Maintenance treatment in metastatic colorectal cancer: in search of the best strategy

Ron, David Arias; Vera, Ruth; Labandeira, Carmen M.; Manrique, Maria Carmen Areses; Núñez, Margarita Ostrowski de; Cid, N. García; Mata, Jesús García; Montes, Ana

doi:10.1007/s12094-019-02267-9

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…Monoclonal antibodies that target the epidermal growth factor receptor (EGFR) are an approved targeted therapy for chemotherapy refractory CRC patients that do not harbor mutations in KRAS [ 62 , 63 ]. We treated the chemotherapy-naive PDX15, which was KRAS wild-type, with cetuximab as a monotherapy, and observed a reduction in tumor burden ( Figure 6 C), consistent with the predicted patient outcome based on clinical criteria for cetuximab treatment.…”

Section: Resultsmentioning

confidence: 99%

A Biobank of Colorectal Cancer Patient-Derived Xenografts

Abdirahman

Christie

Preaudet

et al. 2020

Cancers

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Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation of a biobank of CRC PDXs from stage I to stage IV patients. We demonstrate that PDXs within our biobank recapitulate the histopathological and mutation features of the original patient tumor. In addition, we demonstrate the utility of this resource in pre-clinical chemotherapy and targeted treatment studies, highlighting the translational potential of PDX models in the identification of new therapies that will improve the overall survival of CRC patients.

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Section: Resultsmentioning

confidence: 99%

A Biobank of Colorectal Cancer Patient-Derived Xenografts

Abdirahman

Christie

Preaudet

et al. 2020

Cancers

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“…In the present study, we aimed to assess the clinical implementation and utility of anti-EGFR retreatment strategies in real-world CRC patients. For patients with disease progression in second-, third-, or fourth-line treatment, therapy options are limited; hence, re-exposure to previously utilized agents is a common strategy in oncological practice [ 22 ]. For example, oxaliplatin is frequently reintroduced after prior stop-and-go strategies or discontinuation due to limited peripheral sensory neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis

Schulz

Wolf

Struck

et al. 2022

Cancers

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Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. Methods: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). Results: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). Conclusions: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation.

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“…For patients with metastatic colorectal cancer (mCRC) that is not amenable to curative-intent treatment and whose disease is controlled after induction chemotherapy, the optimal duration of the upfront combination of cytotoxic drugs with a targeted agent remains controversial. Phase 3 randomized trials have shown that de-escalation significantly reduces toxic effects and improves patients’ quality of life, whereas there is no benefit in terms of progression-free survival (PFS) or overall survival (OS) to continuing the full induction regimen until disease progression . However, there is still debate about the best option among de-escalation modalities, including fluoropyrimidine-based maintenance, chemotherapy-free intervals with a targeted agent alone, or planned off-therapy breaks.…”

Section: Introductionmentioning

confidence: 99%

“…Phase 3 randomized trials have shown that de-escalation significantly reduces toxic effects and improves patients’ quality of life, whereas there is no benefit in terms of progression-free survival (PFS) or overall survival (OS) to continuing the full induction regimen until disease progression. 1 , 2 However, there is still debate about the best option among de-escalation modalities, including fluoropyrimidine-based maintenance, chemotherapy-free intervals with a targeted agent alone, or planned off-therapy breaks.…”

Section: Introductionmentioning

confidence: 99%

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer

Boige,

Blons,

François

et al. 2023

JAMA Netw Open

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ImportanceThe optimal maintenance strategy after induction chemotherapy with anti–epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.ObjectiveTo evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.Design, Setting, and ParticipantsThe TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]–UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.InterventionsAfter first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.Main Outcomes and MeasuresThe primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.ResultsOf 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).Conclusion and RelevanceThe randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.Trial RegistrationClinicalTrials.gov Identifier: NCT02404935

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Maintenance treatment in metastatic colorectal cancer: in search of the best strategy

Cited by 7 publications

References 44 publications

A Biobank of Colorectal Cancer Patient-Derived Xenografts

A Biobank of Colorectal Cancer Patient-Derived Xenografts

Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer

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