In a French phase II trial reported in The Lancet Oncology, Kim et al found that the combination of the PD-1 inhibitor ezabenlimab and induction chemotherapy with modified docetaxel, cisplatin, and fluorouracil (mDCF) and adaptive chemoradiotherapy was active in patients with treatment-naive stage III squamous cell anal carcinoma.
Study Details
In the multicenter trial, 54 evaluable patients (modified intention-to-treat population) with stage III disease (TxN1 or T4N0) were enrolled between January 2022 and November 2023. Patients received induction with mDCF every 2 weeks for four cycles (docetaxel at 40 mg/m2 on day 1, cisplatin at 40 mg/m2 on day 1, and fluorouracil at 1,200 mg/m2 on days 1 and 2) and ezabenlimab at 240 mg every 3 weeks for three cycles. After 8 weeks of induction, patients without progression received two additional cycles of mDCF and one additional cycle of ezabenlimab. Patients with a major response (radiologic objective response of ≥ 30% tumor reduction) and pathologic complete or near-complete response (< 10% viable cells) at biopsy and biological complete response (no residual HPV circulating tumor DNA) received intensity-modulated radiotherapy with involved-node chemoradiotherapy (INRT), followed by seven cycles of ezabenlimab maintenance at 240 mg every 3 weeks. Patients without response received standard concurrent chemoradiotherapy. The primary outcome measure was clinical complete response at 40 weeks (with a lower 90% confidence interval [CI] greater than 65%).
Key Findings
After induction, 41 (84%) of 49 evaluable patients had a pathologic complete or near-complete response and 36 (90%) of 40 had a biologic complete response. A total of 38 (75%) of 51 patients received INRT and 13 (26%) received standard concurrent chemoradiotherapy.
Clinical complete response rates at 40 weeks were 86.8% (90% CI = 74.3%–94.7%) with INRT in 33 patients and 69.2% (90% CI = 42.7%–88.7%) with concurrent chemoradiotherapy in nine patients, yielding an overall rate of 77.8% (90% CI = 66.5%–86.7%).
At a median follow-up of 23.0 months (95% CI = 16.5–29.1 months), median progression-free survival, disease-free survival, and overall survival could not be estimated. Estimates at 12 and 24 months were 85.2% and 81.4% for progression-free survival, 86.1% and 80.0% for disease-free survival, and 94.4% and 84.3% for overall survival.
Grade 3 or worse treatment-related adverse events consisted of: neutropenia (6%) and nausea, diarrhea, anemia, and asthenia (4% each) in patients receiving induction; lymphopenia (45%), neutropenia (18%), epithelitis (16%), anal inflammation (13%), and thrombocytopenia (8%) in patients receiving INRT; lymphopenia (100%), thrombocytopenia and anal inflammation (23% each), and neutropenia and diarrhea (15% each) in patients receiving concurrent chemoradiotherapy; and lipase increase, cytomegalovirus colitis, and lichen planus (3% each) in patients receiving maintenance. No treatment-related deaths were reported.
The investigators concluded: “Our study met the primary endpoint, showing antitumour activity (clinical complete response rates) and a manageable safety profile for ezabenlimab and mDCF induction when given with INRT in patients with locally advanced [squamous cell anal carcinoma], enabling personalised INRT, and supporting phase III trials of this treatment in patients with stage III [squamous cell anal carcinoma].”
Christophe Borg, MD, of the Department of Medical Oncology, Centre Hospitalier Universitaire de Besançon, Besançon, France, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Centre Hospitalier Universitaire de Besançon and Boehringer Ingelheim. For full disclosures of all study authors, visit thelancet.com.
