Neoadjuvant blockade of PD-1 by toripalimab, with or without celecoxib, in colorectal cancer (PICC) with high degree of microsatellite instability or mismatch repair (PICC): single center, in parallel groups, non-comparative, randomized , phase 2 trial

Background

Blockade of PD-1 is very effective in patients with metastatic colorectal cancer deficient in mismatch repair or with high microsatellite instability. The role of PD-1 blockade as monotherapy in the neoadjuvant setting of resectable colorectal cancer with mismatch repair deficit or high microsatellite instability remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor, celecoxib, as a neoadjuvant treatment for locally advanced colorectal cancers with repair deficit. mismatches or high microsatellite instability.

Methods

The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-center, open-label, parallel-group, non-comparative, randomized, Phase 2 study conducted at the Sixth Affiliated Hospital of Sun Yat-sen University (Canton, China). Eligible patients were 18 to 75 years old, had histologically confirmed colorectal cancer with mismatch repair deficit or high microsatellite instability, had clinical stage T3 to T4 or any other T with lymph node positivity (N +) , an Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate hematologic, hepatic and renal function. Participants were randomized (1: 1), without any stratification or balanced blocking, to receive toripalimab 3 mg / kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to day 14 of each 14 day cycle, for six cycles prior to surgical resection. Adjuvant therapy with toripalimab with or without celecoxib was permitted at the discretion of the investigators. The primary endpoint was the proportion of patients with a complete pathological response, defined as tumors without any viable tumor cells in the resected primary tumor sample and all regional lymph nodes sampled. All efficacy and safety analyzes were evaluated in the modified intention-to-treat population, which included all patients who were randomized to receive treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing.

Results

Between May 1, 2019 and April 1, 2021, 53 patients were screened, of which 34 were randomized either to the toripalimab plus celecoxib group (n = 17) or to the toripalimab monotherapy group (n = 17). At the data cut-off date (August 10, 2021), the median follow-up was 14.9 months (IQR 8.8–17.0). All patients received study treatment and underwent surgical resection; there was no surgical delay associated with treatment. All 34 patients underwent R0 resection (> 1 mm resection margin). 15 of 17 patients (88% [95% CI 64–99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38–86]) in the toripalimab monotherapy group had a complete pathological response. All patients continued to receive toripalimab adjuvanted with or without celecoxib for a total perioperative period of 6 months and were alive and without recurrence at the data cut-off date. During neoadjuvant therapy, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group experienced grade 1–2 treatment-related adverse events. Only one (3%) of 34 patients, who were in the toripalimab plus celecoxib group, experienced a grade 3 or above treatment-related adverse event during the neoadjuvant phase, namely a grade 3 increase in levels of aspartate aminotransferase. During the adjuvant phase, only one (3%) of 34 patients, who were in the toripalimab monotherapy group, experienced grade 3 or greater treatment-related adverse events, namely a grade 3 increase in levels of d aspartate aminotransferase and alanine aminotransferase.

Interpretation

Neoadjuvant toripalimab with or without celecoxib may be a potential treatment option for patients with locally advanced colorectal cancer with poor mismatch repair or high microsatellite instability. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise the surgery. Longer-term follow-up is necessary to assess the effects on parameters related to survival.

Funding

The key national R&D program of China, the National Foundation of Natural Sciences of China and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research.

Translation

For the Chinese translation of the summary, see the Additional Documents section.


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