Randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment: The CARACAS study.
Authors: Sara Lonardi, Filippo Pietrantonio, Alessandra Anna Prete, Marco Messina, Nicola Renzi, Domenico C. Corsi, Federica Urbano, Giovanni Luca Frassineti, M. Giulia Zampino, Monica Ronzoni, Mario Scartozzi, Mariaelena Casagrande, Alessandra Boccaccino, Francesca Bergamo, Michele Prisciandaro, Cosimo Rasola, Salvatore Corallo, Paola Del Bianco, Valentina Vettore, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2020)

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received &gt; 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .