Cadonilimab as Neoadjuvant Therapy in Resectable Stage II-III MSI-H/dMMR Colorectal Cancer
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ABSTRACT:
DISEASE(S): Microsatellite Instability,Mismatch Repair-deficient (dmmr),Colorectal Cancer,Colorectal Neoplasms,Neoadjuvant Therapy,Microsatellite Instability-high (msi-h)
PROVIDER: 64137 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:This is a two-arm phase II clinical study to evaluate the efficacy and safety of Cadonilimab (a PD-1/CTLA-4 bispecific antibody) in MSI-H/dMMR locally advanced colorectal cancer as the regimen of neoadjuvant treatment. Eligible patients will receive Cadonilimab monotherapy for eight cycles before surgery and part of patients may exempt from surgery.
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Project description:Dickkopf 1 (DKK1) could promote tumor progression by suppressing immunity. Therefore, we investigated whether DKK1 influence prognosis and sensitivity to PD-1 blockade in colorectal cancers (CRCs) with defective DNA mismatch repair genes (dMMR) or microsatellite instability (MSI). We found that elevated DKK1 expression was associated with recurrence and dismissed CD8+ T cell infiltrations, and patients with high serum DKK1 had poor anti-PD-1 response. RNA interference or neutralization of DKK1 in CRCs enhanced CD8+ T cell cytotoxicity, and down-regulation of T-bet and E2F1 following GSK3β activation was detected in DKK1-treated CD8+ T cells. In organoid-lymphocyte co-culture model, apoptosis proportions were elevated after individual neutralization of both PD-1 and DKK1, and the combined neutralization resulted in further increases. In conclusion, DKK1 suppresses tumor immunity in dMMR/MSI CRCs by inactivating CD8+ T cells through GSK3β/E2F1/T-bet axis. DKK1 neutralization may improve the sensitivity to PD-1 blockade in dMMR/MSI CRCs.
2021-04-07 | GSE149206 | GEO
Project description:Colorectal cancer of Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) accounts for approximately 15% of all colorectal cancer patients, with a higher proportion in right colon cancer. Previous studies have found that colon cancer patients with dMMR/MSI-H cannot benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and the prognosis is significantly worse than that of mismatch repair-proficient (pMMR)/microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in 《N Engl J Med》 showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy.
Anti-PD-1 neoadjuvant therapy has proven to be safe and feasible in lung cancer, bladder cancer and malignant melanoma, and can achieve more than 40% of major pathological response. However, there are no reports of anti-PD-1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to find the best multidisciplinary treatment for resectable colorectal cancer patient with the dMMR/MSI-H phenotype and to explore whether cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could further improve efficacy.
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Project description:Colorectal cancer (CRC) is one of the most common malignant tumours of human beings. Mismatch Repair-deficient (dMMR)/ Microsatellite Instability-high (MSI-H) CRC is a specific subtype of CRC, which accounts for approximately 15% of all CRC patients, and can not benefit from 5-fluorouracil (5-FU) adjuvant chemotherapy. Once patients have distant metastases, they are not sensitive to traditional palliative chemotherapy, and thus lead to much worse prognosis than that of mismatch repair-proficient (pMMR)/ microsatellite stability (MSS). A phase II clinical study of anti-PD-1 immunotherapy based on mismatch repair (MMR) status published in "N Engl J Med" showed that the objective response rate (ORR) of advanced colorectal cancer patients with dMMR received anti-PD-1 is 40%, and a longer response time can be obtained compared to conventional chemotherapy. Another study (ClinicalTrials.gov, NCT03926338) which investigating the effect of neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, on mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer. The result revealed that all 34 patients had an R0 resection. 15 of 17 patients (88%) in the toripalimab plus celecoxib group and 11 of 17 patients (65%) in the toripalimab monotherapy group had a pathological complete response.
In theory, anti-PD-L1 drugs should have fewer immune side-effects than anti-PD-1 drugs. However, there are no reports of anti-PD-L1 neoadjuvant therapy for the dMMR/MSI-H colorectal cancer. Therefore, the aim of this study was to investigate the efficacy and safety of anti-PD-L1 monoclonal antibody (Envafolimab) as neoadjuvant immuntherapy for resectable local advanced colorectal cancer patient with the dMMR/MSI-H.
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Project description:This is a trial investigating the efficacy and safety of Toripalimab combined with bevacizumab and chemotherapy as neoadjuvant therapy in patients with advanced microsatellite instability-high (MSI-H) or DNA mismatch repair-deficient (dMMR) colorectal cancer.
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Project description:Neoadjuvant PD-1 blockade may be efficacious in patients with high-risk, resectable oral-cavity, head-and-neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 patients displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T-cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T-cell clones. A high ratio of regulatory to Th17 T cells in pretreatment blood predicts innate resistance, low cytolytic T-cell signature in pretreatment tumor, and low T-cell receptor repertoire diversity in pretreatment blood. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for patients with resectable head-and-neck cancer.
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Project description:KEYNOTE-177 is currently the only randomized controlled phase III clinical trial evaluating the efficacy and safety of pembrolizumab versus standard chemotherapy combined with targeted first-line therapy for dMMR/MSI-H metastatic colorectal cancer. The study was conducted at 192 centers in 23 countries and enrolled a total of 307 subjects. The results of the study showed that the median PFS of pembrolizumab was 16.5 months, which was double the 8.2 months in the chemotherapy group (HR 0.60; 95% CI: 0.45-0.80; P = 0.0002). In addition, the ORR was 45.1% in the pembrolizumab group and 33.1% in the chemotherapy group, and a higher percentage of patients achieving a complete remission (CR) with pembrolizumab than in the chemotherapy group (13.1% vs. 3.9%). The U.S. FDA approved pembrolizumab in June 2020 for the first-line treatment of MSI-H/dMMR metastatic colorectal cancer.
The results of the KEYNOTE-177 study showed that 29% of patients with dMMR/MSI-H metastatic colorectal cancer experienced direct disease progression (PD) after first-line pembrolizumab monotherapy. This may suggest that some dMMR/MSI-H patients have primary resistance to anti-PD-1 monotherapy. In the first-line treatment cohort of the CheckMate 142 study using nivolumab combined with ipilimumab, the proportion of patients with direct PD was 13%, suggesting that the combination of PD-1 inhibitors and anti-CTLA-4 mAb may have help overcome this primary resistance. In addition, in the second-line and above cohort of the CheckMate142 study, 12% of patients receiving nivolumab in combination with ipilimumab experienced PD directly, compared with 26% of patients receiving nivolumab alone.
A study published on 《The Lancet Oncolog》 on the efficacy and safety of ipilimumab monotherapy and ipilimumab combined with anti-PD-1 monoclonal antibody in patients with anti-PD-1 monoclonal antibody-resistant melanoma Retrospective study. The study included 355 patients with unresectable metastatic stage III or IV melanoma who received ipilimumab monotherapy after failure of anti-PD-(L)1 monoclonal antibody (n=162), or Ipilimumab combined with anti-PD-1 therapy (n=193). The ORR was 31% in the combination arm, significantly higher than the 13% in the ipilimumab monotherapy arm. In addition, the median OS and PFS of the combination therapy group were 20.4 months and 3.0 months, respectively, which were also significantly higher than those of the single-agent group of 8.8 months and 2.6 months.
The aim of this study was to evaluate the objective response rate (ORR) of Cadonilimab, a bispecific anti-PD-1/CTLA-4 antibody, for PD-1/PD-L1 blockade-refractory, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), advanced colorectal cancer.
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Project description:dMMR/MSI-H colorectal cancer patients are the dominant population of immunotherapy/neoadjuvant immunotherapy, but imaging evaluation of immunotherapy efficacy is insufficient. There are some cases, although no disease remission was found on imaging,pathological complete response (pCR) was confirmed after surgery. Meanwhile,previous studies have shown that dynamic changes in ctDNA can help assess immunotherapy efficacy. Therefore, we propose to conduct a multicenter, prospective, observational clinical study to explore the efficacy prediction and monitoring value of ctDNA in immunotherapy for advanced or locally advanced dMMR/MSI-H colorectal cancer.
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