Search

Background Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. Patients and methods Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. Results Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P Conclusions Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.

Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment.An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed.No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role.The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Background Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase–inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown. Methods Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided. Results Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P Conclusions HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.

Background A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naive, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients. Patients and Methods PARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety. Aim of the study The aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.

BackgroundImmune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes.Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns.Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation.MethodsAtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee.DiscussionThe AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status.Trial registrationAtezoTRIBE is registered at Clinicaltrials.gov (NCT03721653), October 26th, 2018 and at EUDRACT (2017–000977-35), Februray 28th, 2017.

Oligometastatic disease (OMD) identifies tumours with limited metastatic spread. OMD definition is not univocal and no data from clinical trials are available about the prognostic effect of OMD in metastatic colorectal cancer (mCRC), the impact of locoregional treatments (LRTs) and the effect of chemotherapy intensification in these patients. The role of tumour burden (TB) in driving therapeutic choices is also debated.We performed a pooled analysis of phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bevacizumab (bev) to doublets (FOLFOX or FOLFIRI)/bev. Patients were grouped in OMD versus non-OMD based on the European Society for Medical Oncology definition. Among patients with OMD, those with OMD/low TB were compared with all the others.Of 1187 patients enrolled, 1096 were classified as OMD (N = 312 [28%]) or non-OMD (N = 784 [72%]). Among patients with OMD, 126 (40%) were OMD/low TB. OMD was associated with longer progression-free survival (14.0 versus 10.1 months; p 0.01) and overall survival (38.2 versus 22.0 months; p 0.01). These results were confirmed in multivariable models. The benefit provided by FOLFOXIRI/bev compared with doublets/bev did not differ in accordance with OMD and TB (p for interaction0.05). Patients with OMD underwent LRTs more frequently (p 0.01) and those with OMD/low TB had higher chance to undergo LRTs after the first progression (p 0.01).OMD is a positive prognostic factor in mCRC. The benefit from the upfront treatment intensification is independent of the metastatic spread extent and TB. LRTs should be highly considered in these patients, mainly during the first-line therapy but also at later stages of treatment history in selected cases.

Background: Due to the relative rarity of small bowel adenocarcinoma (SBA), prospective trials, helping to guide therapeutic decisions, are lacking and the optimal therapy for advanced SBA is unknown. The role of targeted agents, such as anti–epidermal growth factor receptor (EGFR) and anti–vascular endothelial growth factor (VEGF), is unknown. Patients and Methods: This is a retrospective multicenter observational study that included patients with metastatic SBA treated with anti-EGFR antibodies (cetuximab or panitumumab) ± chemotherapy in the first (I) or second (II) line. Results: Thirteen patients with metastatic SBA, recruited from 5 Italian referral institutions, were included in the present retrospective analysis. All patients received anti-EGFR inhibitors as a single agent or in association with chemotherapy. More common G2 treatment–related side effects were skin reaction (8 patients, 53.8%), hypomagnesemia (6 patients, 46.2%), and diarrhea (8 patients, 61.5%). Grade 3 diarrhea was observed in only 1 patient. Conjunctivitis was not reported in any patients. Grade 4 toxicity was not reported. In the overall population, median progression-free survival was 5.526 months (95% confidence interval [CI]: 3.684-12.467). Median overall survival was 15.86 months (95% CI: 14.43-24.30). Complete response was observed in 15% of patients, partial response in 39% of patients, stable disease in 23% of patients, and progression disease in 15% of patients. Conclusions: In this retrospective analysis, anti-EGFR inhibitors showed to be a suitable addendum to chemotherapy in the I and II line, with an excellent tolerance and safety profile both in I and II line.

Background Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy. Methods In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan–Meier method and Cox hazards regression models were used for survival analyses. Results A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36–2.03, P P Conclusion PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.

Background FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression. Methods We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction. Results Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045). Conclusions First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS.

Background On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti–epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. Patients and Methods A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type–status tissue samples, who had received a first-line anti-EGFR–based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. Results A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of 2 prior therapy lines and a longer anti-EGFR–free interval were associated with higher ORR, but not with longer PFS or OS. Conclusion Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.

Adenocarcinoma with mucinous histology or mucinous component are histologic subtypes of metastatic colorectal cancers (mCRCs) with limited benefit from cytotoxic agents. Their sensitivity to anti-epithelial growth factor receptors (EGFRs) is not clear.The activity and efficacy of anti-EGFRs was retrospectively evaluated among patients with RAS and BRAF wild-type mCRC with or without mucinous histology or mucinous component. Subgroup analyses according to primary tumor location were conducted.Overall, the study population included 22 mucinous or with mucinous component tumors (11 right- and 11 left-sided tumors) and 83 not mucinous tumors. One patient experienced partial response among mucinous tumors, whereas in the not mucinous group, 42 patients experienced partial response, with an overall response rate of 4% and 51%, respectively (P = .003). The median progression-free survival was 2.8 versus 6.7 months (hazard ratio, 0.28; 95% confidence interval, 0.13-0.59; P .001), and the median overall survival was 6.5 and 16.7 months (hazard ratio, 0.58; 95% confidence interval, 0.33-1.00; P = .022), for the mucinous and not mucinous groups, respectively. Similar results were observed in subgroup analysis according to primary tumor location.Anti-EGFRs may not provide clinically meaningful benefit in mCRCs with mucinous histology or mucinous component compared with those without mucinous component, irrespective of sidedness.

Background: No tools to predict the probability of extrahepatic disease progression (ePD) of initially unresectable, liver-limited metastatic colorectal cancer (mCRC) are currently available. To estimate the likelihood to develop ePD and to identify clinical and molecular factors that could predict extrahepatic progression-free survival (ePFS), we conducted an observational, retrospective, multicentre cohort study. Methods: We retrospectively identified a cohort of 225 patients with initially unresectable liver-limited disease (LLD), treated from January 2004 to December 2017 with first-line doublets or triplet plus a biological agent at two Italian institutions. Results: 173 (77%) patients experienced ePD which occurred within 1, 2 or 3 years from the diagnosis of mCRC in 15%, 49% and 66% of patients, respectively. Globally, 164 (73%) patients underwent a liver resection at some point of their disease history, and 54 (33%) of them underwent a subsequent locoregional treatment. Age > 70 years, locoregional nodal involvement at diagnosis of colorectal cancer and ≥4 liver metastases were significantly associated with higher risk of ePD while liver resections were associated with reduced risk of ePD. In the multivariable model, number of liver metastases (subdistribution HR, SHR 1.63, 95% CI 1.12 to 2.36; p = 0.01) and liver resections (SHR 0.43, 95% CI 0.29 to 0.63; p = 0.001) were still associated with ePD. Number of liver metastases < 4, no nodal involvement at diagnosis and liver resections were also associated with prolonged ePFS. Conclusions: The identified clinical factors could help physicians in personalising the intensity and aggressiveness of liver-directed treatments in patients with mCRC with initially unresectable LLD.

BACKGROUND The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender. PATIENTS AND METHODS Subgroup analyses according to age (

Background: The triplet FOLFOXIRI (fluorouracil, L-leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes of patients with metastatic colorectal cancer, when compared to FOLFIRI (fluorouracil, Lleucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxics when compared with a preplanned sequential strategy of doublets was not clear, as well as the feasibility and efficacy of therapies after progression. To this purpose, we aimed at comparing a pre-planned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression to a sequence of mFOLFOX6 (fluorouracil, L-leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods: TRIBE2 was an open-label, prospective, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0), with unresectable, previously untreated metastatic colorectal cancer, who were recruited from 58 Italian Oncology Units. Patients were stratified according to center, ECOG performance status, primary tumour location and previous adjuvant chemotherapy, and randomly assigned (1:1) via a web-based procedure to two different strategies: first-line mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression (control group) or FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression (experimental group). Combination treatments were administered up to 8 cycles followed by fluorouracil/L-leucovorin plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Both patients and investigators were aware of treatment assignment. The primary endpoint was progression-free survival 2, defined as the time from randomization to disease progression on any treatment given after first disease progression or death, analysed by intention to treat. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. The study recruitment was completed, and follow-up of participants is still ongoing. Findings: Between February 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). 81% of enrolled patients had a right-sided and/or RAS or BRAF mutated tumour. At data cut-off (July 30, 2019) the median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (95% CI 15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p

Background Despite the well-known negative prognostic value of the V600EBRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. Methods Two large retrospective series of V600EBRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. Results A total of 395 V600EBRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a ‘complete’ score (0–16) including all significant covariates and a ‘simplified’ score (0–9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0–4), intermediate (5–8) and high (9–16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44–3.22, p Conclusions These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

e15566 Background: Regorafenib is a treatment option for refractory mCRC patients with no validated predictors of benefit. We previously showed that, among several circulating angiogenic factors, low baseline Ang-2 and Tie-2 plasma levels were associated with good prognosis and that the early increase of Ang-2 during the treatment could predict benefit from regorafenib ( Antoniotti et al, J Clin Oncol 36:675-675, 2018). To prospectively validate these retrospective findings, we conducted the REGOLAND study. Methods: Ang-2 and Tie-2 were assessed by ELISA on plasma samples collected at baseline (d1) and after 15 days (d15) of treatment in a cohort of mCRC patients receiving regorafenib, as per indication. To detect a HR for PFS of 0.50 in favour of the early increase (Δd15-d1) of Ang-2 levels, setting two-sided α = 0.05 and β = 0.10, 87 events were required according to Schoenfeld design. Comparisons among concentrations of each marker at d1 and d15 were performed by Wilcoxon test. Median values at baseline were used as cut-off to discriminate patients with low versus high plasma levels and their correlation with outcome was analysed. Results: One hundred patients were included. Median PFS and OS were 2.5 and 6.7 months, respectively. The early increase of Ang-2 at d15 was reported in 42 patients and was associated with longer PFS (median 2.7 vs 2.4 months; HR for PFS: 0.72 [95%CI:0.48-1.08], P = 0.095). As compared to d1, an overall decrease of Tie-2 levels at d15 was observed ( P = 0.007), but it was not associated with clinical outcome. Low levels of Ang-2 at baseline were associated with longer PFS (HR: 0.59 [95%CI:0.39-0.89], P = 0.005) and OS (HR:0.62 [95%CI:0.41-0.94], P = 0.017), while Tie-2 levels were not. In the multivariate model, the association of Ang-2 levels with PFS was confirmed (HR:0.48 [95%CI:0.31-0.76], P = 0.001), but not with OS (HR: 0.80 [95%CI:0.49-1.28], P = 0.351). Conclusions: Ang-2 is a prognostic marker and its early modulation predicts clinical benefit among mCRC patients treated with regorafenib. We hypothesize that Ang-2 levels early increase as a consequence of the successful inhibition of Tie-2 by regorafenib that leads to a compensatory increase of the ligand and correlates with anti-tumour activity.

Prolonging survival, achieving symptoms palliation and preserving quality of life are the primary therapeutic goals of treatments administered after disease progression in mCRC. Even if the impact of these therapies on the prognosis of affected patients is less relevant than the impact of the upfront treatment, tailoring the optimal second-line therapy is increasingly important. Several therapeutic options are available, and different factors including not only patient- and disease-related characteristics, but also the first-line treatment received (i.e., type, timing of disease progression, observed outcome and reported toxicities) may drive this choice. Herein, we describe the current state of the art in the landscape of treatments after progression in mCRC. Based on a critical review of the literature, we built a patient-oriented therapeutic algorithm, aiming to guide clinicians in their daily decision-making.

4048 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. Here we report the final results of the phase I study of PolyPEPI1018 vaccine as an add-on to maintenance therapy in mCRC patients. Methods: 11 patients with MSS mCRC were vaccinated with PolyPEPI1018 just after the transition to maintenance therapy with fluoropyrimidine/bevacizumab after first-line combo chemotherapy and bevacizumab. Part A: n = 5, single dose; Part B: n = 6, 3 doses, Q12W. Primary endpoint was safety. Immunomonitoring was performed at both blood and tumor levels, as well as prospectively predicted. Results: The vaccine was well tolerated; most common side effects were transient skin reactions. No vaccine-related SAE occurred. Pre-existing immune responses were boosted by the vaccine for 7/10 patients. De novo responses were also induced, overall, 80% of patients had CD8+ T cell responses against at least 3 CTAs. The magnitude of immune responses as well as the density and the ratio of CD8+/CD3+ tumor infiltrating T cells increased with multiple vaccine doses. Three patients had objective tumor response according to RECIST v1.1: one of them in the single dose group and two of them in the 3 doses group. Both patients in the 3 doses group qualified for curative surgery. One of them had no viable tumor cells in his primary tumor at the time of surgery. Post-trial follow-up revealed PFS of at least 12 months for 3 patients. mPFS was longer for patients receiving multiple doses (9.9 months) compared to single dose (6.1 months). Both measured and predicted multiantigenic immune responses tend to correlate with PFS and tumor volume reduction. Conclusions: PolyPEPI1018 was effective in restoring immunological responses to CTAs in patients’ with spontaneous immunity against. Treatment with PolyPEPI1018 vaccine and maintenance therapy was safe and demonstrated evidence of early clinical activity in MSS mCRC tumors. Data support further randomized trials with PolyPEPI1018. Clinical trial information: NCT03391232 .

4077 Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD. We performed a comprehensive NGS analysis of samples from randomized patients in order to investigate the prognostic impact of tumor mutational load (TML), its additional value with respect to the assessment of microsatellite instability (MSI), and the overall prevalence of potentially actionable alterations. Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks from primary tumors of 296 (44%) out of 679 randomized patients and underwent NGS analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined low, intermediate or high if < 7, 7-16 or > 16 mutations/Mb were found. MSI status was determined both by NGS and by IHC. Results: TML and MSI were successfully determined by NGS in 224 (76%) cases. NGS and IHC results were concordant in 221 (99%) cases. TML was low, intermediate or high in 56 (25%), 157 (70%) and 11 (5%) cases, respectively. When compared with TML low and intermediate tumors, TML high were more frequently right-sided (p = 0.013), mucinous (p < 0.001) and MSI-high (p < 0.001). TML high tumors were MSI-high or MSS in 8 (73%) and 3 (27%) cases, respectively. Two out of 3 TML high and MSS tumours showed a pathogenic POLE mutation (p.S459F and p.P286R). The other TML high, MSS and POLE wt tumor was dMMR at IHC (loss of MSH6 expression) and showed a pathogenic MSH6 mutation (p.F1040fs). As compared with low and intermediate TML, high TML was associated with longer PFS (median PFS: 17.3 vs 10.6; HR: 0.54 [95%CI: 0.35-1.09], p = 0.098) and OS (median OS: not reached vs 23.7: HR: 0.45 [95%CI:0-28-1.13], p = 0.106). No interaction effect between TML and treatment arm was observed, and no difference between TML low and intermediate tumors was reported in terms of baseline characteristics and prognosis. Actionable alterations ( HER2 mutations [N = 2] and amplifications [N = 4], KRAS G12C [N = 10] and BRAF V600E mutation [N = 39]) were found in 55 (19%) out of 296 cases. No NTRK/ROS/ALK or MET amplification was found. Conclusions: TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs.

4002 Background: Data on first-line treatment efficacy in elderly patients are limited. Many analyses adopt a questionable cut-off of 65 years and specific evidence with anti-EGFRs is low. FOLFOX-panitumumab (pan) is an option for RAS wild-type (wt) untreated mCRC patients. Guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, but no randomized studies have ever explored the role of the combination with an anti-EGFR. Methods: This is a prospective, open-label, multicenter phase II randomized trial. Unresectable and previously untreated RAS- BRAF wt mCRC patients aged ≥70 were randomized to receive FOLFOX-pan (arm A), or 5FU/LV-pan (arm B) for up to 12 cycles followed by pan maintenance until PD. The primary EP was PFS in both arms. Stratification criteria were age (≤75 vs > 75 years), ECOG PS (0–1 vs 2) and geriatric assessment with G8 Score (≤14 vs > 14). In each treatment arm, the null hypothesis for median PFS was set at ≤6 months. Assuming an expected median PFS time ≥9.5 months with both experimental regimens, a sample size of 90 patients in each arm granted to the study a power of 90%, with a type I error rate equal to 5% (1-sided Brookmeyer-Crowley test) for rejecting the null hypothesis. No formal comparison between the two arms was planned. Results: From Jul 2016 to Apr 2019 a total of 394 patients were screened, 211 were deemed eligible for inclusion and 185 were randomized (92 arm A and 93 arm B). Main pts’ characteristics were (arm A/B): males 66%/61%; median age 77/77y; PS≥1 49%/55%; right colon 23%/21%; G8 > 14 31%/30%. At a median follow up of 20.5 mos, 135 (arm A/B: 64/71) PD events were collected. Median PFS was 9.6 (95% CI 8.8-10.9) in arm A with FOLFOX-pan and 9.1 (95% CI 7.7-9.9) in arm B with 5FU/LV-pan. Response rates were (arm A/B): 65%/57%. Grade 3-4 toxicities were (arm A/B): neutropenia 9.8%/1.1%; diarrhea 16.3%/1.1%; stomatitis 9.8%/4.4%; neurotoxicity 3.3%/0%; fatigue 6.5%/4.4%; skin rash 25%/24.2%, hypomagnesemia 3.3%/7.7%. Conclusions: Large prospective randomized studies in molecularly selected elderly mCRC are feasible with multicenter collaborative efforts. Primary EP was met in both treatment arms. 5FU/LV plus panitumumab for up to 12 cycles followed by panitumumab maintenance until PD might be a reasonable option in elderly mCRC patients with RAS/BRAF wt tumors deserving further investigations in phase III trials. Clinical trial information: NCT02904031 .

Background Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status. Patients and methods Patients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status. Results Information about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09–1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98–1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status. Conclusions FOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.

Background Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3months. TEMIRI (TMZ 150mg/m2 on days 1–5 plus irinotecan 100mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0months; hazard ratio=0.29, 95% CI 0.02–0.41; P=0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Background FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, L-leucovorin 200 mg/m2, 5-fluoruracil 2400 mg/m2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information NCT03231722.

Background The prognosis of brain metastases (BM) in colorectal cancer (CRC) is extremely poor, but the incidence is increasing. The performance of existing prognostic classifications such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) has never been evaluated in this specific setting. Moreover, the development of nomograms for estimating survival in such patients could be extremely helpful for treating physicians. Patients and methods Between 2000 and 2013, data from 227 patients with BM from CRC were collected at 8 Italian institutions. Overall survival (OS) was estimated with the Kaplan–Meier method and statistical comparison between curves was performed using the log-rank test. The discriminative ability for OS of RPA and GPA was assessed by the Harrell C-index from univariable Cox models. Putative prognostic factors for OS were also studied by multivariable Cox analysis, using the Harrell C index to evaluate the model discriminative ability. After a backward variable selection, a nomogram was developed to predict median survival time from individual patient- and tumor-related characteristics. The nomogram was externally validated on an independent series. Results After a median follow-up of 59months, fifty percent of patients were still at risk at 5months. The C index was 0.594 and 0.607 for the RPA and GPA classifications, respectively. The C-index associated with the final multivariable Cox model used for developing the nomogram was 0.643; the favorable prognostic factors for survival were lower age ( p =0.061), better Karnofsky performance status ( p p p =0.035). The C index evaluated on the validation series was 0.733, even better than in the development series; also, the calibration of nomogram predictions was good. Conclusion The C-index associated to the nomogram model was slightly higher than that obtained for the RPA and GPA classifications. Most importantly, the very satisfactory results of nomogram validation on the external series, make us confident that our instrument may assist in prognostic assessment, treatment decision making, and enrollment into clinical trials.

The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally administered combination of the nucleoside analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. In a randomized trial of 800 patients who had received at least two other treatments previously (most patients had received more than four treatments). TAS-102 demonstrated a significant prolongation of overall survival compared with placebo (median survival 7.1 vs. 5.3 months; hazard ratio 0 · 68, 95%CI: 0 · 58-0 · 81; p

First-line therapy for mCRC — the influence of primary tumour location on the therapeutic algorithm

Background The efficacy of risk model scores to predict venous thromboembolism (VTE) in ambulatory cancer patients is under investigation, aiming to stratify on an individual risk basis the subset of the cancer population that could mostly benefit from primary thromboprophylaxis. Materials and Methods We prospectively assessed 843 patients with active cancers, collecting clinical and laboratory data. We screened all the patients with a duplex ultrasound (B-mode imaging and Doppler waveform analysis) of the upper and lower limbs to evaluate the right incidence of VTE (both asymptomatic and symptomatic). The efficacy of the existing Khorana risk model in preventing VTE was also explored in our population. Several risk factors associated with VTE were analyzed, leading to the construction of a risk model. The Fine and Gray model was used to account for death as a competing risk in the derivation of the new model. Results The risk factors significantly associated with VTE at univariate analysis and further confirmed in the multivariate analysis, after bootstrap validation, were the presence of metastatic disease, the compression of vascular/lymphatic structures by tumor, a history of previous VTE, and a Khorana score >2. Time-dependent receiving operating characteristic (ROC) curve analysis showed a significant improvement in the area under the curve of the new score over the Khorana model at 3 months (71.9% vs. 57.9%, p = .001), 6 months (75.4% vs. 58.6%, p Conclusion ONKOTEV score steps into history of cancer-related-VTE as a promising tool to drive the decision about primary prophylaxis in cancer outpatients. The validation represents the goal of the prospective ONKOTEV-2 study, endorsed and approved by the European Organization for Research and Treatment of Cancer Young Investigators Program.

Background Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. Patients and methods We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Results Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P

Background Mutations in PIK3CA, an EGFR downstream effector, and the subsequent activation of AKT pathway plays an important role in colorectal carcinogenesis. Considering the frequent co-occurrence of PIK3CA and RAS mutations, conflicting data exist about its impact on prognosis of mCRC patients (pts) and its predictive role to anti-EGFR therapy. However, PI3K inhibitors have been developed and are currently under investigation in mCRC. Methods Data from mCRC pts treated at Azienda Ospedaliero-Universitaria Pisana from 1 Jan 2005 to 31 Dec 2017, whose tumours had been analysed per clinical practice by MALDI-TOF MassArray were retrieved. Association between PIK3CA mutation and clinico-pathological features was analysed by χ2 test; OS curves were estimated with Kaplan-Meier method and compared by log-rank test. Results Tumours from 90 (17%) out of 542 pts included in this analysis were PIK3CA mutated (mut), most of them in exon 9 (58.9%) or 20 (21.1%). Compared to PIK3CA wild-type (wt) tumours, mut ones were more often RAS mut (P = 0.006), MSI high (P = 0.008), and right-sided (P = 0.0004). Among 53 pts for whom PIK3CA status was available on both primary tumours (PT) and metastasis, the concordance was 92.4%. PIK3CA mutations were not associated with OS (36.4 vs 35.9 mos, HR 1.17, 95%CI 0.85-1.62, p = 0.3), with no difference among those affecting exon 9 and 20 (36.4 vs 27.5 mos, HR 0.77, 95%CI 0.39-1.54, p = 0.44). In RAS/BRAF wt (N 188) and in RAS mut (N 299) subgroup, no difference in terms of OS was found between PIK3CA mut and wt pts (38.1 vs 44.4 mos, HR 1.22, 95%CI 0.60-2.48, p = 0.55 and 27.5 vs 34.4 mos, HR 1.26, 95%CI 0.85-1.86, p = 0.22, respectively), though PIK3CA mut had shorter OS. In BRAF mut subgroup (N 54), PIK3CA mut pts had longer OS compared to PIK3CA wt (not reached vs 14.4 mos, HR 0.37, 95%CI 0.16-0.85, p = 0.09). Among 39 chemorefractory RAS/BRAF wt pts evaluable for response to an anti-EGFR agent, only 2 were exon 9 PIK3CA mut and achieved stable disease. Conclusions PIK3CA mut tumours displayed specific clinico-pathological features and a strong concordance was found between PT and paired metastases. Interestingly, a different impact on prognosis of PIK3CA mutation in RAS/BRAF wt, RAS mut or BRAF mut mCRC pts was observed and deserves validation. Legal entity responsible for the study The authors. Funding Supported by ARCO (Associazione Ricerca e Cure in Oncologia) Foundation. Disclosure All authors have declared no conflicts of interest.

Background This study evaluated the safety, tolerability, immunogenicity and initial efficacy of PolyPEPI1018 as an add-on to maintenance therapy in subjects with mCRC. PolyPEPI1018 peptide vaccine contains 12 unique epitopes derived from 7 conserved cancer antigens frequently expressed in mCRC. The predictive value of the novel Personal EPItopes (PEPI) test was also explored. Methods mCRC patients in first line setting received up to 3 doses of PolyPEPI1018 vaccine (0.2 mg/peptide) 12 weeks apart, just after the transition to maintenance therapy with fluoropyrimidine and bevacizumab. Vaccine-specific T cell responses were first predicted by PEPI test (using the patient’s complete HLA genotype) then measured by ELISpot and Intracellular Cytokine Staining (ICS) after one cycle of vaccination. Tumour responses were evaluated by RECIST. Results Eleven patients were vaccinated with PolyPEPI1018. The vaccine was well tolerated; common adverse events were transient skin reactions and flu-like syndrome. No grade 3+ adverse events related to the vaccine occurred. Initial analysis of 8 patients after a single dose demonstrated that 100% of patients had CD4+ T cell response and 75% had CD8+ T cell responses against at least 3 antigens. Both CD8+ and CD4+ T cells were polyfunctional based on the secretion of multiple cytokines determined by ex vivo ICS. PEPI test correctly predicted ELISpot-measured CD8+ T cell responses (PPV = 65%, p = 0.049). Of the 5 patients who received at least 2 doses of the vaccine, 3 experienced Stable disease and 2 had unexpected tumour size reduction. Patients experiencing tumour shrinkage had higher number of predicted antigens than those without tumour response. Conclusions PolyPEPI1018 was safe, well-tolerated and induced unprecedented broad polyfunctional CRC-specific T cell responses, similar to personalized neoantigen vaccines. The candidate biomarker demonstrated high accuracy for the prediction of subject’s vaccine-specific CD8+ T cell responses and indicated patient’s clinical responses. Based on these encouraging results further development of the PolyPEPI1018 vaccine with companion diagnostic is planned. Clinical trial identification NCT03391232. Legal entity responsible for the study TreosBio. Funding Treos Bio. Disclosure J. Hubbard: Research grant / Funding (institution): Taiho Oncology; Research grant / Funding (institution): TreosBio; Advisory / Consultancy, Honoraria to Mayo Clinic: Bayer; Research grant / Funding (institution): Senhwa Pharmaceuticals; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Effector Therapeutics; Research grant / Funding (institution): Merck. E.R. Tőke: Full / Part-time employment: TreosBio. Z. Csiszovszki: Full / Part-time employment: TreosBio. O. Lorincz: Full / Part-time employment: TreosBio. L. Molnar: Full / Part-time employment: TreosBio. E. Somogyi: Full / Part-time employment: TreosBio. M. Megyesi: Full / Part-time employment: TreosBio. K. Pantya: Full / Part-time employment: TreosBio. J. Toth: Full / Part-time employment: TreosBio. P. Pales: Full / Part-time employment: TreosBio. I. Miklos: Full / Part-time employment: TreosBio. All other authors have declared no conflicts of interest.

3540 Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1st-line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1st-line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need. Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/ BRAF wild-type status on tissue samples, who had received a 1st-line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1st-line; time from the last anti-EGFR administration to 1st-line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1st-line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1st-line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (≥ vs. < 18 mos). Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.6 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.49 vs 4.97 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005). Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.

3557 Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequently expressed in mCRC. These epitopes were designed to be Personal EPItopes (PEPIs), i.e. predicted by our novel PEPI test to bind to at least three autologous HLA alleles and more likely to induce T-cell responses than epitopes presented by a single HLA. Methods: mCRC patients in the first line setting received the vaccine (dose: 0.2 mg/peptide) just after the transition to maintenance therapy with a fluoropyrimidine and bevacizumab. Vaccine-specific T-cell responses were first predicted by the PEPI test (using the patient’s complete HLA genotype and antigen expression rate) and then measured by ELISpot after one cycle of vaccination. Results: Eleven patients were vaccinated with PolyPEPI1018. The most common adverse events were transient skin reactions (local inflammation at the site of the injections, e.g. erythema, redness and itchiness) and flu-like syndrome. No grade 3 or higher adverse events related to the vaccine occurred. Initial analysis on 4 patients demonstrated that T-cell responses were elicited by 96% of vaccine peptides. The overall percentage agreement between PEPI test-predicted and Elispot-measured CD8+ T cell responses was 71%, consistent with our retrospective analysis on 64 vaccine clinical trials involving 1,790 patients. Two of these 4 patients had unexpected tumor size reduction. Based on these encouraging results, the trial was amended to administer 3 doses of PolyPEPI1018 given 12 weeks apart. Conclusions: PolyPEPI1018 combined with maintenance therapy was safe and well-tolerated in mCRC patients. Unprecedented immune responses were induced after single dose, with broad CRC-specific T cell responses and high accuracy prediction of CD8+ T cell responses. This promising activity in mCRC patients led to a trial amendment to administer 3 doses of PolyPEPI1018 in combination with systemic therapy. Clinical trial information: NCT03391232.

3534 Background: Based on retrospective experiences, gender seems to affect the safety profile of chemotherapy (CT), with a higher incidence of CT-related adverse events (AEs) among females than males. Here we focus on the impact of gender on the toxicity of FOLFOXIRI/bevacizumab (bev) as compared with doublets (FOLFOX or FOLFIRI)/bev in two randomized phase III studies by GONO: TRIBE and TRIBE2. Methods: The risk of experiencing CT-related AEs in males and females was estimated in univariable analysis in the overall safety population and according to treatment arms (doublets/bev and FOLFOXIRI/bev). In order to assess the independent weight of gender on the risk of developing AEs, multivariable logistic regression models were built. Results: Among 1187 patients enrolled in TRIBE and TRIBE2 studies, 1176 (684 males, 58%, and 492 females, 42%) were included in the safety population. Overall, women had a significantly higher risk of CT-related AEs, in particular gastrointestinal and hematologic AEs, asthenia and alopecia, independently of the treatment arm. The risk of CT-related AEs was increased with FOLFOXIRI/bev vs doublets/bev independently of gender (p for interaction: 0.329). Notably, among women treated with FOLFOXIRI/bev 50% and 68% experienced any grade of vomiting and nausea, respectively. Conclusions: Female mCRC patients have a higher risk to develop CT-related AEs. In women treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis. [Table: see text]

11591 Background: FOLFOXIRI/bev is a valid option as first-line therapy for unresectable mCRC. TRIBE and TRIBE2 trials reported better activity and efficacy of the triplet/bev when compared with doublets/bev at the price of a higher incidence of chemo-related toxicities, including neutropenia (N). Here we aim at providing a detailed description of this adverse event, including the occurrence of febrile neutropenia (FN) and the use of granulocyte-colony stimulating factors (G-CSFs), in order to estimate the clinical relevance of N during FOLFOXIRI/bev. Methods: Safety data of 1175 pts enrolled in the TRIBE and TRIBE2 studies were reviewed. The incidence of N, the incidence and severity of FN, and the use of G-CSF in the triplet/bev and in the doublets/bev arms were compared using the Chi-square or the Fisher exact test as appropriate. Results: Out of 1175 pts included in the final analysis, 586 (49.8%) were treated with FOLFOXIRI/bev. Five pts (0.8%) in the doublets/bev arms and 29 (4.9%) in the triplet/bev arms received a primary prophylaxis with G-CSF. Among other pts, 118 (20.2%) in the doublets/bev arms and 276 (49.9%) in the triplet/bev arms experienced ≥ G3 N (p < 0.001). FN occurred in 25 (4.3%) and 41 (7.4%) cases respectively (p=0.041). Out of 78 FN episodes, 4 (13.3%) out of 30 in the doublets/bev arms and 13 out of 48 (27.1%) in the triplet/bev arms were associated with a poor MASCC score (

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.

Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver-limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, ≥4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was5 cm in 42% of cases, and ≥6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having6 involved segments (p 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35-0.66], p 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22-0.48], p 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p 0.001). The 5-year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464).

Background: The awareness of venous thromboembolism (VTE) burden in ambulatory cancer patients is growing. Due to the heterogeneity in the individual risk profile, predictive risk scores have been proven to be useful in the identification of high-risk patients for targeting thromboprophylaxis. The first validated risk score, the Khorana score, identified four factors resulting in an increased risk for cancer patients to develop VTE. In our study, we tried to identify additional factors associated with VTE to improve the prediction of high-risk patients. Methods: We performed a prospective, observational study in 544 ambulatory patients (56 ± 12 SD y, BMI 27 ± 5 kg/m?, 382 female [70 %]) with solid tumors and ongoing antineoplastic treatments. Tumor sites were breast n=216 (40 %), colo-rectal n=115 (21 %), gyn/uro n=76 (14 %), pancreas n=45 (8 %), gastric n=22 (4 %), lung n=15 (3 %) and others tumors n=55 (10 %). In 264 (52 %) patients there was metastatic disease. We screened for VTE with ultrasound of the upper and lower extremities and correlated cancer-, treatment- and patient-related conditions with the incidence of VTE. Results: We found a VTE incidence of 10 % (n=54), over a median follow up of 10.1 months. According to Khorana score, 51 % of patients (n=247) belonged to the low-risk (score=0), 44 % (n=213) to intermediate-risk (score=1-2) and 6 % (n=27) to high-risk (score?3) class. Odds Ratio for intermediate risk was 1.18 (95% CI 0.65-2.15, p=.588) and 2.66 (95% CI 1.14-6.17, p=.030) for high-risk patients. In our analysis we identified previous VTE (p

INTRODUCTION Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. PATIENTS AND METHODS Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. RESULTS Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09-7.53; p < .0001). CONCLUSION Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. IMPLICATIONS FOR PRACTICE Right- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices.

Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.

Background FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available. Patients and methods A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters. Results Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Kohne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59–0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56–0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81–2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68–1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported. Conclusions Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients. Trialsr numbers NCT01219920 and NCT00719797

Backgroud Metastatic colorectal cancer (mCRC) pts bearing promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), are suitable for treatment with temozolomide (TMZ) with an expected response rate up to 10% even in the chemorefractory setting. Additionally, the reintroduction of a previously used chemoterapeutic agent with potentially retained sensitivity is often used. We hypothesized that the combination of irinotecan, another DNA damaging agent, and TMZ (TEMIRI regimen) in pts with irinotecan-sensitive, MGMT methylated, microsatellite stable (MSS) mCRC may be a novel treatment approach. Methods Pts with mCRC bearing MGMT methylation were identified in two Italian institutions. Key inclusions criteria were: MSS mCRC, progression after at least two prior chemotherapy lines for advanced disease, irinotecan free interval (IFI) ≥ 3 months, as defined by the time elapsed from the last irinotecan-based regimen and the time of progressive disease. MGMT promoter methylation and MSS status were confirmed centrally. Eligible pts received a maximum of 6 cycles of TEMIRI regimen (TMZ 150mg/sqm on days 1-5 plus irinotecan 100mg/sqm on days1,15 every 28 days) followed by maintenance with single-agent TMZ until progression, unacceptable toxicity or consent withdrawal. Primary endpoint of the study was overall response rate (ORR). Setting p0 = 10%, and p1 = 35%, with 1-sided-α and β errors of 0.05 and 0.20, 25 patients were required. Null hypothesis would have been rejected if RECIST response had been observed in at least 6 patients. Exploratory endpoints included the correlation of activity/efficacy parameters with biomarkers, including MGMT immunohistochemistry (IHC) and MethylBEAMing (MB). Results Twenty-five pts were enrolled between December 2014 and June 2017. Seventeen pts (68%) had extensive metastatic disease. The majority of pts was heavily pretreated: 68% received more than 3 lines of therapy. Median IFI was 6.8 months. The primary endpoint was met: partial responses (PR) according to RECIST v1.1 were detected in six out of 25 patients (ORR 24%, 95% CI, 11%-43%). Median progression free survival (PFS) and overall survival (OS) were of 4.4 and 13.8 months, respectively. Treatment was well tolerated with neutropenia being the most common G3-G4 adverse event (8%) followed by diarrhea (4%). MGMT IHC had a negative predictive value of 100% as all pts whose cancer was MGMT-positive were non-responders. Additionally, pts with MGMT-negative/low tumors had a significantly longer mPFS than those with MGMT-positive ones (6.9 versus 2.0 months; HR=0.29, 95%CI, 0.02-0.41; p=0.003) while no significant difference in OS was observed (17.3 versus 13.8 months; HR=0.56, 95%CI: 0.13-1.85; p=0.303). Similarly, patients with methylation percentage ≥63 by MB had a significantly longer mPFS than others (6.6 versus 3.8 months; HR=0.46, 95% CI, 0.13-0.95; p=0.049), with no OS differences (15.5 versus 12.7 months; HR=0.75, 95% CI 0.24-2.11; p=0.327). Conclusions Given the disappointing results of the available treatments in the chemorefractory setting, TEMIRI regimen is a safe and promising approach for pretreated MGMT-methylated, MSS mCRC pts Citation Format: Federica Morano, Salvatore Corallo, Ludovic Barault, Monica Niger, Rosa Berenato, Roberto Moretto, Giovanni Fucà, Giovanni Randon, Maria Antista, Antonino Belfiore, Alessandra Raimondi, Federico Nichetti, Francesca Vita, Federica Perrone, Massimo Milione, Giancarlo Pruneri, Alfredo Falcone, Maria Di Bartolomeo, Federica Di Nicolantonio, Filippo De Braud, Chiara Cremolini, Filippo Pietrantonio. Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients (pts) bearing MGMT methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT095.