Combination of nivolumab with chemoradiotherapy for locally advanced cervical cancer: NiCOL phase I trial.
Authors: Rodrigues Manuel , Loap Pierre , Dubot Coraline , Durdux Catherine , Bazire Louis , Minsat Mathieu , Fourchotte Virginie , Laas Enora , Chevrier Marion , Romano Emanuela 
Published: June 2022

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Background: Current management of locally-advanced cervical cancers (LACC) relies on chemoradiotherapy (CRT) and brachytherapy. The causal relation between cervical cancer and human papillomavirus infection, which engenders tumor expression of immunoreactive neo-antigens, together with high PD-L1 expression, warrants consideration of immune checkpoint inhibitors (ICI) in the definitive treatment of this disease. We assessed the safety of concurrent and maintenance nivolumab in addition to CRT in patients with LACC. Methods: This prospective, multi-center, dose-confirmation, phase I clinical trial (NiCOL trial; NCT03298893) evaluated the tolerance profile of concurrent and maintenance nivolumab in addition to CRT (45 Gy in 25 fractions with cisplatin 40mg/m² q1w, followed by a brachytherapy boost to 85 Gy) for stage IB3-IVA cervical cancers. Nivolumab was administered at 240 mg q2w starting on day 1 of CRT and in maintenance after CRT completion for up to 6 months (13 cycles). The primary endpoint was the incidence of dose-limiting toxicities (DLT) within 11 weeks after the initiation of treatment (defining the DLT assessment period), corresponding to the first 6 cycles of nivolumab. DLT were defined as grade ≥3 non-hematological toxicities, grade ≥3 immune-related adverse event (irAE), persistent grade ≥2 irAE for ≥1 week despite optimal supportive care, or ≥1-week radiotherapy delay related to treatment toxicity. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and treatment tolerance profile. Results: 16 patients (pts) were recruited between 11/2017 and 07/2020. Median age was 46 years [range: 27-77]. Histological types were squamous cell carcinomas (n = 14) and adenocarcinomas (n = 2). Tumors were staged as FIGO IB3 (n = 2), IIB (n = 8), IIIB (n = 1), IIIC1 (n = 4) and IVA (n = 1); 13 tumors were HPV-positive. Three patients experienced DLT, corresponding to grade 3 hypotension (n = 2) and grade 3 acute kidney injury (n = 1). Following the DLT assessment period, while receiving maintenance nivolumab, one patient developed a grade ≥3 irAE corresponding to a grade 3 diarrhea. Two months after brachytherapy completion, ORR was 93.8% [95%CI: 69.8%-99.8%]. With a median follow-up of 16.6 months, three patients experienced disease control failure (at 3,4 and 5 months); site of disease progression was local for two patients, and simultaneously local and distant for one patient. One-year PFS was 81.2% [95% CI: 64.2%-100%]. Conclusions: Concomitant nivolumab with definitive CRT, followed by maintenance nivolumab, appears to be a safe and feasible therapeutic option for LACC, associated with encouraging PFS rates. Further trials evaluating ICI combined with CRT for LACC are warranted in light of these promising results and of those from recent studies evaluating ICI in the metastatic setting. Clinical trial information: NCT03298893.