JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Grant McArthur discuss the ASCO 2025 Simultaneous Publication paper " A Phase II (Alliance A091802) Randomized Trial of Avelumab Plus Cetuximab vs. Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma (cSCC) ." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, and I'm joined by JCO Associate Editor Dr. Grant McArthur. Today, we will discuss Journal of Clinical Oncology article and abstract presentation " A Phase II Randomized Trial of Avelumab Plus Cetuximab Versus Avelumab Alone in Advanced Cutaneous Squamous Cell Carcinoma ." Let's start with a brief overview of the clinical trial. This is a randomized phase II trial that compared avelumab plus cetuximab to avelumab in PD-1/PD-L1 antibody-naive patients with advanced cutaneous squamous cell carcinoma. This is a cooperative group study conducted in the United States. Sixty patients were randomized one-to-one and stratified by PD-L1 and HIV status. The primary endpoint was progression-free survival. Patients on the cetuximab plus avelumab arm had a median PFS of 11.1 months, while patients on the avelumab arm had a median PFS of 3 months, corresponding to a hazard ratio of 0.48 with a p-value of 0.018. Grade III or higher treatment-related adverse events occurred in 48% of the patients on the combination arm versus 21% of patients on the avelumab arm. Dr. McArthur, can you please explain to our listeners how you interpret this data? Dr. Grant McArthur: These results are very important because they provide proof of concept for inhibiting PD-L1 as a target when combined with EGFR, so inhibiting PD-L1 with avelumab and inhibiting EGFR with cetuximab, in a randomized trial with a very significant impact in terms of efficacy. So, what this does is it provides proof of concept for inhibiting those targets in cutaneous squamous cell carcinoma of the skin. Avelumab is not approved for cutaneous squamous cell carcinoma of the skin, and so further studies would need to be done, particularly asking the question about combination with the approved PD-1 agents cemiplimab and pembrolizumab. Dr. Ece Cali: I still find the difference in median PFS with various PD-1/PD-L1 inhibitors striking in this context. In this trial, avelumab, as you mentioned, the PD-L1 inhibitor, demonstrated a median PFS of 3 months, whereas PD-1 inhibitors cemiplimab and pembrolizumab have demonstrated longer median PFS in other trials. So, what are some potential reasons for this, and do you think this difference impacts the interpretation of the results here? Dr. Grant McArthur: So, the obvious reason for the differences is that avelumab targets PD-L1, where pembrolizumab and cemiplimab inhibit PD-1, so there could be simply a difference in the target to explain those differences in progression-free survival. However, as you point out, cross-trial comparisons, one has to do with caution because you can, in different phase II studies, enroll different patient populations, which would impact the progression-free survival. So, we have to be cautious about that interpretation. However, given that cemiplimab and pembrolizumab are the approved agents, I think they are the logical ones for further clinical development. Nonetheless, this is still a very important proof-of-concept trial showing that there is a strong clinical signal when you combine EGFR inhibition with inhibition of PD-L1 versus PD-L1 alone. Dr. Ece Cali: I want to highlight some of the safety data presented in this trial as well. The treatment discontinuation rate due to adverse events was much higher in the combination arm, reaching 31% compared to the 14% in the single-agent avelumab arm. The most common grade III adverse events were infusion reaction, rash, and diarrhea in the combination arm. So, these adverse events may affect patients' quality of life significantly. So, what are your thoughts on this, Dr. McArthur? Dr. Grant McArthur: So, the safety data is important. What we're seeing is safety related to each individual agent. So, we have diarrhea and skin rash from the cetuximab, and the infusion reactions is a common toxicity of avelumab. I think what's important, given this is proof of concept inhibiting these targets going forward to further studies, is that agents such as cemiplimab and pembrolizumab have a very low infusion reaction rate. So, the treatment discontinuations due to infusion reaction are unlikely to be an issue with cemiplimab and pembrolizumab when further clinical trials are done. Of course, there is still the issue of diarrhea and skin rash. Now, that can be managed in many patients with EGFR inhibition, you know. However, one would have to await safety data from a significant patie
