486 Background: Management of locally advanced gastric and gastroesophageal junction (GOJ) cancer relies on peri-operative chemotherapy and radical surgery. Response to neoadjuvant chemotherapy can be evaluated by Mandard Tumor Regression Grade (TRG) performed on the removed specimens. The aim of this study was to investigate the prognostic value of TRG, in terms of post-surgical disease-free survival (DFS) and overall survival (OS). Methods: Retrospective analysis of all consecutive patients (Jan 2010 to Dec 2021) who underwent oncological gastrectomy for gastric or GOJ adenocarcinoma after neoadjuvant chemotherapy was performed. TRG was evaluated according to Mandard classification, ranging from 1 (complete pathological response) to 5 (absence of response), TRG 1-2 being considered as “good responders” and TRG 3-5 as “bad responders”. Univariate and multivariate analysis were performed for DFS and OS. Results: One hundred and ninety-nine patients were included, 157 treated with FOLFOX and 42 with FOLFOX + Taxanes (either FLOT or FOLFOX + Abraxane). TRG 1-2 was observed in 30% in patients (pts) treated with FOLFOX and 24% in pts treated with FOLFOX + Taxanes. With a median follow-up over 5 years (yrs), median DFS and OS were not reached (DFS rates at 3, 5 and 10yrs of 66.5%, 64.1% and 55.7%, respectively; OS rates at 3, 5 and 10yrs of 75.6%, 66.8% and 60.4%, respectively). In univariate analysis, TRG 1-2 was significantly associated with favorable outcome compared to TRG 3-5 in terms of DFS (HR 2.4, p-value 0.0056) and OS (HR 2.6, p-value 0.0061), as well as ECOG at diagnosis (0 vs. 1), ypT stage (yp T0-2 vs. yp T3-4), ypN stage (ypN- vs. ypN+), tumor localization (antrum + body vs. cardia + esophagus), and lymphatic, vascular and peri nervous embolisms (negative vs. positive) for both DFS and OS. However, in multivariate analysis (selection backward Cox-model), only ypT stage and vascular embolisms for DFS, and ypT and ypN stages for OS were found to be independent prognostic factors. Conclusions: Although TRG is a prognostic factor in patients with gastric or GOJ cancer, it does not appear as an independent factor for DFS and OS in this series of 199 pts. These results raise the issue of “good responder” definition, especially for TRG 3. Prognostic impact of TRG needs to be investigated for patients treated with combination of immune checkpoint inhibitors and chemotherapy in neoadjuvant regimens.

168 Background: Anti-PD1 monotherapy (mono) and anti-PD1 plus anti-CTLA4 therapies (combo) are validated for metastatic colorectal cancer (mCRC) harboring microsatellite instability and/or mismatch repair deficiency (MSI/dMMR). We aimed at assessing the efficacy of combined anti-CTLA4 and anti-PD1 blockade versus anti-PD1 monotherapy and identifying which subgroups benefit more from the combo. Methods: All patients (pts) with MSI/dMMR mCRC treated by anti-PD1 ± anti-CTLA4 included in the prospective monocenter immunoMSI cohort were analyzed. The choice between monotherapy or combination therapy varied according to open studies and regulatory approvals, without taking pt characteristics into account. Datalock date was April 23, 2024. Main endpoints were progression-free survival (PFS) per iRECIST and overall survival (OS) estimated with the Kaplan-Meier method. Univariate Cox proportional hazards models were used to estimate hazard ratios with CI. The interactions between studied subgroups and the treatment group were modelized by adding in a single Cox model the studied subgroups, the treatment group parameters, and their interaction term. Results: Among 210 pts, 97 were treated combo and 113 with mono. Baseline characteristics were similar in both groups. 25% and 17% were in first line, respectively. Median follow-up was 4.4 years: 4.1 years for combo and 5.4 years for mono. Combo was associated with better PFS (HR=0.48; 95%CI 0.31-0.76) and OS (HR=0.49; 0.29-0.84). Best observed response rates were: 78% of objective responses, 17% of stable diseases and 5% disease progressions with combo versus 60%, 25% and 15% with mono. Subgroup analyses showed significant differential effect of the treatment group for gender (PFS HR=0.21 vs 0.87 for females and males, P-interaction: 0.0067), liver metastases (PFS HR=0.30 vs 0.79 for pts without liver mets and those with liver mets, P-interaction: 0.0479) and sidedness (PFS HR=0.27 vs 0.64 for left-sided and right-sided mCRC, P-interaction=0.0922), but not RAS / RAF mutations. We computed a predictive score based on gender (female: 2 points), no liver met (1 point) and left side (1 point). PFS HR was 0.1 (0.03-0.33) for the group ≥3 points (N=67), 0.66 (0.36-1.23) for the group with 1-2 points (N=113) and 1.54 (0.50-4.70) for the group with 0 point (N=30). Conclusions: Combined CTLA4 and PD1 blockade is associated with improved PFS and OS compared to anti-PD1 alone in MSI/dMMR mCRC. The subgroup deriving the highest benefit of the combo seems to be female pts with left sided tumor and no liver met. Data from the randomization between nivolumab versus nivolumab + ipilumumab in the CheckMate-8HW phase III study are expected.

Background:Currently, mismatch repair deficient/microsatellite instable (dMMR/MSI) status constitutes a validated predictive marker of response to immune checkpoint inhibitors (ICIs) in patients with metastatic colorectal cancer (mCRC). Unfortunately, some of these patients do not benefit from ICIs. Very limited therapeutic options for patients with dMMR/MSI mCRC after progression on ICI(s) exist. These patients show poor outcomes with conventional chemotherapy. Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic tropomyosin receptor kinase (NTRK) fusion-driven cancers. NTRK gene fusions are rare (<1%) in CRC and data regarding their prevalence in patients with dMMR/MSI CRC are increased but limited, especially in patients with metastatic disease. Materials and methods:A total of 187 dMMR/MSI mCRC patients, including 120 immune ICI-treated, were screened for NTRK gene fusions. Results:Tumor samples of 10 (5.3%) patients harbored NTRK gene fusions confirmed by FISH (NTRK1 = 8; NTRK3 = 2) including two cases with Lynch syndrome and height sporadic cases with MLH1 promoter hypermethylation and RAS wild-type (wt), out of which only five were positive by pan-TRK immunohistochemistry. One patient with primary resistance to nivolumab received a TRK inhibitor (larotrectinib) and showed a complete response. Conclusions:These results underline the importance of screening for NTRK gene fusions in dMMR/MSI mCRC in sporadic cases with MLH1 promoter hypermethylation RAS/BRAFV600E wt. We highlight several key technical aspects of NTRK fusion testing and interpretation of reports that remain to be explored.

Background:Immune-checkpoint inhibitors (ICIs) are the standard of care for microsatellite instability (MSI) metastatic gastrointestinal cancer (mGIC) patients in first- and later-treatment lines. We compared tolerability and efficacy of ICIs in elderly (aged ≥75 years) versus non-elderly MSI mGIC patients and analyzed the correlation between immune-related adverse events (irAEs) and efficacy. Patients and methods:This single-center prospective cohort study included MSI mGIC patients treated with ICIs, excluding chemotherapy. Assessments covered grade ≥3 irAEs and ≥2 endocrine irAEs (E-irAEs). Results:Among 201 patients, 24 were elderly (mean age 75-90 years) and 177 non-elderly (mean age 22-74 years). In the overall population, grade ≥3 irAEs and E-irAEs incidence was 40% with the anti-programmed cell death protein 1 + anti-cytotoxic T lymphocyte-associated antigen 4 and 23% with anti-programmed cell death protein 1 monotherapy (P = 0.011). Treatment combination was administered to 29% of elderly and 40% of non-elderly patients. The incidence of grade ≥3 irAEs and E-irAEs was 37%/29% with monotherapy (P = 0.48) and 57%/39% with combination (P = 0.43) in elderly/non-elderly patients. No significant difference was observed in progression-free survival [hazard ratio (HR) = 1.15, 95% confidence interval (CI) 0.57-2.32, P = 0.7] and OS (HR = 1.61, 95% CI 0.75-3.43, P = 0.25) between elderly and non-elderly. Cox regression analysis with a time-dependent variable showed no survival difference between patients with/without grade ≥3 irAEs and E-irAEs (progression-free survival: HR = 1.19, 95% CI 0.64-2.19, P = 0.59; overall survival: HR = 0.91, 95% CI 0.44-1.92, P = 0.81). A positive association was found, however, between objective response rate and immune treatment-related adverse event occurrence [77%/59%, immune treatment-related adverse event patients/others (P = 0.0012)]. Conclusion:This study reveals comparable tolerability and efficacy of ICIs in elderly and non-elderly patients with MSI mGIC. Survival outcomes did not differ significantly between patients with and without grade ≥3 irAEs and E-irAEs.

Background: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy.Patients and methods: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 & PLUSMN; anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS).Results: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 x 10e3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS.Conclusions: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

795 Background: Immune checkpoint inhibitors (ICI) are the new standard of care for some MSI/dMMR advanced tumors in first-line setting or after progression under conventional chemotherapy. Frequency of MSI/dMMR increasing with age, the tolerability and efficacy of ICIs in elderly patients, appears as a crucial clinical issue. We aimed to evaluate the tolerability and efficacy of ICIs in ≥ 75 years patients with metastatic MSI/dMMR gastro-intestinal (GI) cancer. Methods: All pts with MSI/dMMR metastatic GI cancer treated by anti-PD1 ± anti-CTLA4 without concomitant chemotherapy at Saint-Antoine hospital and included in our prospective, monocenter cohort, were analyzed. Pts were divided into the elderly (≥75 years) and non-elderly (<75 years) groups. The incidence and evolution of grade ≥ 3 immune-related adverse events (irAE) and grade ≥ 2 endocrine adverse events were evaluated. Secondary objectives were progression-free survival (PFS) and overall survival (OS) regarding age and the occurrence of irAEs. Results: Two hundred and one patients were included: 24 pts≥75 years (75 to 90 years) and 177 pts< 75 years (22 to 74 years). 171 (79%) had mCRC. In the entire population, the incidence of irAEs was 40.5% with anti-PD1 plus anti-CTLA4 and 23% with anti-PD1 monotherapy (p= 0.011). Combination of anti-PD1 and anti-CTLA4 were administered to 29% of the elderly group and 40% of the non-elderly group. There was no statistical difference in the incidence of irAEs between the two populations (37.5% in the elderly group vs 29% in the non-elderly group; p=0.48) neither in their type (12% vs 7% of hepatic cytolysis, 13% vs 16% of endocrine irAEs) or management (17% vs 19% corticosteroid therapy, 21% and 16% of ICI discontinuation). No significant difference was observed between elderly/non elderly for PFS (HR 0.91, 95%CI 0.40-2.06; p=0.83) and OS (HR 1.6, 95%CI 0.65-3.96; p= 0.21). Pts experiencing irAEs had superior survival outcomes than those without irAEs (PFS HR 2.93, 95%CI 1.69-5.09; p=0.02 and OS HR 2.05, 95%CI 1.13-3.74; p=0.045) in the whole cohort (n=201). Conclusions: Tolerability and efficacy of ICIs for pts with MSI/dMMR GI cancers are similar for elderly compare as for non-elderly pts. Pts experiencing irAEs had superior survival outcomes. Further prospective studies with systematic geriatric assessment are required to evaluate the tolerability of ICIs especially for frail elderly pts.

We describe a case of healthcare-associated bloodstream infection due to Mycobacterium fortuitum . Whole-genome sequencing showed that the same strain was isolated from the shared shower water of the unit. Nontuberculous mycobacteria frequently contaminate hospital water networks. Preventative actions are needed to reduce the exposure risk for immunocompromised patients.

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAFV600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p < 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAFV600Emt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAFV600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAFV600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAFV600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]

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Abstract Background We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients and Methods Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. Results Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. Conclusion In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Background Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs. Methods We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset. Results The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement. Conclusions Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.

Background: 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. Methods: 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. Results: 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 Z 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). Conclusions: In patients with dMMR/MSI-H mCRC, an extensive evaluation of clinical variables including PS may be implemented in the therapy decision-making. (C) 2022 Elsevier Ltd. All rights reserved.

Immunotherapies are part of the therapeutic strategy in many cancers and are indicated for metastatic colorectal adenocarcinoma with loss of expression of MisMatch Repair system proteins or with microsatelite instability (dMMR/MSI) in the United States. The rate of pathological response to immunotherapy remains poorly documented, but several cases of complete or major pathological response have recently been described. We decided to report the case of a complete pathological response to immunotherapy of a dMMR/MSI colorectal adenocarcinoma in a 74-year-old patient, initially inoperable due to duodenal invasion. Three months after the introduction of immunotherapy, the patient developed drug-induced colitis that contraindicated further treatment. Histological examination of the subtotal colectomy specimen revealed no residual tumour cells. The patterns of tumour regression were mainly represented by colloid regression, infarctoid-type necrosis and a resorptive inflammatory reaction. Although the operative indications for patients with metastatic dMMR/MSI colorectal cancer treated by immunotherapy are still very limited, the number of such specimens is expected to increase rapidly. The management of these specimens, as well as the possibility of a complete histological response, must be known by pathologists who play a key role in the pathophysiological knowledge of these lesions. (c) 2021 Elsevier Masson SAS. All rights reserved.

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.

Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK (NTRK) fusion-driven cancers. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF, KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We evaluated the frequency and associated clinical characteristics of NTRK fusions among dMMR/MSI metastatic CRCs (mCRCs) patients (pts).

Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Amongst 121 advanced dMMR mCRC patients treated with CPI at two institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on pre-operative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggests that residual radiographic tumor may not require systematic resection following response to anti-PD1 based therapy. However, larger prospective studies are warranted.

In their article, Fucà et al highlight that early tumor shrinkage and depth of response predict the prognosis of patients with metastatic colorectal cancer (mCRC) microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) treated by immune checkpoint inhibitors (ICI). We are surprised that no cases of pseudoprogression (PSPD) were reported in their study. PSPDs were described under ICI in patients treated for MSI/dMMR mCRC. In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort. Of 12 patients with PSPD, 8 secondary achieved an objective response and were alive and free of progression at the data lock. Conversely, in Fucà’s article, no PSDP was observed and the patients with primary radiological progression (21.7%) had a poor overall survival. These differences between the two series could be probably explained by the following points. First, Fucà et al use RECIST 1.1 criteria for radiological evaluation. Second, the first imaging was done after 8–9 weeks of treatment in Fucà’s article, which may be late to detect PSPD. In conclusion, if the first evaluation is made during the first 3 months of treatment, using iRECIST criteria seems mandatory to avoid stopping treatment prematurely, especially in patients receiving anti-PD1 alone.

Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAF V600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.