S5. Proffered paper: Maintenance therapy of metastatic colorectal carcinoma with the TLR-9 agonist MGN1703: clinical and immunological predictive pretreatment factors of activity in the IMPACT trial

3535 Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated increases in ERV mRNA as a result of DNA hypomethylation, and ERV transcription has been associated with increased immunogenicity in metastatic renal cell carcinoma. We performed comprehensive bioinformatics analysis of ERV transcription in metastatic colorectal carcinoma (mCRC), to identify novel links between ERV transcription, epigenetic dysregulation and immunogenicity in metastatic colorectal carcinoma (mCRC). Methods: Tumour samples from 63 patients with mCRC were subjected to RNA sequencing as part of the Personalized OncoGenomics program (POG; NCT02155621) at BC Cancer. Patients were enrolled between 07/2012-07/2017. ERV transcription was quantified across 702,533 distinct loci. Tumors were classified ERV-hi if their total ERV expression (RPKM) was greater than the mean across all samples. High antiviral gene expression tumors (AVG-hi) were designated as having a mean expression of IFIH1, DDX58, TLR3, TANK, TBKBP1, TBK1, IRF3 and IRF7 that was greater than the mean across all samples. All pairwise comparisons of gene expression were subjected to multiple hypothesis correction. Results: Median age was 59 years, with 34 (54%) male and 1 tumor microsatellite unstable. ERV-hi tumors showed increased expression of DNA demethylators TET2 ( q=0.0045) and TET3 ( q<0.0001). Significant overlap existed between ERV-hi and AVG-hi tumors (18/27, p=0.016). Tumors both ERV-hi and AVG-hi trended towards increased PD-L1 expression (p=0.055) and showed a significant increase in survival compared to tumors with high antiviral expression in the absence of high ERV transcription (p=0.0043). Conclusions: Our results suggest DNA demethylation drives increased ERV transcription and ERV-associated immunogenicity in mCRC. Moreover, we provide novel insight into the impact of ERV transcription on the biology of mCRC, highlighting ERV transcription as a potential biomarker and target for precision immunotherapy. Clinical trial information: NCT02155621.

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Phase II study of capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15125 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15125-e15125

Author(s):

R. Xu none ◽

Y. Li ◽

H. Luo ◽

F. Wang

Keyword(s):

Colorectal Carcinoma ◽

Maintenance Therapy ◽

Healthcare Providers ◽

Progression Free Survival ◽

Chinese Patients ◽

Line Treatment ◽

Metastatic Colorectal Carcinoma ◽

First Line ◽

Oral Capecitabine ◽

First Line Treatment

e15125 Background: The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients responding to XELOX is able to maintain the response and improve the duration of disease control (DDC). Methods: Patients with mCRC were treated with a 3-weekly regimen of oxaliplatin at a dose of 130 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15. Patients who did not progress after finished the XELOX therapy were choice to stop or receive oral capecitabine until disease progression or unacceptable toxicity. Results: 124 patients received a total of 637 cycles (median, 6) of treatment. Responses rate was 49.1%. Median overall and median progression-free survival was 20.0 months and 8.0 months, respectively. Main grade 3–4 drug-related toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), and hand-foot syndrome (2.4%). 23 of 101 patients responding to XELOX received oral capecitabine as maintenance therapy.The median DDC was 8 months for patients in the group of not using maintenance therapy, versus 12 months in the group of using capecitabine as maintenance therapy. Conclusions: XELOX is a highly effective first-line treatment for mCRC and provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Furthermore, these results support the feasibility of maintaining good response and improving DDC with oral Capecitabine after combination chemotherapy in mCRC. No significant financial relationships to disclose.

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IMPACT trial: Predictive factors for maintenance therapy with MGN1703 in patients with metastatic colorectal carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.3615 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 3615-3615

Author(s):

Jorge Riera-Knorrenschild ◽

Werner Scheithauer ◽

Hendrik Kröning ◽

Frank Mayer ◽

Dieter Nitsche ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Maintenance Therapy ◽

Predictive Factors ◽

Metastatic Colorectal Carcinoma

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Immunomodulatory Maintenance Therapy with Tlr-9 Agonist Mgn1703 in Patients with Metastatic Colorectal Carcinoma–The Randomized Phase 3 Impala Study

Annals of Oncology ◽

10.1093/annonc/mdu342.30 ◽

2014 ◽

Vol 25 ◽

pp. iv371 ◽

Cited By ~ 1

Author(s):

D. Arnold ◽

A. Zurlo ◽

R. Salazar ◽

M.P. Ducreux ◽

T. Waddell ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Maintenance Therapy ◽

Metastatic Colorectal Carcinoma ◽

Phase 3

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The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.10.1419 ◽

1989 ◽

Vol 7 (10) ◽

pp. 1419-1426 ◽

Cited By ~ 394

Author(s):

N Petrelli ◽

H O Douglass ◽

L Herrera ◽

D Russell ◽

D M Stablein ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Low Dose ◽

Phase Iii ◽

High Dose ◽

Metastatic Colorectal Carcinoma ◽

Phase Iii Trial ◽

Severe Diarrhea ◽

Gastrointestinal Tumor Study Group ◽

The Impact ◽

Dose Limiting Toxicity

A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

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