Julian, Ricklie

PURPOSE Continued improvement in outcomes is needed for advanced cutaneous squamous cell carcinoma (cSCC). Methods Alliance A091802 is a randomized phase II trial of avelumab (800 mg IV once every 2 weeks) plus cetuximab (500 mg/m 2 IV once every 2 weeks) versus avelumab alone once every 2 weeks for up to 2 years. Cetuximab was given for 1 year in the avelumab + cetuximab arm. Crossover at progression to avelumab + cetuximab was allowed. Randomization was 1:1, stratified by PD-L1 and HIV status. Patients had distant metastatic or unresectable locally advanced cSCC, were anti–PD-1/PD-L1 monoclonal antibody–naive, had no previous cetuximab in the advanced setting, had an Eastern Cooperative Oncology Group performance status of 0-2, and could be HIV+ (CD4 >200, viral load <200). Patients with chronic lymphocytic leukemia, immunosuppression, or active autoimmune diseases were excluded. The primary end point was progression-free survival (PFS; null hypothesis: median = 12 months v alternative hypothesis: 21 months or a 75% improvement, power of 80% with one-sided alpha .2, n = 57, 37 PFS events required). Secondary end points were overall survival, objective response rates (ORRs), clinical benefit rate, and toxicity. RESULTS Sixty patients were enrolled; 57 patients were evaluable. The median age was 72 years, all were HIV–; 75.4% was PD-L1+, 84.2% had head/neck origin, 47.4% had distant metastasis, and there were no differences in baseline characteristics by arm. Avelumab + cetuximab significantly improved PFS versus avelumab (median, 11.1 [7.6-not reached (NR)] v 3.0 months [2.7-13.6] hazard ratio, 0.48 [95% CI, 0.23 to 0.97], P = .018). Avelumab patients who crossed over (n = 9) to combination had a median PFS after crossover of 11.3 months (5.8-NR). The confirmed ORR was 27.6% with avelumab + cetuximab and 21.4% with avelumab. Grade 3 treatment-related adverse events occurred in 48.3% and 21.5% of patients with avelumab + cetuximab (most common: rash [20.7%], infusion reaction [20.7%]) and avelumab, respectively. CONCLUSION Avelumab + cetuximab significantly improved PFS versus avelumab alone in patients with advanced cSCC. Alliance A091802 supports a larger confirmatory study with the combination of cetuximab and PD-1:PD-(L)1 blockade.

6002 Background: There is a need for continued improvement in outcomes with systemic therapy for advanced cSCC. Pre-clinical data suggest immunologic synergy between IgG1 mAb therapy targeting EGFR and PD-1:PD-(L)1 blockade. Methods: Alliance A091802 is a randomized phase II trial of avelumab (AV) (800 mg) plus cetuximab (C) (500 mg/m2) vs. AV alone every 2 weeks for up to 2 years (yrs). C was given for 1 yr in the AV+C arm. Crossover at progression to AV+C was allowed in the AV arm. Randomization was 1:1 and stratified by PD-L1 [+(>1%) vs. -] and HIV status (+ vs. -). Eligible patients (pts) had distant metastatic or unresectable locally advanced cSCC, anti-PD-1/PD-L1 mAb naive, no prior cetuximab in the advanced setting, ECOG PS 0-2, HIV+ if CD4 >200 and VL <200. Pts with CLL, immunosuppression, or active autoimmune diseases were excluded. The primary endpoint was progression-free survival (PFS) (Ho: Median=12 mo vs Ha: 21 mo or a 75% improvement, power of 80% with one-sided alpha 0.2, n=57, 37 PFS events required). Secondary endpoints were overall survival (OS), confirmed response rate (ORR), clinical benefit rate, and toxicity. After 31/37 events, an early unplanned analysis (along with sensitivity analyses) was performed because it became apparent that 37 events would not be reached. These results were submitted to the Alliance Data and Safety Monitoring Board, which recommended releasing the data. Data cutoff was 1/16/25. Results: 60 pts were enrolled between 2019-2023; 57 pts were evaluable. Median age was 72 yrs (41‒93), 96.5% were white, 91.2% male, all HIV-; 75.4% PD-L1+. 84.2% were head/neck origin, 47.1% had distant metastasis, and there were no differences in baseline characteristics by arm. AV+C significantly improved PFS compared to AV [median 11.1 months (mo) (7.6‒not reached (NR)) vs. 4.8 mo (2.8‒NR) hazard ratio (HR) 0.53 95% CI (0.26‒1.09), one-sided p=0.041]. The median OS of AV+C vs. AV was NR (25.2‒NR) vs. 35.8 mo (18.6‒NR) HR 0.77 (0.33‒1.78) p=0.267. ORR was 31.0% in the AV+C arm and 21.4% in the AV arm. Treatment-related adverse events (TRAE) of any grade (G) occurred in 93% and 78.6%, respectively, and were G>3 in 48.3% and 21.5% of pts in the AV+C [most common G3 TRAEs were rash (20.7%) and infusion-related reaction (20.7%)] and AV arms, respectively. There were no G5 events. Outcomes after crossover and by PD-L1 status will be presented subsequently. Conclusions: Avelumab plus cetuximab significantly improved PFS vs. avelumab alone in advanced cSCC pts, without unexpected toxicity. Alliance A091802 supports a larger confirmatory study with combination cetuximab and PD-1:PD-(L)1 blockade. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180868 (NRG Oncology); U10CA180888 (SWOG); https://acknowledgments.alliancefound.org . EMD Serono CrossRef Funder ID: 10.13039/100004755. Clinical trial information: NCT03944941 .