Interestingly, these cells were more immunogenic and triggered immune surveillance in mice . Additionally, analysis of tumor biopsies from mCRC patients relapsing after TMZ-based therapeutic regimens revealed MMR mutations as a potential resistance mechanism in two out of five cases . Finally, our data suggested that MMR inactivation in mouse and human CRCs could lead to increased TMB and predicted neoantigens . These data led to the design of ARETHUSA , an ongoing proof-of-concept, two-step clinical trial.

However, due to the heterogeneity of the tumors, these markers are commonly used in other solid tumors and exhibit limited value in mCRC. It has been shown that MSS mCRC patients with POLE mutations can achieve an ideal immunotherapeutic effect . https://kelleysbookkeeping.com/ The theory of tumor immunotherapy is complex, which is the result of multiple factors, temporal and spatial heterogeneity, and network co-regulation. A single theory or a single indicator cannot adequately explain the mechanism of immunotherapy.

Assessment of TMB in Tissue Biopsies after TMZ Priming

This is due to the fact that a high TMB does not correspond to a high tumor neoantigen level. It is therefore clear that the mutation quality is much more important than the mutation quantity. However, tumor neoantigen burden is an indicator that reflects the total neoantigen quantity in tumor cells, which can be used as an adjunct to the TMB indicator . Responses were observed regardless of tumor programmed cell death ligand 1 (PD-L1) expression, BRAF or KRAS mutation status, or a clinical history of Lynch syndrome. The median time to response was 2.8 months (range, 1–14 months), and the median duration of response has not yet been reached. April 6th 2023 Article Progression-free survival and overall survival appear to be worse in patients with metastatic colorectal cancer who have a high- vs low-BRAF allele fraction after treatment with a BRAF inhibitor plus an anti-EGFR agent plus or minus a MEK inhibitor.

Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey. Metastatic colorectal cancer with deficient DNA mismatch repair shows frequent and durable responses to programmed cell death 1 blockade. Cost-effectiveness of immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer.

Identification of the TMZ Signature in Colorectal Cancer Cells Treated with TMZ

The ORRs were 39% (95% CI, 28%-51%) in cohort 1, 65% (95% CI, 55%-73%) in cohort 2, and 71% (95% CI, 56%-84%) in cohort 3. Notably, the benefit was consistent across subgroups including age (BRAF/KRAS wild-type vs BRAF mutant vs KRAS mutant), and ECOG performance status (0 vs ≥1) and was comparable to that of the overall population. Significant and clinically meaningful improvements in quality of life were largely Durable Clinical Benefit With Nivolumab Plus Ipilimumab In Dna Mismatch Repair maintained with continuous treatment. The 48-month rates of progression-free survival and overall survival were 53% and 71%, respectively. The individual statistical tests used are specified in the relevant Results section and figure legends. Only alterations with fractional abundance ≥10% were used for clonal analysis, whereas alterations with fractional abundance ≥1% were used for subclonal analysis.

• In terms of safety, grade 3 treatment-related adverse effects included colitis (4%) and 1 case (2%) each of adrenal insufficiency, asthenia, congestive cardiomyopathy, and gastroenteritis.
• After the filtering step , a median depth 376× and coverage ≥96.82% at 100× depth with a median of 124 million reads per sample were obtained .
• However, some of its unique adverse effects reduce its clinical efficacy, and certain rare adverse effects could be life-threatening, which result in skin, endocrine, hepatic, gastrointestinal, pulmonary, and skeletal muscle toxicity.
• The most common prior chemotherapies were fluoropyrimidine (99%), oxaliplatin (93%), and irinotecan (73%).
• Particular enrichment was seen in the subgroup of dMMR/MSI-H BRAFwt/RASwt CRC cases with MLH1 promoter hypermethylation where the occurrence of these aberrations was as high as 42% .

“These updated data further support current treatment recommendations for second-line nivolumab with or without ipilimumab and frontline nivolumab plus ipilimumab for patients with MSI-H/dMMR mCRC,” the study authors wrote in the poster. Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1).

NIVOLUMAB IN dMMR/MSI-H TUMORS

CheckMate -142 is an international Phase 2, multi-cohort, open-label, non-comparative trial of Opdivo, or Opdivo combinations, in recurrent or metastatic MSI-H and non-MSI-H colorectal cancer. The primary endpoint is investigator-assessed ORR using the Response Evaluation Criteria In Solid Tumors version 1.1. Other key endpoints include DOR, OS, PFS, DCR, ORR per blinded independent central review , patient reported outcomes and safety. Patients received Opdivo 3 mg/kg every two weeks plus Yervoy 1 mg/kg every six weeks until disease progression, death or unacceptable toxicity. Grade 3-4 treatment-related adverse events occurred in seven patients (16%), and any grade TRAEs leading to treatment discontinuation occurred in three patients (7%).