A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial

Hagman, Helga; Frödin, Jan-Erik; Berglund, Åke; Sundberg, Jan; Vestermark, Lene Weber; Albertsson, Maria; Fernebro, Eva; Johnsson, Anders

doi:10.1093/annonc/mdv490

Cited by 54 publications

(35 citation statements)

References 12 publications

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“…64 The primary end point of time to progression was not met (4.1 months for bevacizumab continuation vs 2.9 months for no continuation; HR, 0. 66 A meta-analysis identified 3 randomized trials (682 patients) and concluded that maintenance therapy with bevacizumab/erlotinib significantly increases OS and PFS, with manageable toxicity. 67 Another phase III trial investigated the role of capecitabine in the maintenance phase, after initial treatment with FOLFOX or CapeOx.…”

Section: Maintenance Therapymentioning

confidence: 99%

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Cederquist³

et al. 2017

J Natl Compr Canc Netw

749

515

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OverviewColorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 people will die of colon and rectal cancer combined. AbstractThis portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, KRAS/NRAS mutational status, and patient comorbidities and preferences. Location of the primary tumor, the BRAF mutation status, and tumor microsatellite stability should also be considered in treatment decisions. J Natl Compr Canc Netw 2017;15(3): 370-398 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

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Section: Maintenance Therapymentioning

confidence: 99%

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Benson¹,

Venook²,

Cederquist³

et al. 2017

J Natl Compr Canc Netw

749

515

View full text Add to dashboard Cite

show abstract

“…Interesting results were shown by Nordic ACT2 trial, in which patients with mutated KRAS were randomized to receive maintenance bevacizumab or metronomic capecitabine. The OS was longer in capecitabine, than in bevazizumab arm (28.0 and 26.4 months respectively) (Hagman et al, 2016). These results should be interpreted with caution due to small sample size, but still non-inferiority of metronomic regimen seems to be very promising for future studies.…”

Section: Discussionmentioning

confidence: 73%

Maintenance Metronomic Chemotherapy in Treatment of Metastatic Colorectal Cancer

Streltsova¹,

Prokharau²,

Portyanko³

et al. 2019

CCO

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Treatment of metastatic colorectal cancer (mCRC) is one of the most challenging and important problems in oncology at present moment. This article presents the interim results of treatment of patients with colorectal cancer, who were enrolled from 2016 till 2019 (n=60) with the use of maintenance metronomic chemotherapy. Metronomic regimen consisted of oral capecitabine 500 mg 3 times a day and oral cyclophosphane 50 mg daily. The control arm consisted of mCRC patients who received the same induction chemotherapy without maintenance from 2011 till 2015 (n=70). Median follow-up time was 18.5 months. Median progression-free survival (PFS) was 9.0 and 7.4 months in the maintenance and control arms respectively. Median overall survival (OS), counted from the beginning of induction chemotherapy, is currently 22.9 months in the maintenance arm, and 14.7 months in control. High expression levels of genes, encoding enzymes TS (thymidylate synthetase), DPD (dihydropyrimidine dehydrogenase) and receptor VEGFR1, low expression level of gene TP (thymidylate phosphorylase), as well as low levels of tumor markers CEA and СА 19-9 are the prognostic factors of sensitivity to metronomic chemotherapy given to colorectal cancer patients. Based on these data, we identified a group of patients who are recommended to use this method of treatment.

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“…Nevertheless, until such biomarkers are identified, dual targeting of EGFR and angiogenesis in maintenance therapy without chemotherapy remains disappointing. Combination therapy with bevacizumab and cetuximab during induction chemotherapy did not show any synergistic activity (36), and subsequently the Nordic ACT2 trial found that bevacizumab plus erlotinib was no better than bevacizumab alone for maintenance therapy (37). Despite studies suggesting that there may be a role for first-generation EGFR TKI in metastatic colorectal cancer, we have yet to find a way to safely dose and schedule these agents with other therapies and to identify predictive biomarkers that could select patients who are most likely to benefit.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study Alternating Erlotinib With Second-line mFOLFOX6 or FOLFIRI for Metastatic Colorectal Cancer

et al. 2018

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Background: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer. Patients and Methods: A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate. Results: The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%. Conclusion: In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity. Colorectal cancer is the third most common type of adult cancer in the world, with an estimated 1.8 million cases and 881,000 deaths annually by the GLOBOCAN estimate in 2018 (1). While more than 20% of these patients are diagnosed with metastatic disease, advancement in systemic treatment options have improved their expected median survival from 11-12 months with fluoropyrimidine alone to approximately 2.5 years with modern combination therapies (2, 3). Combination chemotherapy of either oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) or irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) has similar response rates and survival outcomes in the first-line metastatic setting (3-5). Moreover, these chemotherapy platforms have further incorporated biological agents, such as bevacizumab or monoclonal antibodies to epidermal growth factor receptor (EGFR), thereby improving response rates to approximating 60% in the first-line metastatic setting, as well as prolonging survival endpoints (3, 5, 6). However, second-line chemotherapy platforms using the alternate chemotherapy regimen with a biological agent, typically demonstrates less clinical activity and lower response rates of 6-35% (7-9). Given the expanding repertoire of biological agents, tyrosine kinase inhibitors (TKIs), and most recently immune checkpoint inhibitors for the treatment of metastatic colorectal cancer, there is a continued need to optimize second-line treatment options by integrating chemotherapy with more targeted approaches. This is particularly true as our knowledge based on colorectal cancer subtypes increases (10). Indeed, tumor location and molecular biomarkers, such as extended RAS mutations [testing beyond KRAS proto-oncogene, GTPase (KRAS) exon 2 to also include both KRAS and NRAS proto-oncogene, GTPase (NRAS) from exons 2 through 4], B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, and mismatch repair deficiency, ...

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A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial

Cited by 54 publications

References 12 publications

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Maintenance Metronomic Chemotherapy in Treatment of Metastatic Colorectal Cancer

A Phase II Study Alternating Erlotinib With Second-line mFOLFOX6 or FOLFIRI for Metastatic Colorectal Cancer

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