Highlight
Key points
– The INTERACT-ION phase 2 trial combined the PD-1 inhibitor ezabenlimab with modified docetaxel, cisplatin and fluorouracil (mDCF) induction, using radiologic, pathologic, and HPV circulating tumour DNA (ctDNA) biomarkers to select patients for involved-node radiotherapy (INRT).
– The regimen met its primary endpoint: clinical complete response (cCR) at 40 weeks was 77.8% overall (90% CI 66.5–86.7), with 86.8% for those treated with INRT (90% CI 74.3–94.7).
– Responses after induction were high: pathological complete/near-complete response in 41/49 evaluable patients (84%) and biological complete response (HPV ctDNA negative) in 36/40 (90%).
– Safety was consistent with expectations for multi-agent cytotoxic chemotherapy, immunotherapy, and pelvic radiotherapy; serious adverse events occurred in 36% and seven patients died during the study (investigator-attributed none as treatment-related).
Background and clinical need
Squamous cell carcinoma of the anal canal (SCAC) is a human papillomavirus (HPV)-associated malignancy for which chemoradiotherapy is the established standard of care in locally advanced disease. Historic evidence and randomized trials have established combined modality treatment as curative in many patients, but up to approximately 30–40% experience locoregional failure or require salvage surgery with colostomy. Late toxicities and treatment-related morbidity can be substantial. There is therefore an unmet need for strategies that (1) increase disease control, (2) reduce treatment-related morbidity including colostomy risk, and (3) enable treatment personalization based on early response.
Checkpoint inhibitors targeting PD-1 have shown activity in recurrent and metastatic HPV-associated SCAC, providing biological rationale for earlier incorporation of immune checkpoint blockade into curative-intent treatment. The INTERACT-ION study examined whether combining induction ezabenlimab (an anti–PD-1 antibody) with an established multi-agent induction chemotherapy regimen (mDCF) could induce deep responses that permit de-escalated, involved-node radiotherapy for good responders, thus personalizing definitive therapy.
Study design
The INTERACT-ION trial was an open-label, single-arm, phase 2 study conducted at ten French hospitals (ClinicalTrials.gov NCT04719988). Key eligibility criteria included age ≥18 years, stage 3 SCAC (TxN1 or T4N0), ECOG performance status 0–1, and adequate organ function. The trial used an adaptive pathway predicated on early response assessment.
Intervention and adaptive pathway:
– Induction: mDCF every 2 weeks for four cycles (docetaxel 40 mg/m2 day 1, cisplatin 40 mg/m2 day 1, fluorouracil 1200 mg/m2 days 1–2) plus ezabenlimab 240 mg IV every 3 weeks for three cycles.
– Response assessment at 8 weeks using RECIST v1.1; non-progressing patients received two further cycles of mDCF and one more ezabenlimab dose.
– Patients with a major radiological objective response (≥30% reduction), a pathological complete or near-complete response on biopsy (<10% viable tumor), and a biological complete response (undetectable HPV ctDNA) went on to receive intensity-modulated INRT with concurrent chemotherapy (involved-node chemoradiotherapy), followed by seven cycles of ezabenlimab maintenance (240 mg IV q3w).
– Patients who did not meet the major-response criteria received standard concurrent chemoradiotherapy.
Primary endpoint: clinical complete response (cCR) at 40 weeks in the modified intention-to-treat (mITT) population, prespecified to be positive if the lower bound of the 90% confidence interval exceeded 65%.
Key results
Population and disposition:
– 60 patients were assessed; 55 enrolled and 54 were evaluable for the mITT analysis. Median age was 63.9 years (IQR 57.1–72.3); 76% were female.
Induction activity:
– After induction, 41 of 49 evaluable patients (84%) achieved pathological complete or near-complete response on biopsy.
– Biological complete response (undetectable HPV ctDNA) was achieved in 36 of 40 evaluable patients (90%).
Adaptive radiotherapy allocation:
– 38 of 51 patients (75%) received involved-node radiotherapy (INRT) as the consolidated local treatment plan.
– 13 of 51 (26%) received standard concurrent chemoradiotherapy.
Primary endpoint—clinical complete response at 40 weeks:
– INRT group: cCR 86.8% (90% CI 74.3–94.7) in 33 evaluable patients.
– Standard concurrent chemoradiotherapy group: cCR 69.2% (90% CI 42.7–88.7) in nine evaluable patients.
– Overall cCR (mITT): 77.8% (90% CI 66.5–86.7). The study met its primary endpoint because the lower bound of the 90% CI exceeded the prespecified 65% threshold.
Safety and tolerability:
– During induction, grade ≥3 treatment-related adverse events (TRAEs) included neutropenia (6%), nausea, diarrhea, anemia, and asthenia (each 4%). Serious adverse events were reported in 20 patients (36%), the most common being diarrhoea, nausea, and neutropenia (2 patients each during induction).
– During INRT, common grade ≥3 toxicities included lymphopenia (45%), neutropenia (18%), epithelitis (16%), anal inflammation (13%), and thrombocytopenia (8%).
– During standard concurrent chemoradiotherapy, lymphopenia was common (grade ≥3 in 100% of those reported), with thrombocytopenia and anal inflammation also notable.
– During ezabenlimab maintenance, immune-mediated events were uncommon but included lipase increases, CMV colitis, and lichen planus (each reported in 1 patient, 3%).
– Seven patients (13%) died during the study; three deaths were attributed to adverse events. Investigators judged that there were no treatment-related deaths.
Interpretation of effect size and clinical relevance:
– The high rates of pathological and biological complete responses after induction suggest biologic synergy of cytotoxic induction plus PD-1 blockade in stage 3 SCAC.
– The majority of patients qualified for INRT, and cCR rates in the INRT cohort were numerically higher than in those receiving standard chemoradiotherapy; however, numbers in subgroups were small and non-randomized comparisons are hypothesis-generating only.
Expert commentary and contextualization
Biological plausibility and translational rationale:
– HPV-driven tumors are immunogenic; cytotoxic chemotherapy can promote antigen release and immune priming, potentially enhancing response to PD-1 blockade. The combination of mDCF and ezabenlimab is therefore mechanistically rational.
– The use of HPV ctDNA to define a biological complete response is an important advance: ctDNA enables dynamic, minimally invasive assessment of residual disease and may help identify patients suitable for reduced radiotherapy volumes.
Strengths of the trial:
– Prospectively defined adaptive pathway using multi-modality response criteria (radiology, tissue pathology, and ctDNA) to personalize radiotherapy intensity.
– Multicentre execution demonstrates feasibility in routine tertiary care settings.
– The combination produced deep responses and allowed organ-preserving radiation in most patients.
Limitations and cautions:
– Single-arm, open-label design limits causal inference and prevents direct comparison with standard-of-care chemoradiotherapy for long-term outcomes such as overall survival, colostomy-free survival, and late toxicity.
– Subgroup numbers (for example, the concurrent CRT cohort) were small, limiting precision of effect estimates.
– Follow-up in this interim report is likely insufficient to fully characterize durability of response, late radiation toxicities, and oncologic outcomes such as local control, progression-free survival, and overall survival.
– Safety signals—particularly grade 3–4 lymphopenia during pelvic radiotherapy and serious adverse events during induction—require careful monitoring in larger trials and long-term follow-up.
Implications for clinical practice and future research:
– INTERACT-ION supports the principle that induction chemoimmunotherapy can induce deep responses in locally advanced HPV-associated anal cancer and can be used to select patients for targeted, less-extensive radiotherapy.
– The findings justify an adequately powered randomized phase 3 trial comparing induction chemoimmunotherapy followed by adaptive INRT versus standard concurrent chemoradiotherapy, with endpoints including colostomy-free survival, patient-reported quality of life, locoregional control, and overall survival.
– Critical secondary questions include validation of HPV ctDNA as a reliable surrogate for residual disease and long-term safety of the approach. Biomarker-driven strategies must ensure that de-escalation does not compromise cure rates.
Conclusion
The INTERACT-ION phase 2 trial demonstrates that ezabenlimab combined with mDCF induction produces high rates of pathological and biological response in stage 3 SCAC and that a biomarker-driven pathway can safely deliver involved-node radiotherapy to most patients while achieving high clinical complete response rates at 40 weeks. These encouraging results warrant randomized phase 3 evaluation to determine whether this strategy improves long-term oncologic outcomes and reduces morbidity compared with standard chemoradiotherapy.
Funding and trial registration
The study was funded by Centre Hospitalier Universitaire de Besançon and Boehringer Ingelheim. ClinicalTrials.gov identifier: NCT04719988.
References
1. Kim S, Boustani J, Iseas S, et al; INTERACT-ION Study Team. Ezabenlimab and induction chemotherapy followed by adaptive chemoradiotherapy in patients with stage 3 squamous cell anal carcinoma (INTERACT-ION): an open-label, single-arm, phase 2 trial. Lancet Oncol. 2025 Nov 4:S1470-2045(25)00605-9. doi: 10.1016/S1470-2045(25)00605-9. Epub ahead of print. PMID: 41202834.
2. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for squamous cell carcinoma of the anus. Cancer. 1974;34(3): 182-187. (Classic description of combined modality therapy establishing chemoradiation as organ-preserving standard.)
3. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation for squamous-cell carcinoma of the anus (ACT II): results from a randomized, factorial trial. Lancet Oncol. 2013;14(6):516–524. (Randomized trial informing contemporary chemoradiation regimens.)
Note: For full guideline recommendations and additional trial data on systemic and radiotherapeutic management of anal carcinoma, readers should consult up-to-date ESMO/NCCN resources and the primary literature.