Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials

Pietrantonio, Filippo; Randon, Giovanni; Bartolomeo, Maria Di; Luciani, Andrea; Chao, Joseph; Smyth, Elisabeth; Petrelli, Fausto

doi:10.1016/j.esmoop.2020.100036

Cited by 96 publications

(65 citation statements)

References 17 publications

(17 reference statements)

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“…Finally, in the KEYNOTE-062 trial, in the MSI-H subgroup median OS was not reached versus 8.5 months, median PFS was 11.2 versus 6.6 months, and ORR was 57.1% versus 36.8% with pembrolizumab versus standard chemotherapy, respectively [ 25 ]. These data, together with the global burden of evidence collected so far, highlight how immunotherapy-based combinations could represent a novel standard of care for patients with MSI-H metastatic GC [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, in the setting of resectable GC/GEJC, the powerful positive prognostic effect for improved disease-free survival (DFS) and OS and the potential negative predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy in MSI-H patients was shown [ 12 ]. Moreover, the importance of dMMR/MSI-H status emerged when it proved to represent one of the most powerful predictors of benefit from immunotherapy with anti-programmed death receptor 1 and its ligand (PD1/PD-L1) immune-checkpoint inhibitors (ICIs) so that pembrolizumab received the agnostic approval for adult and pediatric patients with advanced tumors bearing this alteration [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

Raimondi

Palermo

Prisciandaro

et al. 2021

Cancers

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In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

Raimondi

Palermo

Prisciandaro

et al. 2021

Cancers

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“…Regarding post-hoc analyses of the predictive role of MSI-high status in RCTs, the KEYNOTE-061, the KEYNOTE-062, the CHECKMATE-649 and the JAVELIN Gastric 100 [91] are in the limelight of a recent meta-analysis carried out by Pietrantonio and colleagues [92]. The authors merged together data deriving from the above-mentioned phase III trials, enrolling a total of 2545 patients.…”

Section: Immunotherapy In Msi Gcmentioning

confidence: 99%

Microsatellite instability in Gastric Cancer: Between lights and shadows

Puliga

Corso

Pietrantonio

et al. 2021

Cancer Treatment Reviews

103

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Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA and ACRG classifications, the microsatellite instable (MSI) group represents a significant subset of GCs and is currently in the limelight of many researches due to its favorable survival outcome in resectable stages compared to microsatellite stable tumors. MSI GCs hypermutated phenotype triggers immunosurveillance, making this molecular subgroup a promising candidate for immune checkpoint inhibitors treatment. Conversely, conflicting outcomes have been reported in chemotherapy settings. Due to the clinical relevance of these observations, in this review we report and discuss the molecular, pathological, prognostic, and predictive features of MSI gastric tumors.

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“…Currently, PD-L1 expression, tumor mutation burden (TMB), and microsatellite instability-high (MSI-H) are the primary biomarkers for guiding the clinical practice of immune therapy and predicting survival benefit in several types of cancer ( 4 , 5 ). However, neither PD-L1 expression nor TMB is a perfect biomarker for immune therapy prediction in melanoma, as responses are also observed in PD-L1-negative and low TMB patients.…”

Section: Introductionmentioning

confidence: 99%

Tumor Immune Microenvironment Characterization Identifies Prognosis and Immunotherapy-Related Gene Signatures in Melanoma

Liú

Yang

2021

Front. Immunol.

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BackgroundThe tumor microenvironment (TME) involves infiltration of multiple immune cell subsets, which could influence the prognosis and clinical characteristics. The increasing evidence on the role of tumor-infiltrating lymphocytes (TILs) in primary and metastatic melanomas supports that the immune system is involved in the progression and outcomes of melanoma. However, the immune infiltration landscape in melanoma has not been systematically elucidated.MethodsIn this study, we used CIBERSORT and ESTIMATE algorithms to analyze immune infiltration pattern of 993 melanoma samples. Then we screened differential expression genes (DEGs) related to immune subtypes and survival. The immune cell infiltration (ICI) score was constructed by using principal-component analysis (PCA) based on immune signature genes from DGEs. Gene set enrichment analysis (GSEA) was applied to explore high and low ICI score related pathways. Finally, the predictive ability of ICI score was evaluated in survival prognosis and immunotherapy benefit.ResultWe identified three ICI clusters and three gene clusters associated with different immune subtypes and survival outcomes. Then the ICI score was constructed, and we found that high ICI score exhibited activated immune characteristics and better prognosis. High ICI score was significantly enriched in immune pathways and highly expressed immune signature genes. More importantly, we confirmed that melanoma patients with high ICI score had longer overall survival and rate of response to immunotherapy.ConclusionWe presented a comprehensive immune infiltration landscape in melanoma. Our results will facilitate understanding of the melanoma tumor microenvironment and provide a new immune therapy strategy.

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Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials

Cited by 96 publications

References 17 publications

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study

Microsatellite instability in Gastric Cancer: Between lights and shadows

Tumor Immune Microenvironment Characterization Identifies Prognosis and Immunotherapy-Related Gene Signatures in Melanoma

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