A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or &lt;i&gt;POLE&lt;/i&gt;-Mutated Metastatic or Unresectable Colorectal Cancer

Kim, Jwa Hoon; Kim, Sun Young; Baek, Ji Yeon; Jun, Yong Chul; Ahn, Joong Bae; Kim, Han Sang; Lee, Moon Hyoung; Kim, Ji Won; Kim, Tae You; Chang, Won Jin; Park, Joon Oh; Kim, Jihun; Kim, Jeong Eun; Hong, Yong Sang; Kim, Yeul Hong; Kim, Tae Won

doi:10.4143/crt.2020.218

Cited by 54 publications

(46 citation statements)

References 31 publications

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“…While pMMR/MSS CRCs are mainly resistant to ICIs (i.e., cold tumors), MSI/dMMR tumors were associated with high sensitivity to immunotherapy (i.e., hot tumors). The activity of ICIs for patients with chemoresistant MSI/dMMR mCRC was demonstrated in several phase II trials, with objective response rates ranging from 33% to 58% and 12-month PFS rates between 31% and 71% [ 50 , 89 , 90 , 91 , 92 , 93 , 94 ]. Importantly, results of the non-randomized CheckMate-142 trial suggest that combinations of anti-PD1 and anti-CTLA4 mAbs might be more effective than anti-PD1 or anti-PDL1 agents alone.…”

Section: Microsatellite Instability and Immune Checkpoint Inhibitomentioning

confidence: 99%

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Cohen

Pudlarz

Delattre

et al. 2020

Cancers

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Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

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Section: Microsatellite Instability and Immune Checkpoint Inhibitomentioning

confidence: 99%

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Cohen

Pudlarz

Delattre

et al. 2020

Cancers

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“…Reports from human dMMR CRC describe contradictory PD-L1 abundance on tumor-in ltrating lymphocytes or tumor cells [47,48]. Its role to mediate immune escape is undebatable and results from a phase II study already con rmed antitumor activity of Avelumab with manageable toxicity in most, but clearly not all patients with previously treated dMMR mCRC and recurrent/persistent endometrial cancer [25,49]. Heterogeneity among tumors, such as the varying TMB, different genomic variations (in cMS), and the activated Wnt/β-catenin signaling may provide an explanation for the heterogeneity in response.…”

Section: Discussionmentioning

confidence: 99%

“…PD-L1 expression on tumor-in ltrating lymphocytes is a potential predictor for patients' response to α-PD-1 therapy [24]. A recent phase II study in patients with dMMR metastatic or unresectable CRC revealed antitumor activity of Avelumab monotherapy [25]. Additional clinical trials are ongoing with different combinations being employed.…”

Section: Introductionmentioning

confidence: 99%

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

Salewski

Kuntoff

Kuemmel

et al. 2020

Preprint

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Background: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, characterized by the upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune checkpoint inhibitor therapy using α-PD-L1 monoclonal antibody clone 6E11.Design: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays.Results: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n=3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt and TGF-signaling, leading to T cell infiltration and reduced numbers of macrophages, neutrophils, and MDSC.Conclusions: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.

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“…Moreover, alterations in DNA repair genes such as the MMR genes, POLE and HR genes have been shown to have a positive predictive effect and are correlated to increased TMB values (83)(84)(85)(86). In contrast, other gene alterations such as JAK1/2 and STK11/LKB1, KEAP1 and PTEN mutations are related to resistance to PD-1 Blockade (80,(87)(88)(89).…”

Section: Immunotherapy Biomarkersmentioning

confidence: 99%

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

Özdoğan¹,

Papadopoulou²,

Tsoulos³

et al. 2020

Preprint

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Background: Tumor molecular profile is of great importance for the detection of biomarkers of response to targeted treatment due to the increased availability, with concomitant reduction of cost, of Next Generation Sequencing technology (NGS). In parallel to targeted therapies’, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite Instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly.Methods: In the present study, a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection, was used for tumor molecular profile analysis. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied.Results: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. At least one actionable alteration was detected in 77.70% of the patients. 54.59% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers’ analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.40%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. Conclusions: Tumor molecular profile analysis by NGS is a first-tier methodology for a variety of tumor types, which provides critical information for treatment decision making in cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to a better tumor characterization and provide actionable information in the majority of patients. Moreover, our results indicate that one in two patients is eligible for ICI treatment based on the biomarkers’ analysis. However, when these analyses are performed, the challenge is their implementation in clinical practice. Multidisciplinary patient management is critical to the refinement of the strategy incorporating such information.

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A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or <i>POLE</i>-Mutated Metastatic or Unresectable Colorectal Cancer

Cited by 54 publications

References 31 publications

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors

A Comprehensive Tumor Molecular Profile Analysis in Clinical Practice: A Single Center’s Experience

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