A large retrospective multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancer with microsatellite instability

Tougeron, David; Cohen, Romain; Sueur, Benjamin; Sefrioui, David; Gentilhomme, Lucie; Lecomte, Thierry; Aparicio, Thomas; Guetz, G. Des; Artru, Pascal; Fouchardiere, C. de la; Moulin, Valérie; Hautefeuille, Vincent; Touchefeu, Yann; Lecaille, Cédric; Goujon, Gaël; Ferru, Aurélie; Taı̈eb, Julien; Thewis, André; Zaanan, Aziz

doi:10.1093/annonc/mdx393.059

Cited by 12 publications

(9 citation statements)

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“…However, the poor prognosis of BRAF V600E ‐mutation was exclusively observed in patients with pMMR tumors, in contrast to previous publications that did not show any significant survival difference between patients with dMMR and those with pMMR mCRC. Similarly, Tougeron et al reported no prognostic impact of BRAF mutation, as well as Lynch syndrome status, in a multivariate analysis of prognostic factors from a large cohort of 284 patients with dMMR mCRC . Our exploratory analysis in the population of patients with a specified MMR status reported that dMMR was significantly associated with better OS, independently of immune checkpoint inhibitor treatment.…”

Section: Discussionsupporting

confidence: 53%

“…It must nevertheless be interpreted with caution because less than 20% of the patients had received anti‐EGFR therapies in the first‐line setting. Contrary to what was previously published, patients with dMMR tumors did not derive any statistically significant survival benefit from the addition of bevacizumab . Furthermore, we included patients in the present cohort before the publication of the TRIBE study, which explains the low percentage of patients treated with tri‐CT (<10%) .…”

Section: Discussionmentioning

confidence: 74%

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Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients

et al. 2019

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Background. BRAF V600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. Materials and Methods. We built a multicenter clinicobiological database gathering data from patients with BRAF V600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. Results. We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). Conclusion. Despite that BRAF V600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAF V600E mCRC in day-to-day practice. The Oncologist 2019;24:e1331-e1340 Implications for Practice: Mismatch repair (MMR) testing and resectability discussion in patients with BRAF V600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAF V600E -mutant mCRC.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 74%

Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients

et al. 2019

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“…Patients with MSI‐H/dMMR mCRC have poorer outcomes with chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC . Nivolumab plus low‐dose ipilimumab demonstrated durable responses, high DCR, and high survival rates in previously treated patients with MSI‐H/dMMR mCRC .…”

Section: Resultsmentioning

confidence: 97%

“…Outlook remains poor for patients with metastatic CRC (mCRC), with a 5‐year survival rate of 14% . Patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) mCRC benefit less from conventional chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC ; conversely, MSI‐H/dMMR is a predictive marker of response to treatment with anti‐programmed death (PD)‐1 checkpoint inhibitor therapy .…”

Section: Introductionmentioning

confidence: 99%

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer

et al. 2019

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Background Early detection and management of treatment‐related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low‐dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12‐month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC). In‐depth safety and additional efficacy outcomes from CheckMate 142 are presented. Materials and Methods Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune‐mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune‐modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs. Results Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2–12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5–9.0 weeks). IMMs were used to manage sTRAEs in 22%–56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12‐month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%). Conclusion The benefit‐risk profile of nivolumab plus low‐dose ipilimumab provides a promising treatment option for patients with previously treated MSI‐H/dMMR mCRC. Implications for Practice Nivolumab (NIVO) plus low‐dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment‐related adverse events (sTRAEs) occurred early, were managed using evidence‐based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune‐modulating medications. The benefit‐risk profile of NIVO + low‐dose IPI provides a promising treatment option for MSI‐H/dMMR mCRC.

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“…It is clinically defined by its tissue of origin in the colon or rectum but is mainly a heterogeneous disease classified by its genetics [2][3][4]. Patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic CRC are closely associated with a mutation in the BRAF gene and benefit to a lesser degree from conventional chemotherapy [5][6]. Despite well-known genetic differences in the disease, patients with newly diagnosed metastatic CRC are generally treated with fluorouracil-based chemotherapy combined with agents targeting angiogenesis or the epidermal growth factor receptor [7].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Immune Checkpoint Inhibitors in Patients with Mismatch Repair-Deficient or Microsatellite Instability-High Metastatic Colorectal Cancer: Analysis of Three Phase-II Trials

Cancanelli¹,

Rivano²,

Spazio³

et al. 2021

Cureus

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Programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitors are increasingly used in a variety of solid tumors. In patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer, their efficacy has been demonstrated in recently published phase-II trials. However, an indirect comparison of effectiveness between pembrolizumab, nivolumab, and nivolumab+ipilimumab is not yet available.After a standard literature search, we analyzed four overall survival (OS) curves from three phase-II trials. Individual patient data were reconstructed from each curve using a specific web-based technique (Shiny method). Indirect statistical comparisons were made based on hazard ratio (HR) and restricted mean survival time (RMST).Nivolumab+ipilumumab had a better HR compared with pembrolizumab (0.65, 95% confidence interval [CI], 0.43 to 1.002, p=0.051); the difference being close to statistical significance. In the analysis based on RMST, the combination of nivolumab+ipilimumab showed a significantly longer OS than pembrolizumab (improvement in RMST, 1.08 mos; 95%CI, 0.11 to 2.06; p=0.029). The other two pairwise differences in RMST (nivolumab vs. pembrolizumab and nivolumab+ ipilimumab vs. nivolumab) had a smaller magnitude (0.25 mos, 95%CI, -0.99 to 1.48, and 0.84 mos, 95%CI, -0.40 to 2.07, respectively) and were far from statistical significance.Our results favoring the combination of nivolumab+ipilimumab in metastatic colorectal cancer must be viewed with caution owing to the indirect nature of our statistical comparisons. With this limitation in mind, the magnitude of the incremental benefit for the above combination treatment was estimated to be around one month over a follow-up of 15 months.

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A large retrospective multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancer with microsatellite instability

Cited by 12 publications

References 0 publications

Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients

Characteristics of BRAF V600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer

Efficacy of Immune Checkpoint Inhibitors in Patients with Mismatch Repair-Deficient or Microsatellite Instability-High Metastatic Colorectal Cancer: Analysis of Three Phase-II Trials

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