Immune checkpoint inhibitors (ICIs) yielded unprecedented efficacy in patients with microsatellite instability (MSI)–high metastatic colorectal cancer (mCRC). Since the Pan-Immune-Inflammation Value ...(PIV) is a blood-based biomarker with prognostic usefulness in mCRC, it might predict clinical outcomes and primary resistance to ICIs.
We retrospectively analysed the association of PIV and its early modulation at 3/4 weeks after treatment initiation with the outcomes of MSI-high mCRC patients receiving anti-programmed death-(ligand)1 (PD-L1) +/− anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. PIV cut-offs were determined using the maximally selected rank statistics.
A total of 163 patients were included. In the multivariable models for overall survival (OS) and progression-free survival (PFS), both high (>492) baseline PIV (OS: adjusted a HR, 3.00; 95% CI, 1.49–6.04, p = 0.002; PFS: aHR, 1.91; 95% CI, 1.06–3.44, p = 0.031) and early PIV increase ≥+30% (OS: aHR, 3.21; 95% CI, 1.65–6.23, p < 0.001; PFS: aHR, 2.25; 95% CI, 1.30–3.89, p = 0.003) confirmed an independent prognostic impact. After stratifying patients according to baseline PIV and ICI regimen, OS and PFS were significantly worse in subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy. Early PIV increase was an independent predictor of clinical benefit (aOR, 0.23; 95% CI, 0.08–0.66; p = 0.007), whereas a trend was observed for baseline PIV (aOR, 0.33; 95% CI, 0.10–1.07; p = 0.065).
PIV is a strong predictor of outcomes in MSI-high mCRC patients receiving ICIs. Prospective validation of these results is required to establish its role as a stratification factor for personalised combination strategies.
•PIV is a composite immune-inflammation biomarker with prognostic usefulness in mCRC.•High baseline PIV identifies MSI-high mCRC patients with poorer outcomes upon ICIs.•Early PIV increase ≥+30% at 3/4 weeks independently correlates with poor OS and PFS.•Subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy have worse OS and PFS.•Baseline PIV and early PIV variation correlate with primary ICIs resistance.
Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour ...mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes.
We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen.
We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8–251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio aHR = 4.26, 95% confidence interval CI:1.85–9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76–14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949).
Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination.
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•The TMB stratifies the outcomes of dMMR/MSI-H mCRC receiving ICIs.•Patients with a low TMB has poor outcomes regardless of the ICI type.•Patients with the highest TMB have greater benefit from anti-CTLA-4 combos.•TMB could be used to drive future research projects and trials’ design.
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Background: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% ...of patients with MSI mCRC will experience a primary resistance to ICI. Methods: In a cohort of 103 patients with MSI mCRC treated with ICI, 3’RNAseq was performed from primary tumors resected before the beginning of ICI. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: The unsupervised clustering of this cohort allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromal
HIGH
-proliferation
LOW
”), cluster B (“stromal
HIGH
-proliferation
MED
”), and cluster C (“stromal
LOW
-proliferation
HIGH
”), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p < 0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. Similar results were observed for overall survival (OS).In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.26 95%CI 0.11-0.58, p = 0.001) and cluster C (HR: 0.35 95%CI 0.16-0.78, p = 0.01), compared to patients belonging to cluster A (Table). No association of identified clusters with PFS during non-ICI-based regimens was identified. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromal
HIGH
-proliferation
LOW
” cluster is associated with a lower efficacy of ICI. Table: see text
Immune checkpoint inhibitors yielded unprecedented outcomes in patients with mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), but clinical ...decision-making in this rapidly evolving treatment landscape is challenging. Since performance status (PS) represents a well-established prognostic factor in clinical practice, we investigated whether worse PS, overall or related to either patients' frailty or high tumour burden, could affect the outcomes in this whole patients’ population and according to immune checkpoint inhibitor treatment type.
We conducted a global study at Tertiary Cancer Centres and collected data of patients with dMMR/MSI-H mCRC treated with anti- programmed-death (ligand)-1 (PD(L)-1) monotherapy or anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination.
The cohort included 502 patients. At a median follow-up of 31.2 months, worse PFS and OS were reported in patients with patient-related PS ≥ 1 (adjusted-HRs: 1.73, 95%CI: 1.06–2.83, p = 0.004 and 2.06, 95%CI: 1.13–3.74, p = 0.001, respectively) and cancer-related PS ≥ 1 (adjusted-HRs: 1.61, 95%CI: 1.19–2.17, p = 0.004 and 1.87, 95%CI: 1.32–2.66, p = 0.001, respectively). Anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination did not provide significantly better survival compared to anti-PD(L)-1 monotherapy in PS 0 subgroup (PFS HR = 0.62, 95%CI: 0.37–1.02, p = 0.059; OS HR = 0.59, 95%CI: 0.32–1.11, p = 0.100) and in patient-related PS ≥ 1 (PFS HR 0.93, 95%CI: 0.31–2.83, p = 0.899; OS HR 1.22, 95%CI: 0.34–4.37, p = 0.760), but the difference was significant and clinically meaningful in the subgroup with cancer-related PS ≥ 1 (PFS HR = 0.32, 95%CI: 0.19–0.53, p < 0.001; OS HR = 0.26, 95%CI: 0.14–0.48, p < 0.001).
In patients with dMMR/MSI-H mCRC, an extensive evaluation of clinical variables including PS may be implemented in the therapy decision-making.
•We investigated Eastern Cooperative Oncology Group performance status in 502 patients with mismatch repair deficient/ microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors.•Eastern Cooperative Oncology Group performance status is independently associated with outcomes of immune checkpoint inhibitors.•Programmed-death 1 blockade alone may be preferred in patients with performance status (PS) 0.•Adding cytotoxic T-lymphocyte antigen 4 blockade seems not beneficial if worse PS is patient-related.•Adding cytotoxic T-lymphocyte antigen 4 blockade yields meaningful benefit if worse PS is cancer-related.
Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains ...uncertain.
In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed.
to describe the molecular landscape of paired BM/prCRC.
to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS).
Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06-8.93; p = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97-30.40; p = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03-11.53; p = 0.0449) and KRAS
BM (HR 0.31; 95%CI 0.12-0.80; p = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01-0.91; p = 0.0403).
This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS.
Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with ...MSI mCRC will experience a primary resistance to ICI.
In 2 cohorts of patients with MSI mCRC treated with ICI (exploratory: N=103, validation: N=35), 3'RNAseq was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed.
In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p=0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p<0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.19 95%CI 0.08-0.45, p<0.001) and cluster C (HR: 0.25 95%CI 0.10-0.59, p=0.02), compared to patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster.
This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.
Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those ...with left-sided tumours and ECOG-PS > 0.
The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples.
A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population.
Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.
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Background: Encorafenib and cetuximab (EC) is the standard of care for pre-treated patients (pts) with BRAF V600E mut mCRC. DpR and ETS previously showed a strong correlation with survival ...outcomes in mCRC pts receiving 1
st
-line therapy. We assessed these tumour dynamic response parameters and their association with clinical outcome in pts with BRAF V600E mut mCRC treated with TT in second-line. Methods: Patients treated in a real-life setting with EC or EC plus binimetinib (ECB) in 20 Italian centres were included. Pts with measurable disease and at least one available disease reassessment by CT scan were eligible. Pts experiencing disease progression as best response (i.e. primary resistant) were not evaluable for DpR and ETS. Associations between DpR and ETS and progression free survival (PFS) and overall survival (OS) were tested by univariate and multivariate models. Results: 105 pts were included: 89 (85%) and 16 (15%) pts were treated with EC and ECB, respectively. Median PFS and OS were 5.2 and 10.3 mos, respectively. Twenty-nine pts (28%) were primary resistant, while 76 (72%) pts achieved disease control (51 48% and 25 24% pts had SD or CR/PR, respectively). Among baseline characteristics, the presence of peritoneal metastases was a predictor of primary resistance (p = 0.04). Among pts evaluable for response parameters (n = 76), median DpR was 15% and ETS occurred in 28 pts (37%). Mucinous histology was associated with a significantly lower magnitude of DpR (p = 0.005) and a lower rate of ETS (p = 0.002). A significant association between DpR and PFS was observed, both as a dichotomous ( ie, ≥ or < median value) and continuous variable in univariate and multivariate analyses. Also RECIST response correlated with PFS in the two models (table). DpR was associated with OS in the univariate analyses, but this was not confirmed in the multivariate models (table). No correlation between ETS and survival, either as a dichotomous ( ie, ≥ or < 20%) or a continuous variable, was observed. Conclusions: Having a DpR of at least 15% predicts longer PFS and OS in patients with BRAF V600E mut mCRC receiving TT as second-line treatment. An independent cohort of pts treated with second-line chemotherapy +/- antiangiogenic is under investigation as control group. Table: see text
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