Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer

Mazzoli, Giacomo; Cohen, Romain; Corti, Francesca; Élez, Elena; Fakih, Marwan; Jayachandran, Priya; Colle, Raphaël; Shah, Aakash Tushar; Salati, Massimiliano; Fenocchio, Elisabetta; Salvatore, Lisa; Ambrosini, Margherita; Ros, Javier; Intini, Rossana; Cremolini, Chiara; Overman, Michael J.; Thewis, André; Pietrantonio, Filippo

doi:10.1016/j.ejca.2022.05.044

Cited by 20 publications

(13 citation statements)

References 26 publications

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“…The advantage of anti-PD1/PD-L1 plus other therapy versus conventional chemotherapy with or without targeted therapy of improving OS was also observed, though the p value was not significant, which might partly result from the small sample size and the cross of therapy (HR 0.78, 95% CI 0.25–2.41, p = 0.664). Consistent with the discovery of prior studies [ 38 ], we also found that a worse ECOG performance seemed to negatively impact PFS and OS. Patients with acquired resistance to prior anti-PD1/PD-L1 monotherapy were related to better PFS and OS, while the best response to prior anti-PD1/PD-L1 seemingly had no impact on PFS or OS.…”

Section: Discussionsupporting

confidence: 91%

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Chen

Wang

Liu

et al. 2022

Cancers

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Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

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Section: Discussionsupporting

confidence: 91%

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Chen

Wang

Liu

et al. 2022

Cancers

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“…This trial also provides prospective data on PFS with chemotherapy alone or in combination with antiangiogenic or anti–epidermal growth factor receptor drugs in patients with dMMR/MSI mCRC as second-line treatment. The median PFS of 6.2 months and the objective response rate of 26.2% observed with chemotherapy are consistent with or even better than previously published data suggesting the efficacy of chemotherapy with or without targeted agents in the second-line setting for these particular patients with mCRC.…”

Section: Discussionsupporting

confidence: 89%

“…This underlines the importance of identifying patients with dMMR/MSI status and upfront resistance to immunotherapy to select them for different treatment approaches such as immunotherapy combined with standard chemotherapeutic regimens or combinations of PD-1 or PD-L1 and CTLA-4 inhibitors or other immune-active compounds, currently explored in ongoing phase 3 studies . Many markers of progressive disease during the first 2 months of PD-1 blockade therapy have been explored to date, but no clear marker of resistance has been identified . The 1-year PFS rate is only 31%, suggesting that secondary resistance is also observed in a substantial number of patients.…”

Section: Discussionmentioning

confidence: 99%

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability

Taïeb,

Bouche,

André

et al. 2023

JAMA Oncol

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ImportanceOnly 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting.ObjectivesTo determine whether avelumab (an anti–programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC.Design, Setting, and ParticipantsThe SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis.InterventionsPatients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal.Main Outcome and MeasuresThe primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population).ResultsA total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E–mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months.ConclusionsThe SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT03186326

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“…Consequently, it is of importance to generate data about the efficacy and tolerability of ICI for elderly/frail patients with dMMR/MSI-H mCRC. 48,49 Strengths of this study are the largest sample size of dMMR/MSI-H mCRC patients in the pre-immunotherapy era up until now and the high-quality data, including knowledge of BRAF V600E and RAS mutations, proven/suspected Lynch syndrome status and consecutive regimens of chemotherapy with or without targeted therapy. One of the limitations is the retrospective nature of this study.…”

Section: Discussionmentioning

confidence: 99%

“…The inclusion period of our cohort was mainly in the pre‐immunotherapy era and a subset of these patients might nowadays be eligible for immunotherapy. Consequently, it is of importance to generate data about the efficacy and tolerability of ICI for elderly/frail patients with dMMR/MSI‐H mCRC 48,49 …”

Section: Discussionmentioning

confidence: 99%

Prognostic value of Lynch syndrome, BRAF^V600E, and RAS mutational status in dMMR/MSI‐H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts

et al. 2023

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BackgroundCurrent knowledge on prognostic biomarkers (especially BRAFV600E/RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors.MethodsThis observational cohort study combined a population‐based Dutch cohort (2014–2019) and a large French multicenter cohort (2007–2017). All mCRC patients with a histologically proven dMMR tumor were included.ResultsIn our real‐world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first‐line palliative systemic chemotherapy. Mean age of first‐line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66–1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67–1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64–1.59), with similar results for PFS.ConclusionBRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision‐making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

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Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer

Cited by 20 publications

References 26 publications

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability

Prognostic value of Lynch syndrome, BRAF^V600E, and RAS mutational status in dMMR/MSI‐H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts

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Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer

Cited by 20 publications

References 26 publications

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability

Prognostic value of Lynch syndrome, BRAFV600E, and RAS mutational status in dMMR/MSI‐H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts

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Prognostic value of Lynch syndrome, BRAF^V600E, and RAS mutational status in dMMR/MSI‐H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts