up is planned to evaluate for differences in OS.