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Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.

Introduction: Characteristic of some rare pediatric and adult malignancies, addiction to the NTRK oncogene family is also observed in a small fraction of common cancers. Inhibition of their protein products, the Trk kinases, proved a successful treatment strategy for these tumors.Areas covered: The current paper reviews the clinical development of larotrectinib, a selective inhibitor of the Trk kinase family, for the treatment of NTRK fusion-positive cancers. The manuscript includes an overview of the efficacy, safety, pharmacokinetics and pharmacodynamics. The authors sum up by providing the reader with their expert opinion on larotrectinib and its potential future use.Expert opinion: Larotrectinib showed tolerability and high efficacy, regardless of the primary site. In 2018, larotrectinib was granted by the Food and Drug Administration a tissue-agnostic approval for the treatment of solid tumors harboring an NTRK fusion. The major challenges will be the implementation of the screening for NTRK fusions in the general oncologic population, and the incorporation of larotrectinib into the therapeutic algorithms.

AimThe aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens.Study design and methodsClinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1–2), and intensity of chemotherapy regimen (doublet vs. triplet).ResultsAmong 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users.ConclusionIn patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.

Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients’ quality of life without compromising the continuity and efficacy of antineoplastic therapy.

Background Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available. Methods This multicenter, retrospective study aimed at evaluating clinicians’ attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR). Results At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9–35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3–17.7, 86 events), 13.0 (95%CI = 11.4–14.5, 56 events), 14.0 (95%CI = 8.1–20.0, 8 events), and 10.1 months (95%CI = 9.0–11.2, 136 events), respectively (p < 0.001). The median OS values were 39.6 (95%CI = 31.5–47.7, 43 events), 36.1 (95%CI = 31.6–40.7, 36 events), 39.5 (95%CI = 28.2–50.8, 4 events), and 25.1 months (95%CI = 22.6–27.6, 99 events), respectively (p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44–0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51–0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38–0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51–0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts. Conclusion Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a “real-life” setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen.

Background Analysis of deficiency in DNA mismatch repair (dMMR) is currently considered a standard molecular test in all patients with colorectal cancer (CRC) for its implications in screening, prognosis and prediction of benefit from immune checkpoint inhibitors. While the molecular heterogeneity of CRC has been extensively studied in recent years, specific data on dMMR status are lacking, and its clinical consequences are unknown. Case presentation We report the case of a metastatic CRC (mCRC) patient with immunohistochemical and molecular heterogeneity in dMMR/microsatellite instability status in the primary tumour. The patient was treated with nivolumab plus ipilimumab and achieved a deep and lasting response with clear clinical benefit. Whole-exome sequencing and RNA-seq data are reported to support the evidence for molecular heterogeneity. Re-biopsy at the time of progression ruled out the selection of MMR proficient clones as an escape mechanism. A large single-institution retrospective dataset was interrogated to further explore the real incidence of heterogeneity in its different presentations. Conclusions The present case supports the efficacy of immune checkpoint inhibition in mCRC with heterogeneity in MMR/microsatellite instability status. Clinical issues that may arise in these rare patients are discussed in detail.

Background: An accurate risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first-line chemotherapy. Methods: Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS). Results: 114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut-off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (1 (P36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC. Conclusions: We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first-line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.

Background Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking. Patients and Methods Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of “super” responders and “clearly” refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS). Results In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463). Conclusion A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy. Implications for Practice Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability–high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.

Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8–15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the “serrated” CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.

Despite the well-known negative prognostic value of theTwo large retrospective series ofA total of 395These 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.

Background Fluoropyrimidines (FP) are the backbone chemotherapy (CT) for colorectal cancer (CRC). Although the most common toxicities have been extensively studied, FP-induced cardiotoxicity (FIC), an infrequent but potentially life-threatening toxicity, still lacks of a comprehensive characterization. The correlation between FIC and known cardiovascular (CV) risk factors remains controversial and based on retrospective observations. Methods CRC patients (pts) treated for the first time with FP at Candiolo Cancer Institute have been enrolled since January 2016. All pts were screened for potential CV risk factors; if needed, the treatment of preexisting CV comorbidities was optimized before starting CT. During the first 3 CT cycles, a monitoring with CV symptoms collection, seriated electrocardiograms and brain natriuretic peptide (BNP) measurements was performed. Primary objective was to assess the incidence of FIC. Secondary objectives included the analysis of the relationship of FIC with known CV risk factors and BNP levels. Results An interim analysis was conducted on 101 pts (65% male, median age 71.6 years). We found high prevalence of CV risk factors (BMI ≥25 54.2%, smoker 50%, heavy drinker 23%, sedentary lifestyle 63.3%) and comorbidities (diabetes mellitus 19.2%, dyslipidemia 34.7%, arterial hypertension 54%, stroke 3%, coronary artery disease 6%, arrhythmias 8%, heart failure 4%). 19 pts (18.8%) experienced FIC: 1 acute coronary syndrome (ACS), 1 coronary vasospasm, 1 paroxysmal supraventricular tachycardia (PSVT), 1 complete left bundle branch block (LBBB), 2 syncope, 4 typical chest pain, 6 sudden dyspnea, 3 sudden palpitations. After treatment of the CV events, only 3 pts had to discontinue FP (ACS, LBBB and PSTV). Among symptomatic pts, only 47% had CV comorbidities and/or CV risk factors. BNP levels increased on average by 73% [CI 99%: +39% - +106%] after the first cycle. Conclusions A high incidence of CV events, with no apparent correlation with CV comorbidities or risk factors, was observed. Prompt identification and treatment of CV events allowed most pts to complete the treatment with FP. Clinical trial identification NCT02665312. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Aglietta: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche. All other authors have declared no conflicts of interest.

Summary Background We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2 -amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. Methods HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Findings Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. Interpretation The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Funding Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.

Background: Metastatic colorectal cancer still has a dismal 5-yr survival of less than 10%. Chemotherapy, targeted therapies, and immune-checkpoint inhibitors are effective in only a fraction of patients, and even in responders, long-term remission are rare. To harness insight into the evolving heterogeneity of mCRC, and to combat it therapeutically, we have established the logistic research matrix FUNNEL that integrates the topographic acquisition of patient samples with the clinical validation of hypothesis-driven trials in primary or secondary resistance disease. Methods: FUNNEL will follow 1000 sequential cases from diagnosis to death, acquiring biologic specimens, imaging, and clinical data at critical steps along the disease continuum. At diagnosis of metastatic disease, patients are genotyped with a CRC-specific panel designed to map the landscape of primary resistance to anti-EGFR therapies (Bertotti A. et al,, Nature 2015). Paraffin samples are centrally processed and tested using Sequenom® (with a 5% detection sensitivity for 168 mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, HER2, IDH1, MEK1) and NanoString® technologies [measuring gene copy number variation (CNV) for RAF1, EGFR, FGRF1/2/3, HER2, IGF1/2, IGF1R, KRAS, MET, and NF1]. Genes are considered amplified with a CNV ≥ 10 cut-off validated by FISH. Dynamic data of centralized disease assessments imaging coupled with longitudinal liquid biopsies are also collected at significant clinical events (baseline, response to therapy, and progression of sequential treatment’s lines). Proteomics and neoantigenic profile of cancer cells in parallel with function and tumor specificity of infiltrating T cells will also be determined in retrospectively selected patients. Results: From 7/2015 to 6/2017, 428 patients have been successfully genotyped. Overall we found 52% mutated and 6% amplified tumors (2% both amplified and mutated). Of these, 81% (N 180) had a single gene mutation in KRAS (67%), BRAF (13%), PIK3CA (11%), or NRAS (9%). Remaining cases had a double gene alteration in PIK3CA (N 38) and KRAS (81%) or BRAF (7%) or NRAS (5%), or BRAF (N3: KRAS, NRAS, IDH1 ). 29% of the 24 amplified tumors showed concomitant mutations, while 16% had multiple amplifications. Interestingly, 2 out of 13 HER2-amplified tumors also harbored KRAS (G12D) and PIK3CA mutations (E542K and E545A). Conclusion: Upfront genotyping detected 44% multiple wild type and 9% patients with potentially actionable drivers including HER2, FGFR1 and 3, EGFR, MET, IGF1 and 2, and IGF1R. Two embedded trials for HER2-amplified (HERACLES - EudraCT 2012-002128-33, NCT03225937) and multiple wild type patients (CHRONOS EudraCT 2016-002597-12, NCT03227926) are ongoing. Beyond "molecular triage" purposes, FUNNEL is also building an integrated repository of lifetime clinical and molecular information, that all together will allow a comprehensive insight of mCRC clonal evolution, laying the groundwork to design further innovative trials, and, eventually, inform patient care. Funded by AIRC Grant 9970; Italian Ministry of Health grant NET-2011-02352137. Citation Format: Cosimo Martino, Enrico Berrino, Carmine Dell'Aglio, Laura Casorzo, Mara Panero, Salvatore Siena, Andrea Sartore-Bianchi, Andrea Cassingena, Vittorina Zagonel, Sara Lonardi, Fotios Loupakis, Giuseppe Tonini, Patrizia Racca, Livio Trusolino, Andrea Bertotti, Ilaria Depetris, Antonella Balsamo, Anna Sapino, Silvia Marsoni. Empowering precision medicine in metastatic colorectal cancer: preliminary results from the FUNNEL platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A087.

TPS3636Background: The goal of precision medicine is to match a selective drug with a genetic lesion that predicts for drug sensitivity. Over 50% of metastatic colorectal cancer (mCRC) patients (PT...