Dan Zandberg, MD, UPMC Hillman Cancer Center, Pittburgh, Pennsylvania, discusses the results from a phase 2 trial evaluating the combination of cetuximab and avelumab compared with avelumab alone for patients with advanced cutaneous squamous cell carcinoma.

Dr Zandberg concluded, “The main impact of our study is the prospective comparison of combination IgG1 and checkpoint blockade versus checkpoint blockade alone.” However, he noted that as “the control arm did worse than expected … the trial doesn't support that avelumab is used with cetuximab, but rather a standard-of-care anti–PD-1 with cetuximab in a larger trial.”

These data were first presented at the 2025 American Society of Clinical Society (ASCO) Annual Meeting in Chicago, Illinois.

Transcript:

I am Dan Zandberg. I'm a medical oncologist at the UPMC Hillman Cancer Center and my focus is in head and neck [cancer], and I co-lead our Head and Neck program. The trial I presented today was an Alliance trial that I chair, a phase 2 trial of avelumab plus cetuximab versus avelumab alone in an advanced cutaneous squamous cell carcinoma.

We've made headway in advanced cutaneous squamous carcinoma with the approval of cetuximab and pembrolizumab with high response rates and durability, but there's still a need for improvement in outcomes. Back when we initiated this trial or development of it, we had preclinical rationale for anti–PD-1/PD-L1 therapy, and also for combination with cetuximab. Cetuximab is an IgG1 monoclonal antibody that targets EGFR and as an IgG1, it stimulates antibody dependent cellular cytotoxicity, which stimulates NK cells and innate immunity. But beyond that, those NK cells get activated and crosstalk with dendritic cells that then can present antigen and induce CDAT cells that can target EGFR expressing tumor cells.

With that rationale, we created this trial, which is a phase 2 trial that randomizes 1-to-1 to avelumab monotherapy as the control arm versus avelumab plus cetuximab in the avelumab plus cetuximab arm. Avelumab is given at 800 mg IV Q2 weeks, cetuximab 500 mgs IV Q2 weeks, calling a cycle every 28 days. And patients get combination for 12 cycles followed by avelumab maintenance if they haven't progressed. And that was compared to avelumab monotherapy given at 800 mgs IV Q2 weeks. The primary endpoint was progression-free survival, comparing combination versus monotherapy. Secondary endpoints were overall response rate, clinical benefit rate, toxicity, and overall survival. The trial was stratified, or the randomization was stratified for PD-L1 expression by a TPS ≥1 as positive versus negative, and also HIV positive versus negative. We also allowed crossover for patients that were on the avelumab monotherapy arm. They were allowed to crossover after progression if they maintain their performance status to combination. And one of the secondary endpoints was PFS two or the progression-free survival after crossover.

The trial was powered for progression-free survival requiring 37 events with a sample size of at least 54 evaluable patients with a projection of 12 months for the control arm to try to increase that by experimental arm to 21 months. RECIST was used for response and we did allow modifications, modifications for progression. If someone maintained their clinical stability, they could continue on therapy to confirm progression at least 4 weeks afterwards with a scan, we confirmed progression that patient was taken off.

The inclusion/exclusion criteria were advanced cutaneous squamous cell carcinoma defined as patients with distant metastatic disease and or regional disease without a surgical resection option. Patients could have an ECOG performance status of 0 to 2. They could not have received prior anti–PD-1 or anti–PD-L1. They could not have received prior cetuximab for advanced disease, although they could have received cetuximab in the curative-intent setting and long as it had been 6 months since prior therapy. And they required a lesion by RECIST for a target lesion. We did exclude those that are immunosuppressed other than including HIV positive. So those organ-transplant patients were excluded or any other reasons for immunosuppression. And we also excluded autoimmune disease as well as CLL.

The trial enrolled 60 patients for 57 evaluable patients. There was no difference in baseline characteristics by arm. The median age for patients was 72. The study was predominantly male, predominantly white, predominantly head and neck site of origin, 84% patients. Actually, no HIV patients ended up being enrolled. Seventy-five percent of patients were PD-L1 expressors and again that was balanced by arm. And 47% of patients had distant metastatic disease.

The primary endpoint was progression-free survival and avelumab plus cetuximab significantly improved progression-free survival compared to avelumab monotherapy with a median progression-free survival of 11 months compared to 3 months in the avelumab monotherapy arm with the hazard ratio of 0.48 and a P-value of 0.018. In terms of secondary endpoints, we saw the progression-free survival–2, that is the progression-free survival for those that progressed on avelumab and crossed over to avelumab plus cetuximab with that crossover. The second PFS was 11.3 months. We looked at in an exploratory fashion at PD-L1 expression, and we saw that those that were PD-L1 expressors, it enriched for those that had higher efficacy, both in the avelumab arm and the combination arm, albeit neither one was statistically significant. We did do subgroup analysis for different subgroups and all of them, whether age, ECOG performance status, PD-L1 status, and presence of distant metastatic disease, all subgroups favored the combination arm. 

And toxicity wise, we saw really expected toxicity. Nothing unexpected in terms of toxicity. There are no grade 5 events, 1 grade 4 event of glucose intolerance in the avelumab monotherapy arm and otherwise expected grade 3 events with infusion reaction and also acne form rash in the combination arm in about 20% of patients.

The limitations of the study are that we had only 57 total patients, so the results are not definitive, and we powered the trial based on cemiplimab, when that data first came out. However, we expected that avelumab and anti–PD-L1 monoclonal antibody would have similar efficacy to cemiplimab. A limitation is that the control arm of avelumab had worse than expected efficacy, and the efficacy is lower than that of cemiplimab and pembrolizumab, for example.

The main impact of our study is the prospective comparison of combination IgG1 and checkpoint blockade versus checkpoint blockade alone. However, because the control arm did worse than expected, as far as next steps, the trial doesn't support that avelumab is used with cetuximab, but rather a standard-of-care anti–PD-1 with cetuximab in a larger trial.

Source:

Zandberg DP, Allred JB, Rosenberg AJ, et al. Phase II (Alliance a091802) randomized trial of avelumab plus cetuximab versus avelumab alone in advanced cutaneous squamous cell carcinoma. Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract #6002