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Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab., Methods: We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done., Results: Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14-19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders., Conclusion: Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC.EUDRACT 2017-004195-58., Competing Interests: Competing interests: MF: family relation with Merck; AM: Consultancy and Advisory Boards: Roche, AstraZeneca, Boehringer, Pfizer, Takeda, BMS, MSD; EM: Consultancy and Advisory Boards: Eli Lilly, Sanofi, Cellgene, Servier; FC: Advisory Boards: Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly; Institutional Research Grants: Bayer, Roche, Merck, Amgen, AstraZeneca, Ipsen; FM: Advisory Boards MSD, Lilly; Institutional Research Grants: AstraZeneca., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting., Methods: HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1)., Results: Thirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue., Conclusions: HERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource., Trial Registration Number: 2012-002128-33 and NCT03225937., Competing Interests: Competing interests: AS-B is advisory board member for Amgen, Bayer, Sanofi and Servier. SL reports consulting or advisory roles in Amgen, Bayer, Merck, Lilly and Servier; speakers’ bureau roles at Lilly, Roche and BMS, and research funding from Amgen and Merck. VZ is advisory board member for Bristol-Myers Squibb and Merck; speakers’ bureau for AstraZeneca and Lilly; reports personal fees from Bayer, Roche, Servier. FC reported recepit of honoraria or consultation fees for speaker, consultancy or advisory roles at Amgen, Bayer, Bristol-Myers Squibb, Celgene, Merck Serono, Pfizer, Roche, Servier; direct research funding as the principal investigator for institutional research projects from Amgen, Bayer, Merck Serono, Roche, Ipsen; institutional financial interests, financial support for clinical trials or contracted research from Merck Serono, Roche, Symphogen, Array; leadership Positions in Professional Societies (non-financial interests) including ESMO past president, and president of the Associazione Italiana Oncologia Toracica. AAr reports grants and personal fees from BMS, personal fees from MSD, personal fees from Eli-Lilly, personal fees from Boehringer, personal fees from Pfizer, grants from Celgene, grants and personal fees from Roche, outside the submitted work. AAm is advisory Board from Amgen, Roche, Bayer. LT reports grants from Symphogen, grants from Servier, grants from Merus, grants from Pfizer, grants from Menarini, personal fees from AstraZeneca, personal fees from Merck KGaA, personal fees from Eli Lilly, outside the submitted work. SS is advisory board member for Amgen, Bayer, BMS, CheckmAb, Clovis, Daiichi-Sankyo, Merck, Roche-Genentech, Seattle Genetics., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Colorectal cancer is the second leading cause of cancer-related death worldwide. About 20% of patients suffer from metastatic disease at diagnosis, while about one-third of patients treated with curative intent relapsed. In these patients, an accurate staging allows to plan a treatment strategy within a multidisciplinary team in order to achieve predefined goals. Patient's clinical features, tumour characteristics and molecular profile ( RAS/BRAF and microsatellite instability (MSI) status) should be considered during the treatment choice. Combination of chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) plus biological agents (antiepidermal growth factor receptor or antiangiogenic drugs) in addition to surgery, could give a chance of cure in resectable or potentially resectable tumours. However, in never resectable tumours, disease control and prolonging survival should be the goal to achieve simultaneously with control of symptoms. In addition to standard therapies, especially in case of unresectable oligometastatic disease, several local ablative treatment are available. In later lines, when improving quality of life become predominant, regorafenib and trifluridine/tipiracil demonstrated survival benefit, while re-challenge therapies represent an option only in selected patients. In patients with BRAFV600E -mutant tumour or with MSI, new therapies showed survival gain and probably will be a new piece in the treatment algorithm., Competing Interests: Competing interests: TT: Advisory board for Amgen, Bayer, Merck, Novartis, Roche and Sanofi. FC: Advisory board for Merck, Roche, Amgen, Bayer, Servier, Symphogen and Pfizer, and research funding from Roche, Merck, Amgen, Bayer and Ipsen. AC: Institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, BeiGene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas and FibroGen, and advisory board or speaker fees from Merck Serono, Roche, Servier, Takeda and Astellas in the last 5 years., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: The emerging role of next-generation sequencing (NGS) targeted panels is revolutionising our approach to cancer patients, providing information on gene alterations helpful for diagnosis and clinical decision, in a short time and with acceptable costs., Materials and Methods: In this work, we evaluated the clinical application of FoundationOne CDx test, a hybrid capture-based NGS. This test identifies alterations in 324 genes, tumour mutational burden and genomic signatures as microsatellite instability. The decision to obtain the NGS assay for a particular patient was done according to investigator's choice., Results: Overall, 122 tumour specimens were analysed, of which 84 (68.85%) succeeded. The success rate was influenced by type of specimen formalin-fixed paraffin embedded (FFPE block vs FFPE slides), by origin of the sample (surgery vs biopsy) and by time of fixation (<5 years vs ≥5 years). The most frequent subgroups of effective reports derived from colorectal cancer (25 samples), non-small-cell lung cancer (16 samples), ovarian cancer (10 samples), biliary tract cancer (9 samples), breast cancer (7 samples), gastric cancer (7 samples). The most frequent alterations found in whole population referred to TP53 (45.9%), KRAS (19.6%) and APC (13.9%). Furthermore, we performed an analysis of patients in whom this comprehensive genomic profiling (CGP) had a relevance for the patient's disease., Conclusions: On our opinion, CGP could be proposed in clinical practice in order to select patients that could most benefit from the analysis proposed, like patients with good performance status without any available treatments or with unexpected resistance to a therapy., Competing Interests: Competing interests: TT: advisory board for Amgen, Bayer, Merck, Novartis, Roche, Sanofi. FM: advisory board for Lilly, MSD. EM: advisory board for Amgen, Bayer, Merck, Roche, Sanofi, Servier, Biocartis and expert opinion for ESMO (European Society of Medical Oncology). MO: Honoraria from Epionpharma, Italfarmaco and research funding from Eisai, travel and accommodation expenses for meetings rom Roche. FDV: advisory board for Amgen, Lilly, Roche, Celgene. FCi: advisory board for Merck, Roche, Amgen, Bayer, Servier, Symphogen, Pfizer and research funding from Roche, Merck, Amgen, Bayer, Ipsen. FM: BMS, MSD, Astrazeneca, Incyte., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background . Thrombotic microangiopathies (TMA) are relatively rare but severe disorders characterised by non-immune haemolytic anaemia, thrombocytopaenia and organ failure. In patients with metastatic cancer, sporadic forms of TMA can be triggered by chemotherapeutic agents or can occur as complication of malignancy itself or of infections. Case report. Hereby, we report a case of a patient diagnosed with metastatic colorectal cancer who experienced an atypical haemolytic-uraemic syndrome (aHUS) during chemotherapy treatment with FOLFOX6 scheme. The use of eculizumab led to prompt recovery of laboratory parameters that was maintained despite treatment discontinuation due to appearance of pneumonia infectious. Additionally, genetic analyses revealed the presence in heterozygosis of CFH gene polymorphisms associated with aHUS. Conclusion. This case emphasises the importance of considering TMA as a possible diagnosis in patients with cancer presenting with haemolytic non-immune mediate anaemia and thrombocytopaenia associated with worsening of renal function. Prompt diagnosis is crucial for the requirement of its specific treatment that can impact on long-term outcome and prognosis., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Introduction: In the era of precision medicine, research studies are aiming to design patient-tailored treatment strategies. In this work, we present a clinical case of a patient with non-small cell lung cancer (NSCLC) accompanied by a translational study with the intent to assess the correspondence of drug sensitivity in ex vivo spheroidal tumour cultures and peripheral blood biomarkers with clinical outcome., Methods: Primary tumour tissue, patient-derived tumour spheroids, peripheral blood mononuclear cells and circulating DNA were analysed to assess drug sensitivity and immunological profiling, and all these data were correlated with clinical and radiological evaluations., Results: Immunohistochemistry, immunofluorescence, next generation sequencing analysis and T-lymphocyte receptor repertoire assay results showed elevated concordance among primary tumour tissue, ex vivo three-dimensional tumour spheroid specimen and circulating DNA. Cisplatin-based chemotherapy and anti-programmed death 1 drug sensitivity assessed in spheroidal cultures were strictly consistent with patient clinical response to adjuvant chemotherapy and first-line immune therapy., Conclusion: These results revealed that ex vivo drug sensitivity testing in three-dimensional spheroidal culture can reproduce clinical response to chemotherapy and immunotherapy, with the potential to use those culture models to predict patients' outcome from anticancer treatments and, therefore, the feasibility to select individualised therapy., Competing Interests: Competing interests: FC: Advisory Boards: Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly; Institutional Research Grants: Bayer, Roche, Merck, Amgen, AstraZeneca, Ipsen. FM: Advisory Boards MSD, Lilly; Institutional Research Grants: AstraZeneca.

Background: In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate., Methods: We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti-EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebo-controlled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months., Results: The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm., Conclusion: RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance setting., Competing Interests: Competing interests: FC has participated in advisory boards for Merck KgA, Bayer, Amgen, Roche, Servier, Pfizer and he has received instutional research grants from Merck KgA, Bayer, Amgen, Roche, Ipsen. EM has participated in advisory board for Amgen, Bayer, Merck, Roche, Sanofi, Servier and gave expert opinion for European Society of Medical Oncology. TT is in the advisory board for Amgen, Bayer, Merck, Novartis, Roche, Sanofi. RGC has participated in advisory boards or received honorarium from Merck KgA, MSD, Bayer, Amgen, Roche, Servier, Sanofi-Aventis, Pfizer, Ipsen, Novartis, AAA. AC declares institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas and Fibrogen and advisory board or speaker fees from Merck Serono, Roche, Bayer, Servier and Pierre Fabre in the last five years. JF declares consulting and advisory role in Amgen, Ipsen, Eissai, Merck, Roche and Novartis; research funding from Merck; travel and accommodation expenses from Amgen and Servier.

Gastrointestinal (GI) cancers are common in all parts of the world. Effective prevention and early detection of GI cancers are not universally implemented. Therefore, it must be anticipated that the incidence and the mortality of GI cancers will remain high within the next decades. The European Society for Medical Oncology (ESMO) Gastrointestinal Cancer Faculty aims to increase the skills of medical oncologists and other disciplines involved in treating GI malignancies. We aimed to increase the survival chances for patients with GI cancers, augment their quality of life and enable successful return to normal social and professional life during the period of survivorship. ESMO also aims to decrease the economic burden of GI cancer in our societies and national healthcare systems. Therefore, the ESMO Gastrointestinal Cancer Faculty initiated a consensus process based on the Delphi method to identify the most important educational needs of physicians who are concerned with GI malignancies. This paper summarises the process and its results and outlines the mission of ESMO in education., Competing Interests: Competing interests: FL reports receiving grants, personal fees and non-financial support from BMS; and personal fees from Astellas, Astra Zeneca, Biontech, Eli Lilly, Elsevier, Infomedica, Merck, MSD, Roche, Servier and Amgen outside the submitted work. EVC reports participation in advisory boards for Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier, and receiving research grants from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier paid to the institution outside the submitted work. JT reports personal fees and others from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics outside the submitted work. FC reports receiving personal fees from Roche/Genentech, Merck Serono, Pfizer, Amgen, Servier, Lilly, Bayer, Bristol-Myers Squibb and Celgene; and grants from Bayer, Amgen, and Merck Serono outside the submitted work. AC reports having a consultant or advisory role at Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas and Pierre Fabre; receiving research funding from Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD and Pierre Fabre; receiving speaker honoraria from Merck Serono, Roche, Angem, Bayer, Servier and Foundation Medicine; and receiving grant support from Merck Serono and Roche. RO, DV, JYD and KMG have no conflict of interest to declare.

Although lung cancer remains the leading cause of death from cancer worldwide, the advent of immunotherapy is changing the survival of patients affected by non-small cell lung cancer (NSCLC). A multitude of clinical trials are evaluating different immune checkpoints inhibitors in this new field of thoracic oncology. At the beginning of the immunotherapy era, nivolumab, pembrolizumab and atezolizumab showed high efficacy in patients with advanced NSCLC in second-line setting, receiving approvals for clinical practice. Nivolumab and atezolizumab are approved independently from programmed death lig and 1 (PD-L1) expression, while pembrolizumab is currently approved only for patients with PD-L1 expression ≥1%. The role of PD-L1 expression acquired more interest considering first-line clinical trials, in which the role of immunotherapy as monotherapy was confirmed only for pembrolizumab in patients with PD-L1 expression ≥50%. These data were analysed in this paper, focusing on the implications in clinical practice and how to use them to an accurate clinical benefit of patients with advanced NSCLC. We report a review based on a MEDLINE/PubMed, searched for randomised phase 2/3 trials evaluating immune checkpoint inhibitors and NSCLC, that moved to an approval from Food and Drug Administration (FDA) and European Medicine Agency (EMA). The evidence discussed in this manuscript and the final therapeutic algorithm, coming out from an International Experts Panel Meeting of the Italian Association of Thoracic Oncology., Competing Interests: Competing interests: FdM received honoraria from BMS, Roche, Pfizer, AstraZeneca, Celgene, MDS, Boehringer and Novartis. PB has received research grants from or has served as a consultant for Merck, Bristol-Meyers Squibb, Polaris and Pfizer. MDH received honoraria from Genentech, Merck, AstraZeneca, Novartis, Janssen and Mirati. TSKM received honoraria from AstraZeneca, Roche Genentech, Eli Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Novartis, MSD and Pfizer. HL receiving honoraria from Novartis, Bristol-Myers Squibb, Lilly, Pierre Fabre Oncologie, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Roche and Amgen. LP-A receiving honoraria AstraZeneca, Pfizer, Bristol-Myers Squibb, MerckSharp & Dohme, Lilly, Roche, Merck Serono, Novartis and Boehringer Ingelheim. DR-A receiving advisory fees from MSD, Bristol-Myers Squibb, Roche and Boehringer Ingelheim.

The cancer burden is rising globally, exerting significant strain on populations and health systems at all income levels. In May 2017, world governments made a commitment to further invest in cancer control as a public health priority, passing the World Health Assembly Resolution 70.12 on cancer prevention and control within an integrated approach. In this manuscript, the 2016 European Society for Medical Oncology Leadership Generation Programme participants propose a strategic framework that is in line with the 2017 WHO Cancer Resolution and consistent with the principle of universal health coverage, which ensures access to optimal cancer care for all people because health is a basic human right. The time for action is now to reduce barriers and provide the highest possible quality cancer care to everyone regardless of circumstance, precondition or geographic location. The national actions and the policy recommendations in this paper set forth the vision of its authors for the future of global cancer control at the national level, where the WHO Cancer Resolution must be implemented if we are to reduce the cancer burden, avoid unnecessary suffering and save as many lives as possible., Competing Interests: Competing interests: AE: Currently conducting research sponsored by AstraZeneca, Pfizer, Celltrion, Novartis, Roche. JT: Advisory Boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. FCi: Advisory Boards: Merck Serono, Amgen, Roche, Bayer, Lilly, Servier. Research funding: Bayer, Roche, Merck Serono. GP: Honorarium for advisory boards or speakers fee: Roche, Celgene, Shire, Merck, Amgen, Lilly, BMS, Servier, Taiho, Halozyme, Sanofi. PC: Honoraria for consultancy/advisory role and/or for lectures from: Bayer, Blueprint Medicines, Deciphera Pharmaceuticals, Eisai, Eli Lilly, Nektar Ther., Novartis, Pfizer, PharmaMar. At his institution, his Unit received funds for research from: AmgenDompé, Arog Pharmaceuticals, Bayer, Eisai, Eli Lilly, Daiichi Sankyo Pharma, Epizyme Inc., Novartis, PharmaMar. MS: Conducts research sponsored by Janssen Pharmaceuticals. Advisory Boards: BMS, Novartis, Janssen Pharmaceuticals, Leo Pharma. Speaker bureau for BMA, Novartis. Travel funding: Novartis, BMS, Astellas, Ipsen. All other authors declare no competing interests related to this paper.

Background: Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients., Patient and Methods: HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay)., Results: We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease., Conclusion: The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy., Competing Interests: Competing interests: None declared.

Background: TAS-102 improves overall survival (OS) in patients with metastatic colorectal cancer (mCRC) refractory to standard treatments. However, predictive biomarkers of efficacy are currently lacking., Patients and Methods: We treated a cohort of 43 chemorefractory mCRC patients treated with TAS-102, in a single institution expanded access, compassionate use programme. We stratified patients in two groups according to number of cycles received (<6 cycles and ≥6 cycles). OS, progression-free survival (PFS) and safety were evaluated., Results: Thirteen out of 43 patients (30%) obtained a clinically relevant disease control with TAS-102 therapy. Eleven of them were treated for ≥6 cycles with TAS-102, reaching a median PFS of 7.5 months (95% CI 5.8 to 9.2 months) and a median OS of 11.2 months (95% CI range not reached yet). A trend towards significance (p=0.08) between a good performance status and response to TAS-102 was observed. Further, 7 out of the 11 TAS-102 long-treated patients achieved a clinical benefit from a previous treatment with regorafenib. A significant correlation between regorafenib and TAS-102 clinical efficacy was observed (p=0.008). Six out 13 regorafenib-naïve patients were treated with regorafenib after progression from TAS-102. All these patients achieved SD with a median duration of treatment with regorafenib of 6.1 months (range, 1.6-6.7)., Conclusion: Patients with mCRC in good clinical conditions, even though having been heavily pretreated with all the available treatment options, could obtain a significant clinical benefit from treatment with TAS-102. Moreover, a previous clinical benefit obtained with regorafenib is potentially predictive of clinical efficacy of subsequent TAS-102 treatment., Competing Interests: Competing interests: None declared.

Background: To investigate the potential predictors of response to regorafenib, in chemorefractory metastatic colorectal cancer (mCRC) patients with long-term efficacy from regorafenib treatment., Methods: Retrospective, single institution analysis of patients with chemorefractory mCRC treated with regorafenib, in clinical practice setting. 123 patients were treated and stratified into two groups according to number of cycles received (<7 and ≥7). Overall survival (OS), progression-free survival (PFS) and safety were evaluated. 20 tumour samples (10 poor and 10 long responders) were analysed with the OncoMine Comprehensive Assay for 143 genes., Results: A good Eastern Cooperative Oncology Group performance status, a lung limited metastatic disease and a long history of metastatic disease were significantly associated with better OS and PFS from treatment with regorafenib. Mutations were mostly found in TP53 , KRAS and PIK3CA as well as in NRAS , ERBB2, SMAD4 and PTEN genes. BCL2L1, ERBB2, KRAS, MYC, GAS6 gene amplifications were detected as well as ALK rearrangement. No significant correlation between molecular alterations and response to regorafenib was observed. However, HER2 gene alterations were found in three poor responder patients, suggesting a potential role in regorafenib resistance. Conversely, GAS6 amplification and SMAD4 mutation, detected in two long responder patients, might suggest a role of epithelial-mesenchymal transition phenotype in regorafenib response., Conclusion: A subgroup of long responder patients to regorafenib treatment was identified and a comprehensive molecular characterisation was performed; however, further research efforts are essential to confirm our data., Competing Interests: Competing interests: None declared.

Background: On the basis of the results of two pivotal phase III clinical trials, eribulin mesylate is currently approved in EU for the treatment of advanced breast cancer (aBC) in patients who have previously received an anthracycline and a taxane in either the adjuvant or the metastatic setting, and at least one chemotherapeutic regimen for metastatic disease., Methods: In our study, we investigated the efficacy and tolerability of eribulin as second or further line chemotherapy in 137 women affected by aBC., Results: Eribulin as monotherapy provided benefit in terms of progression-free survival (PFS), response rate (RR) and disease control rate (DCR) independently of its use as second or late-line therapy. The overall RR and DCR were 17.5% and 64%, respectively. In particular, DCR and overall RR were 50% and 13.6%, 65.4% and 21.1%, 70.4% and 14.8% and 66.7% and 16.7% in second, third, fourth and further lines of treatment, respectively. Median PFS (mPFS) according to the line of therapy was 5.7, 6.3, 4.5 and 4.0 months in patients treated with eribulin in second, third, fourth and over the fourth line, respectively. No significant difference in terms of mPFS was found between the various BC subtypes. Overall, eribulin resulted safe and most adverse events were of grade 1 or 2 and easily manageable. Grades 3-4 toxicities were neutropaenia and neurotoxicity., Conclusions: With the limitations due to the observational nature of our findings, eribulin was shown to be an effective and safe therapeutic option in heavily pretreated patients with aBC., Competing Interests: Competing interests: None declared.

Purpose: Our previous works demonstrated the ability of metformin to revert resistance to gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in non-small-cell lung cancer (NSCLC) EGFR/LKB1 wild-type (WT) cell lines. However, the optimal dose of metformin to be used in non-diabetic patients still remains to be defined. The phase I-II trial METformin in Advanced Lung cancer (METAL) was designed to identify the maximum tolerated dose and to evaluate safety and activity of metformin combined with erlotinib in second-line treatment of patients with stage IV NSCLC, whose tumours harbour the WT EGFR gene., Patients and Methods: We report results from the safety run-in part designed to detect acute toxicities, to study pharmacokinetics and to identify the recommended phase II dose (RPD) to be used for the following phase of the study. In the run-in phase, metformin treatment was administered according to a dose escalation scheme and, subsequently, combined with erlotinib., Results: Twelve patients were enrolled. Common adverse events were diarrhoea, decreased appetite, abdominal pain, vomiting and skin toxicity, mostly reversible with symptomatic medical treatment. Dose-limiting toxicities were vomiting and diarrhoea registered in the initial cohort receiving metformin 2000 mg plus erlotinib at 150 mg die, which was declared the maximum administered dose. Only one of nine patients treated at the next lower dose of 1500 mg of metformin plus erlotinib at 150 mg experienced G3 gastrointestinal toxicity. Metformin plasma-concentration profile confirmed the trend already observed in non-diabetic population. Glycemic profiles showed stability of the blood glucose level within the physiological range for non-diabetic subjects. At a follow-up of 30 weeks, six (50%) patients experienced a disease control (5 SD and 1 partial response)., Conclusions: The RP2D of metformin dose was defined at 1500 mg/day to be combined with erlotinib 150 mg., Trial Registration Number: EudraCT number: 2014-000349-59., Competing Interests: Competing interests: None declared.

Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups., Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years)., Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years., Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years., Trial Registration Number: 2009-014041-81., Competing Interests: Competing interests: None declared.

Biosimilars present a necessary and timely opportunity for physicians, patients and healthcare systems. If suitably developed clinically, manufactured to the correct standards and used appropriately, they can positively impact on the financial sustainability of healthcare systems. A critical consideration regarding the introduction of biosimilars into the clinic centres on the required information concerning all the respective procedures. This position paper aims to describe the issues revolving around biosimilars that are relevant to the field of oncology, especially the prescribers. More specifically, we discuss aspects related to definition, forms of biosimilars, labelling, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, responsibilities among prescribers and pharmacists, potential impact on financial burden in healthcare and the current scenario and future prospects of biosimilars in Europe and the rest of the world., Competing Interests: Competing interests: JT serves on advisory boards for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho and Takeda. DA has, in the last 2 years, participated in advisory boards and/or acted as a speaker at meetings and/or recipient of travel support for participation in medical meetings for/from Roche, Merck Serono, Amgen, Bayer Healthcare, Sanofi-Aventis, Terumo and Sirtex. AC has acted as a consultant or advisor to Amgen, AstraZeneca, Sanofi-Aventis, Merck Serono, MSD, Genentech and Roche.

The European Society for Medical Oncology (ESMO) is one of the leading societies of oncology professionals in the world. Approximately 30% of the 13 000 ESMO members are below the age of 40 and thus meet the society's definition of young oncologists (YOs). ESMO has identified the training and development of YOs as a priority and has therefore established a comprehensive career development programme. This includes a leadership development programme to help identify and develop the future leaders in oncology. Well-trained and highly motivated future generations of multidisciplinary oncologists are essential to ensure the optimal evolution of the field of oncology with the ultimate goal of providing the best possible care to patients with cancer. ESMO's career development portfolio is managed and continuously optimised by several dedicated committees composed of ESMO officers and is directly supervised by the ESMO Executive Board and the ESMO President. It offers unique resources for YOs at all stages of training and includes a broad variety of fellowship opportunities, educational courses, scientific meetings, publications and resources. In this article, we provide an overview of the activities and career development opportunities provided by ESMO to the next generation of oncologists., Competing Interests: Competing interests: None declared.

Epidermal growth factor receptor (EGFR) plays a key role in tumour evolution, proliferation and immune evasion, and is one of the most important targets for biological therapy, especially for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). In the past 15 years, several EGFR antagonists have been approved for the treatment of NSCLC and metastatic CRC (mCRC). To optimise the use of anti-EGFR agents in clinical practice, various clinical and molecular biomarkers have been investigated, thus moving their indication from unselected to selected populations. Nowadays, anti-EGFR drugs represent a gold-standard therapy for metastatic NSCLC harbouring EGFR activating mutation and for RAS wild-type mCRC. Their clinical efficacy is limited by the presence of intrinsic resistance or the onset of acquired resistance. In this review, we provide an overview of the antitumour activity of EGFR inhibitors in NSCLC and CRC and of mechanisms of resistance, focusing on the development of a personalised approach through 15 years of preclinical and clinical research., Competing Interests: Conflicts of Interest: None declared.

Despite the improvement in clinical outcomes derived by the introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumours harbour EGFR-activating mutations, prognosis remains unfavourable because of the occurrence of either intrinsic or acquired resistance. We reviewed the published literature and abstracts of oral and poster presentations from international conferences addressing EGFR-TKIs resistance mechanisms discovered in preclinical models and in patients with NSCLC. The molecular heterogeneity of lung cancer has several implications in terms of possible mechanisms of either intrinsic or acquired resistance to EGFR-targeted inhibitors. Several mechanisms of resistance have been described to EGFR-TKIs, such as the occurrence of secondary mutation (T790M, C797S), the activation of alternative signalling (Met, HGF, AXL, Hh, IGF-1R), the aberrance of the downstream pathways (AKT mutations, loss of PTEN), the impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism) and histological transformation. Although some of the mechanisms of resistance have been identified, much additional information is needed to understand and overcome resistance to EGFR-TKI agents. The majority of resistance mechanisms described are the result of a selection of pre-existing clones; thus, studies on the mechanisms by which subclonal alterations have an impact on tumour biology and influence cancer progression are extremely important in order to define the best treatment strategy., Competing Interests: Conflicts of Interest: None declared.

Objective: To assess the correlation between presurgery neutrophil to lymphocyte ratio (NLR) and distant metastasis-free survival (DMFS) in patients with early breast cancer., Design: Retrospective analysis., Participants: 300 Caucasian patients with early (T1-2, N0-1, non-metastatic) breast cancer who were followed from July 1999 to June 2015 at our Institution., Main Outcome Measures: Distant metastasis-free survival (DMFS)., Results: Of whole populations (300 patients), 134 and 166 patients were grouped as low and high NLR, respectively, on the basis of NLR value of 1.97, as established by receiver operating characteristic (ROC) curve analysis (area under curve (AUC)=0.625, p=0.0160). The DMFS rates for 1, 3, 6, 9, 12 and 15 years were better in low NLR patients (100%, 98.9%, 91.7%, 82.7%, 82.7%, 82.7%, respectively), than in high NLR patients (99.4%, 94.3%, 84.5%, 69.2%, 66.0%, 51.4%, respectively), with a statistically significant association. On multivariate analysis, premenopausal status (HR=2.78, 95% CI 1.36 to 5.67, p=0.0049), N1 stage (HR=2.31, 95% CI 1.16 to 4.60, p=0.0167) and a high NLR value (HR=2.64, 95% CI 1.22 to 5.638, p=0.0133) were shown to be independent prognostic factors related to poor recurrence rate. To avoid risk of confounding bias, a propensity score-matched analysis was performed and multivariate analysis according to the Cox model confirmed premenopausal status (HR=2.94, 95% CI 1.25 to 6.93, p=0.0136), N1 stage (HR=2.77, 95% CI 1.25 to 6.12, p=0.0117) and high NLR values (HR=2.52, 95% CI 1.11 to 5.73, p=0.0271), as independent prognostic variables of worse outcome., Conclusions: This is the first study, to our knowledge, to show a significant correlation between high NLR and worse prognosis in Caucasian patients with early breast cancer by means of propensity score-matched analysis. Further well designed prospective trials with a large sample size are needed to verify our findings and to justify introducing NLR assessment in clinical practice for prediction of cancer recurrence., Competing Interests: Conflicts of Interest: None declared.