Single Arm Study of Neoadjuvant Dostarlimab in Stage II and III Deficient Mismatch Repair Colon Cancers
Ontology highlight
ABSTRACT:
DISEASE(S): Dmmr Colorectal Cancer,Colon Cancer,Colonic Neoplasms
PROVIDER: 2404658 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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2024-07-19 | GSE268903 | GEO
Project description:PurposeEvaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.Experimental designdMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.ResultsOf 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < 0.003).ConclusionsOver one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
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Project description:High microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) phenotype is a distinct molecular signature across gastrointestinal cancers characterized by high tumor mutational burden and high neoantigen load. Tumors harboring dMMR are highly immunogenic and heavily infiltrated by immune cells; consequently, they are uniquely vulnerable to therapeutic strategies enhancing immune antitumor response such as checkpoint inhibitors. The MSI-H/dMMR phenotype arose as a powerful predictor of response to immune checkpoint inhibitors with evidence supporting significantly improved outcomes in the metastatic setting. On the other hand, the genomic instability characteristic of MSI-H/dMMR tumors appears to be associated with decreased sensitivity to chemotherapy, and the benefits of standard adjuvant or neoadjuvant chemotherapy approaches in this subtype are being increasingly questioned. Here, we review the prognostic and predictive impact of MMR status in localized gastric and colorectal cancers, and highlight the emerging clinical data incorporating checkpoint inhibitors in the neoadjuvant setting.
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Project description:Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. Four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short-term efficacy and toxicities of this strategy. Results: All the enrolled eight patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a clinical complete response (cCR) tumor response. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.
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Project description:Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.
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