Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial
Mené sur 34 patients atteints d'un cancer colorectal de stade localement avancé et présentant une haute instabilité des microsatellites ou une déficience du système de réparation MMR, cet essai de phase II évalue l'efficacité, du point de vue de la proportion de patients obtenant une réponse pathologique complète, et la toxicité de l'ajout du célécoxib (un inhibiteur de COX-2) à un traitement néoadjuvant à base de toripalimab (un anticorps anti-PD-1)
Background : PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockadein the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib,as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high,locally advanced, colorectal cancers.
Methods : The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial wasa single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou,China). Eligible patients were aged 18–75 years, had histologically confirmed mismatchrepair-deficient or microsatellite instability-high colorectal cancer, had clinicalstage T3–T4 or any T with lymph node positivity (N+), Eastern Cooperative OncologyGroup performance score of 0 or 1, and adequate haematological, hepatic, and renalfunction. Participants were randomly assigned (1:1), without any stratification orbalanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with orwithout celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle,for six cycles before surgical resection. Adjuvant treatment with toripalimab withor without celecoxib was permitted at the investigators' discretion. The primary endpointwas the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampledregional lymph nodes. All efficacy and safety analyses were assessed in the modifiedintention-to-treat population, which included all patients who were randomly assignedto treatment and who received at least one dose of toripalimab. This trial is registeredwith ClinicalTrials.gov, NCT03926338, and is ongoing.
Findings : Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9months (IQR 8·8–17·0). All patients received study treatment and underwent surgicalresection; there were no treatment-related surgical delays. All 34 patients had anR0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64–99]) in thetoripalimab plus celecoxib group and 11 of 17 patients (65% [38–86]) in the toripalimabmonotherapy group had a pathological complete response. All patients continued toreceive adjuvant toripalimab with or without celecoxib for a total perioperative durationof 6 months and were alive and free of recurrence at data cutoff. During neoadjuvanttreatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%)in the toripalimab monotherapy group had grade 1–2 treatment-related adverse events.Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, hada grade 3 or higher treatment-related adverse event during the neoadjuvant phase,which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase,only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had agrade 3 or higher treatment-related adverse events, which was grade 3 increased aspartateaminotransferase and alanine aminotransferase levels.
Interpretation : Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high,locally advanced, colorectal cancer. This treatment was associated with a high pathologicalcomplete response rate and an acceptable safety profile, which did not compromisesurgery. Longer term follow-up is needed to assess effects on survival-related endpoints.
The Lancet Gastroenterology & Hepatology , résumé, 2020