Phase II INTERACT-ION study: ezabenlimab (BI 754091) and mDCF (docetaxel, cisplatin, and 5-fluorouracil) followed by chemoradiotherapy in patients with Stage III squamous cell anal carcinoma

Abstract

Background: Chemoradiotherapy alone is the standard treatment for locally advanced squamous cell anal carcinoma (SCAC). However, up to 50% of patients will experience recurrence; thus, there is a need for new treatments to improve outcomes. Modified docetaxel, cisplatin and 5-fluorouracil (mDCF) is a treatment option for first-line metastatic SCAC, having shown efficacy in the Epitopes-HPV01 and -02 trials (NCT01845779 and NCT02402842). mDCF treatment also plays a role in the modulation of anti-tumor immunity, suggesting it may be a good combination partner for immunotherapy in patients with SCAC. Anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in metastatic SCAC. We therefore designed the INTERACT-ION study to assess the combination of mDCF with ezabenlimab (BI 754091), an anti-PD-1 antibody, followed by chemoradiotherapy, in patients with Stage III SCAC.

Methods: INTERACT-ION is a pivotal, open-label, single-arm phase II study in patients with treatment-naïve Stage III SCAC. Patients will receive induction treatment with mDCF (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on Day 1, 5-fluorouracil 1200 mg/m2/day for 2 days) every 2 weeks for 4 cycles and ezabenlimab (240 mg given intravenously) every 3 weeks for 3 cycles. In the absence of disease progression at 2 months, two additional cycles of mDCF and one additional cycle of ezabenlimab will be administered. Patients with radiological objective response, pathological complete/near-complete response and biological complete response will then receive an involved-node radiotherapy with intensity-modulated radiation therapy and concurrent chemotherapy, followed by ezabenlimab alone for seven cycles. All other patients will receive standard chemoradiotherapy. The primary endpoint is the clinical complete response rate 10 months after the first cycle of mDCF plus ezabenlimab. Major secondary endpoints are major pathological response and biological complete response after induction treatment. An extensive ancillary biomarker study in tumor tissue and peripheral blood will also be conducted.

Discussion: The addition of immunotherapy to chemotherapy is an area of active interest in metastatic anal cancer. This pivotal study will evaluate this combination in the locally advanced setting. Ancillary biomarker studies will contribute to the understanding of predictors of response or resistance to treatment.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT04719988, identifier NCT04719988.

Keywords: 5-Fluorouracil (DCF); Cisplatin; Stage III; anal carcinoma; ezabenlimab; modified Docetaxel; squamous.

Conflict of interest statement

SK reports a consulting or advisory role for Ipsen, Incyte, Boehringer Ingelheim, Sanofi and BeiGene and has received research funding from Pfizer, Roche, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim and Sanofi. LE reports honoraria from Servier, Merck, Pierre Fabre and Amgen and travel and accommodation expenses from Merck and Servier. EF reports a consulting or advisory role for Pierre Fabre; has received travel and accommodation expenses from Pierre Fabre and honoraria from Amgen, Novartis, Pierre Fabre, and Merck Sharp & Dohme. LQ reports research funding from AstraZeneca, and travel and accommodation expenses from Astellas and Ipsen. CF reports a consulting or advisory role for Amgen, Bristol-Myers Squibb, Eisai, Pierre Fabre Oncologie, Roche, Servier and Ipsen; and travel and accommodation expenses from Eisai and Amgen. LD reports honoraria from Amgen, Bristol-Myers Squibb, Servier, Oseus and Mylan. OB reports honoraria from Roche, Amgen, Merck Serono, Servier, Pierre Fabre, Bayer, Sanofi and Grünenthal. BC reports a consulting or advisory role for BeiGene, Roche, Sanofi and Servier; travel and accommodation expenses from Sanofi, Merck, Merck Sharp & Dohme and Roche; and honoraria from Pfizer, Roche, Sanofi, Servier and Bayer. AF and CM are employees of Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Boehringer Ingelheim.

Copyright © 2022 Kim, Boustani, Vernerey, Vendrely, Evesque, Francois, Quero, Ghiringhelli, de la Fouchardière, Dahan, Bouché, Chibaudel, Hajbi, Vernet, Rebucci-Peixoto, Feuersinger, Maritaz and Borg.

Figures

Figure 1

Study Design of INTERACT-ION. *Concomitantly given with capecitabine (825 mg/m2 orally twice daily) only on days of radiotherapy, and mitomycin C (10 mg/m2 Day 1 ± Day 29). †59.4 Gy for primary tumor and involved residual nodes + 45 Gy for elective nodal irradiation for initially involved lymph node(s) with complete response. 5-FU, 5-fluorouracil; bCR, biological complete response; cCR, complete clinical response; CT, computed tomography; ctDNA, circulating tumor DNA; DC, disease control; IMRT, intensity-modulated radiation therapy; MRI, magnetic resonance imaging; pCR, pathological complete response; PD, progressive disease; PET, positron emission tomography; pnCR, pathological near-complete response; Q2W, every 2 weeks.

Figure 2

Flow Chart of Chemoradiotherapy. CTV, clinical target volume; Dmean, mean dose; GTV, gross tumor volume; Gy, Gray.

Figure 3

Study Flow Chart and Visit Schedule. aClinical examination: height (only at baseline), weight, Eastern Cooperative Oncology Group performance status; bVital signs: pulse, blood pressure and body temperature; cOnly if no radiologic assessment performed within 28 days prior to this visit; dRadiologic assessment mandatory; eRadiologic assessment highly recommended; fRadiologic assessment if indicated ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; bCR, biological complete response; BUN, blood urea nitrogen; cCR, clinical complete response; cOR, clinical objective response; CT, computed tomography; ctDNA, circulating tumor DNA; CTV, clinical target volume; D, day; DPD, dihydropyrimidine dehydrogenase; ECG, electrocardiogram; EDTA, ethylenediaminetetraacetic acid; F, Friday; γ-GTP, gamma-glutamyl transpeptidase; GTV, gross tumor volume; Gy, Gray; HIV, human immunodeficiency virus; IMRT, intensity-modulated radiation therapy; INRT, involved-node radiotherapy; LDH, lactate dehydrogenase; mDCF, modified docetaxel, cisplatin and 5-fluorouracil; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; pCR, pathologic complete response; PET, positron emission tomography; pnCR, pathologic near complete response; TSH, thyroid stimulating hormone; W, week.