Durvalumab + monalizumab, mFOLFOX6, and bevacizumab in patients (pts) with metastatic microsatellite-stable colorectal cancer (MSS-CRC)

Cho, M.; Bendell, J.C.; Han, Sang-Man; Naidoo, Jarushka; Lieu, Christopher H.; Carneiro, Benedito A.; Varga, Edit; Li, X.; Kourtesis, Panagiotis; Abdullah, Shaad E.; Patel, Shivani

doi:10.1093/annonc/mdz253.027

Cited by 8 publications

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“…Recent trials have found that the combination of NKG2A and PD-L1 checkpoint blockade could enhance patients’ survival for microsatellite stabilized (MSS) colorectal cancer (NCT02671435) and non-small cell lung cancer (NCT03822351). 18 19 However, the clinical value of the combination of NKG2A and PD-L1 expression remains scarcely explicit in MIBC.…”

Section: Introductionmentioning

confidence: 99%

NKG2A and PD-L1 expression panel predicts clinical benefits from adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

Yan

Zeng

Jin

et al. 2022

J Immunother Cancer

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BackgroundProgrammed cell death ligand-1 (PD-L1) expression as a single biomarker for immune checkpoint blockade (ICB) was controversial. NKG2A was a PD1/PD-L1 axis-related immunity-dependent factor. NKG2A and PD-L1 expression as a combinatorial biomarker might improve the prediction of PD-L1 in patients with muscle-invasive bladder cancer (MIBC).MethodsThree independent cohorts were enrolled in our study. 195 patients with bladder-derived metastatic urothelial carcinoma on PD-L1 inhibitor treatment from the IMvigor210 trial were enrolled. 124 MIBC patients from Zhongshan Hospital and 391 patients with MIBC from The Cancer Genome Atlas database were included in this study.The PD-L1/NKG2A-based risk stratification was validated in three independent cohorts, and its association with response to ICB and adjuvant chemotherapy (ACT), immune contexture and molecular features was evaluated. Histologic staining and genomic algorithm were performed to detect characteristics of NKG2A and PD-L1 expression and infiltration of immune cells.ResultsWe identified NKG2AhiPD-L1hi patients could benefit more from cisplatin-based ACT and PD-L1 inhibitor. Further analyses revealed NKG2A and PD-L1 expression panel was linked to an immune-active tumor microenvironment with highly immune effector cells and effector molecules. In addition, NKG2A and PD-L1 expression panel was intrinsically correlated with genomic alterations related to therapeutic response in MIBC.ConclusionsNKG2A and PD-L1 expression panel was associated with an immune inflamed microenvironment and acted as a combinatorial biomarker to predict the therapeutic response to ACT and PD-L1 blockade in MIBC.

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Section: Introductionmentioning

confidence: 99%

NKG2A and PD-L1 expression panel predicts clinical benefits from adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

Yan

Zeng

Jin

et al. 2022

J Immunother Cancer

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“…To date, the dMMR/MSI status remains the only clear marker for benefit from PD-1 blockade therapy in patients with intestinal cancer. However, according to a new report, first-line durvalumab combined with monalizumab showed a manageable safety profile and preliminary activity in patients with advanced/metastatic MSS CRC in a phase I/II trial (NCT02671435) [ 7 ]. The above data strongly indicate that novel immunotherapy biomarkers for MSS COAD will be identified.…”

Section: Discussionmentioning

confidence: 99%

“…However, the vast majority of CRC patients (85%) have microsatellite instability-low (MSI-L) or microsatellite-stable (MSS) tumors, and these populations are historically not responsive to ICIs. However, preliminary data on the combination of monalizumab and durvalumab in a cohort of patients with MSS CRC are encouraging (NCT02671435) [ 7 ]. Therefore, potential predictive therapeutic biomarkers are urgently needed to increase the benefit of ICIs for patients with MSS CRC.…”

Section: Introductionmentioning

confidence: 99%

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

Zhou

Chen

et al. 2020

Aging

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Background: Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD. Methods: The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clinical outcomes in two COAD genomic datasets were analyzed via bioinformatics. Results: In the Chinese cohort, seventy (17%) patients exhibited genomic alterations in HRR genes; ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%) were the most frequently mutated. In the MSK-IMPACT COAD cohort (immune checkpoint inhibitor-treated), HRR-mut patients (n=34) survived longer than HRR-wt patients (n=50) (log-rank P < 0.01). Based on the TCGA MSS COAD cohort, HRR gene mutations increased immune activities, such as infiltration of cytotoxic cells ( P < 0.05) and exhausted CD8+ T cells ( P < 0.01), and increased the IFN-γ scores ( P < 0.05). The results differed in MSI-H COAD patients (all P > 0.05). Conclusion: HRR gene mutations significantly increased immune activities in MSS COAD patients, implying the feasibility of the HRR-mut status as an immunotherapy response predictor in MSS COAD.

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“…In a study of mFOLFOX6, bevacizumab, durvalumab and the NKG2 NK cell checkpoint inhibitor monalizumab 17 patients were evaluable for response at 16 weeks resulting in a 53% partial responses 35% stable disease 12% progressive disease; there were no complete responses. Median time to response for the 7 confirmed responders was 15.4 weeks; median duration of response was not yet reached (72).…”

Section: Colorectal Adenocarcinomamentioning

confidence: 96%

Finding the hot spot: identifying immune sensitive gastrointestinal tumors

Souza¹

2020

Transl Gastroenterol Hepatol

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Although researchers have been trying to harness the immune system for over 100 years, the advent of immune checkpoint blockers (ICB) marks an era of significant clinical outcomes in various metastatic solid tumors, characterized by complete and durable responses. ICBs are monoclonal antibodies that target either of a pair of transmembrane molecules in tumors or T-cells involved in immune evasion.Currently 2 ICBs targeting the checkpoint program death 1 (PD-1), nivolumab and pembrolizumab, and one cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitor (ipilimumab) are approved in gastrointestinal malignancies. We review herein the current evidence on predictive biomarkers for ICB response in gastrointestinal tumors. A review of literature based on the National Cancer Institute list of FDA-approved drugs for neoplasms and FDA-approved therapies at the FDA website was performed. An initial literature review was based on the American Association for Clinical Research meeting 2019, the American Society of Clinical Oncology meeting 2019 and the European Society of Medical Oncology 2019 proceedings.A systematic search of PubMed was performed involving MeSH browser terms such as biomarkers, immunotherapy, gastrointestinal diseases and neoplasms. When appropriate, American and British terms were used in the search. The most relevant predictor of response to ICBs is microsatellite instability (MSI) and the data is strongest for colorectal cancer. At least 3 prospective trials show evidence of PD-L1 as a predictive biomarker for ICB response in gastroesophageal malignancies. At least one prospective trial has described tumor mutational burden high (TMB-H), independent of MSI, as predictive of response in anal and biliary tract carcinomas. DNA Polymerase Epsilon (POLE) or delta (POL-D) mutations have been implicated in a subset of MSS colorectal cancer with TMB-H but this biomarker requires prospective validation. There is evolving data based on retrospective observations that gene alterations predicting acquired resistance and hyper-progression. Ongoing clinical research is assessing the role of the human microbiome and RNA-editing complex mutations as predictive biomarkers of response to ICBs. MSI has the strongest predictive power among current biomarkers for ICB response in gastrointestinal cancers. Data continue to accumulate from ongoing clinical trials and new biomarkers are emerging from pre-clinical studies, suggesting that drug combinations targeting pathways complimentary to the PD-1/PD-L1 axis inhibition will define a robust field of clinical research.

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Durvalumab + monalizumab, mFOLFOX6, and bevacizumab in patients (pts) with metastatic microsatellite-stable colorectal cancer (MSS-CRC)

Cited by 8 publications

References 0 publications

NKG2A and PD-L1 expression panel predicts clinical benefits from adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

NKG2A and PD-L1 expression panel predicts clinical benefits from adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

Finding the hot spot: identifying immune sensitive gastrointestinal tumors

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