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PURPOSE: The European medicines agency (EMEA) has stated that the degree of pre-treatment could modify the patient's tolerance to new treatments in paediatric oncology. It is current practice to divide a phase I trial into two groups to identify the maximum tolerated dose (MTD) in each group separately. The aim of this study was to investigate the relevance of this approach. METHODS: We reanalysed a large phase I trial of Irinotecan that included 80 children (32 heavily pretreated patients and 48 less heavily pretreated). An extended simulation study was performed to investigate the robustness of the conclusions in the context of small sample sizes. Dose recommendations were studied according to scenarios with group differences, as measured by odds ratio (OR), ranging from 1 (no difference) to 10 (large difference) and sample sizes increasing from 20 x 2 to 60 x 2 patients. RESULTS: This study shows a high risk of misidentification of the MTD in each of the two groups, regardless of the group difference. With a group difference corresponding to OR=8 and balanced sample sizes (20 x 2 patients), the same MTD was identified in 11% of the simulations. Even with larger sample sizes (40 x 2 patients), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD (52% for 40 x 2 patients) although the risk is similar in both groups. CONCLUSIONS: Two independent sample designs in paediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data. [ABSTRACT FROM AUTHOR]

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3–17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml×min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients’ characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from −41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was −11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between −7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children. [Copyright &y& Elsevier]

Chemotherapy remains the main tool for the treatment of cancers, but is often hampered by tumor cell resistance. In this context, the transfer of genes able to accentuate the effect of anticancer drugs may constitute a useful approach, as exemplified by inactivation of nuclear factor (NF)-κB via direct transfer of a gene encoding a negative dominant of its natural inhibitor IκB, leading to improved response to cancer chemotherapy. Following our previous report that transfection of human growth hormone (hGH) gene into human monocytic cell lines may also inactivate NF-κB in another situation, we decided to test the consequences of hGH gene transfer on cancer treatments. We demonstrated that hGH-transfected human myeloid leukemia U937 cells were sensitized to an apoptotic signal mediated by the anticancer drugs. In parallel, we found that, by inhibiting degradation of IκB, hGH gene transfer diminished NF-κB entry into the nuclei of U937 cells exposed to daunorubicin. Finally, we report that hGH-transfected tumor cells engrafted in nude mice responded in vivo to chemotherapy with nontoxic doses of daunorubicin whereas, under the same conditions, control tumor cells remained insensitive. Overall, this study therefore suggests that hGH gene transfer may offer new therapeutic prospects in cancer therapy. Cancer Gene Therapy (2002) 9, 497–504 doi:10.1038/sj.cgt.7700467 [ABSTRACT FROM AUTHOR]

Although infants with stage 4 neuroblastoma (NB) usually have a good prognosis, metastatic relapses after 1 year of age and amplification of the N-myc oncogene are established poor prognostic factors. In order to improve the survival of patients with such high-risk factors, we performed consolidation with a busulfan (600 mg/m2)-melphalan (140 mg/m2)-containing regimen followed by autologous stem cell transplantation (SCT). From 1986 to 1998, 12 patients were treated according to this strategy. Their median age at diagnosis was 9 months (1–11). Consolidation was performed after a metastatic relapse in five children, because of persistent bone metastases in one and as first-line consolidation in six patients whose tumor exhibited N-myc amplification. The 5-year EFS rate is 64.5% (36–85%) with a median follow-up of 92 months (20–126). One toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. This busulfan-melphalan combination appears to dramatically improve the prognosis of these high-risk infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high-risk infants and a lower dose of busulfan (480 mg/m2) is recommended in children weighing less than 10 kg. Bone Marrow Transplantation (2000) 25, 937–942. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to study prognostic factors in neuroblastoma patients treated with high-dose chemotherapy and hematopoietic stem cell transplantation. Two hundred and eighteen children over 1 year of age and treated for stage 4 neuroblastoma were enrolled in this study. The median age at diagnosis was 39 months, the sex ratio 1.5 and 84% of patients had an abdominal primary tumor. Skeletal disease was detected in 79% of cases and bone marrow involvement in 93%. N-myc oncogene amplification was present in 27% of the patients studied. The probability of event-free survival at 5 years post-diagnosis was 29% in this series. Three major favorable prognostic factors were significant and independent in the multivariate analysis: age under 2 years at diagnosis (P < 0.01), absence of bone marrow metastases at diagnosis (P < 0.04) and the high-dose conditioning regimen containing busulfan–melphalan combination (P = 0.001). The quality of response to conventional primary chemotherapy was close to significance (P = 0.053). We conclude that factors related to the patient (age) and extent of disease are predictive of outcome in patients with neuroblastoma treated with conventional chemotherapy followed by surgical excision of the primary and consolidation with high-dose chemotherapy. They should be taken into account in future prospective studies. Moreover, the type of conditioning regimen appears to be the most important prognostic factor. This should encourage new investigations into innovative drug combinations. [ABSTRACT FROM AUTHOR]

BACKGROUND Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in (children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS We conducted an open-label, international!, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes maiins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [Cl], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% Cl, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% Cl, 0.15 to 0.66; onesided P=0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were diseaserelated, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatmentrelated) (hazard ratio, 0.36; 95% Cl, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximabchemotherapy group and 24.2% in the chemotherapy group (P=0.G7); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580). [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Methods: Busulfan was administered four times daily for 4days to children aged 0.7–13.1years, either orally (1.45–1.55mg/kg) or by the IV route (0.8–1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Results: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146±187μM.min (range 838–1622), as compared to 953±290μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177±189μM.min versus 913±256μM.min; p =0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. Conclusion: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial. [Copyright &y& Elsevier]

Abstract: Objective: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. Study design and setting: The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. Results: R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. Conclusion: These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed. [Copyright &y& Elsevier]

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support. [ABSTRACT FROM AUTHOR]

In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8–14-fold) as compared to sensitive tumors, and was increased (2–4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN failed to demonstrate implication in resistance to CPT-11 in vitro but could influence sensitivity to CPT-11 exclusively through an in vivo mechanism. Indeed, vasculature was significantly enhanced in resistant NB xenografts compared to sensitive and reverted xenografts, and we suggest that PTN is acting in our resistant in vivo NB model as an angiostatic factor.Oncogene (2006) 25, 3150–3159. doi:10.1038/sj.onc.1209348; published online 27 February 2006 [ABSTRACT FROM AUTHOR]

Abstract: A multidisciplinary therapeutic approach has led to significant increase in survival of children with cancer, however often with a high rate of severe sequela. Better understanding in tumor cell biology and transformation process allowed to describe active tyrosine kinases (mainly growth factor receptors) as a new target for cancer treatment. This review presents 2 approaches to target receptor tyrosine kinase activity: on one hand, antibodies that target the extracellular domain, the natural ligand binding site, and on the other hand, small inhibiting molecules, such as imatinib, targeted against the activated intracellular receptor tyrosine kinase. We focus on their clinical development and current application in the treatment of childhood cancer. Targeted therapies are in full rise and new perspectives are explored, such as their association to other treatment modalities and the targeting of microenvironment. This new therapeutic approach necessitates well designed clinical trials that include relevant biomarkers to evaluate its real therapeutic potential. [Copyright &y& Elsevier]

Childhood cancer is a relatively rare disease, representing just 1% of all malignancies. Within Europe, this represents some 12,000 new cases each year, with approximately 1600 a year in the United Kingdom and 1800 in France. International collaboration in phase III trials of childhood cancer has been the norm for many years, traditionally within Europe, but, largely because of organisational considerations, phase I and II trials have only been conducted on a national basis. With overall cure rates in the region of 70%, relatively few children are available for these early drug trials. Access to new drugs is also a major problem. Against this background, a United Kingdom (UK)/French `new agent'' collaboration was established, expanding subsequently into a wider European grouping. This paper documents the history of that collaboration, the outcomes and future challenges. [Copyright &y& Elsevier]

Summary:A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600?mg?m-2. In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6?h after the 13th dose (6201±607?h?ng?ml-1) than those who did not (5024±978?h?ng?ml-1) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.Bone Marrow Transplantation (2003) 32, 979-986. doi:10.1038/sj.bmt.1704275 [ABSTRACT FROM AUTHOR]

Paediatric medicines are often prescribed off label because appropriate clinical and pharmacological studies have not been conducted in children. A European directive is being written to promote the development of paediatric medicines through incentives to pharmaceutical companies, as is already the case in the US.Method. – In order to evaluate the status of anticancer drugs, we analyzed the paediatric information available in the Vidal® 2000 dictionary for cytotoxic chemotherapy.Results. – Among the 76 products, 48 were currently used to treat children with cancer. An indication for paediatric use was described in only 29% of them. Paediatric use was mentioned in the posology chapter in 56% of cases, and in the warning or contra-indication chapter in 17% of cases. Ten products (21%) were devoid of paediatric information.Discussion. – The paucity of this official paediatric information contrasts with the number of clinical and pharmacological studies that have been conducted and published by paediatric oncology societies and groups. Indeed, almost 80% of children with cancer are treated using prospective therapeutic research protocols. In conclusion, anticancer medicines have been evaluated in children, but official paediatric information is poor. This situation can be significantly improved with the literature currently available. On the other hand, prospective clinical studies are needed to better define the optimal dose in children under one year of age, to evaluate long-term sequelae in cured patients and to provide appropriate galenic forms for oral chemotherapy.Conclusion. – Incentives are urgently needed to facilitate access to therapeutic innovations in oncology and their development in children with cancer. [Copyright &y& Elsevier]

Background The comprehensive genomic profile (CGP) by next generation sequencing (NGS) ctDNA can identify a wide spectrum of GA that range from drivers with approved targeted therapies for routine use to other GA with lack of evidence for actionability. We aimed to assess the clinical utility of NGS-ctDNA based on ESCAT in a large cohort of NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled between 11.2015-05.2019 in the Liquid Biopsy Program in our institution. Plasma ctDNA was collected at diagnosis, under therapy or at progressive disease (PD) and analyzed by InVisionFirstTMLung. We evaluated the detection of driver GA on ctDNA and the clinical utility for accessing targeted therapies approved for routine use (EGFR mutation (m), ALK rearrangement (r), BRAFV600Em, ROS1r), according to ESCAT tiers. Results Preliminary results are available for 308 patients/547 samples (n = 117 untreated; 217 at PD). 58% were females, 42% nonsmokers, with median age of 61 (24-90) and 87% had adenocarcinoma. At diagnosis, ≥1 ctDNA GA was found in 79% (91/115; 2 failed analyses): 29% (26/91) were ESCAT tier I (16 EGFRm ex19/21, 1 ALKr, 1 ROS1r, 8 BRAFV600Em), 2% ESCAT tier II (2 METa ; 1 case co-driver with EGFRm) and 31% tier III (21 KRASm with 8 cases G12C; 5 HER2m, 2EGFRm ex20). ctDNA provided clinically informative results for 33% (38/115). At PD, ≥1 ctDNA GA was found in 75% (163/217); 2 failed analyses): 65% (106/163) in ESCAT tier I (66 EGFRm ex19/21, 7 ALKr, 32 BRAFV600Em, 1 ROS1r), <1% ESCAT tier II (1 METa) and 18% tier III (16 KRASm with 10 cases G12C; 10 HER2m, 3 EGFR others). ctDNA provided clinically informative results for 60% (130/217). We detected EGFR T790M in 49% (17/35) after 1st-2nd generation TKI, C797Sm in 75% (3/4) after Osimertinib and ALK mutations in 4/7 (57%) at TKI failure, with a total of 50% (21/42) cases where ctDNA provided clinical utility. Conclusions ctDNA proved clinically informative results for 33% in untreated patients, most of them ESCAT tier I GA (22%) directing targeted therapies in routine. At time of TKI failure, ctDNA was clinically informative assessing resistance in 50% of EGFR/ALK patients. Legal entity responsible for the study Gustave Roussy. Funding Has not received any funding. Disclosure L. Mezquita: Advisory / Consultancy: Roche Diagnostics; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Tecnofarma; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Travel / Accommodation / Expenses: Chugai. D. Planchard: Advisory / Consultancy: Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. F. de Kievit: Shareholder / Stockholder / Stock options: INIVATA Ltd. L. Lacroix: Advisory / Consultancy: Abbott, Astrazeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ca Bayer Healthcarer, Illumina, Genomic Health, Myriad, Novartis, Pfizer, Roche, Siemens, Thermofisher, VelaDx. J. Remon Masip: Advisory / Consultancy: Pfizer, MSD, BMS, Astrazeneca, Boehringer Ingelheim; Travel / Accommodation / Expenses: OSE Immunotherapeutics, BMS, Astrazeneca, Roche; Honoraria (self): OSE Immunotherapeutics. P. Lavaud: Travel / Accommodation / Expenses: Astellas-Pharma, AstraZeneca, Ipsen, Janssen Oncology, Mundi Pharma. A. Gazzah: Travel / Accommodation / Expenses: Boehringer Ingelheim, Novartis, Pfizer, Roche; Advisory / Consultancy: Novartis; Research grant / Funding (institution), Clinical trials at Gustave Roussy: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies, Drug supply: Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. C. Morris: Shareholder / Stockholder / Stock options: INIVATA Ltd. K. Howarth: Shareholder / Stockholder / Stock options: INIVATA Ltd. E. Green: Shareholder / Stockholder / Stock options: INIVATA Ltd. C. Massard: Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion; Research grant / Funding (institution), Clinical Trials at Gustave Roussy: AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveopharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomed. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma; Research grant / Funding (institution), Clinical Trials at Gustave Roussy: Nerviano, GSK, Pfizer, Roche-Genentech, Lilly, OSE Pharma, MSD, Celgene, Stemcentrx, Ignyta, AbbVie, Loxo Oncology, AstraZeneca, Blueprint Medicines. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Despite a primary benefit, almost all patients (pts) develop acquired resistance to EGFR TKIs. Some mechanisms were related to the selective pressure of the different generations (G) EGFR TKIs, but the complete alteration profile at resistance remains to be elucidated. Methods Metastatic NSCLC pts who performed a tissue and plasma biopsy at EGFR TKI progression, and optionally before, were identified from the prospective MATCH-R trial (NCT02517892). Targeted next-generation sequencing (NGS, 74 to 82 genes), comparative genomic hybridization (CGH), whole-exome sequencing (WES), and RNA sequencing (RNA-Seq) were performed on the tissue. All molecular oncogenic alterations were classified as definitive/potential resistance mechanism or concomitant genetic alterations using OncoKB and Cancer Genome Interpreter. Results Among 62 pts included, tissue analysis at TKI progression was successful with NGS (94%), CGH (76%) and WES+RNA-Seq (53%). In the post 1st-2nd G EGFR TKI cohort (31 pts) the most frequent resistance alteration was p.T790M (n = 23, 74%). EGFR amplification (amp) was found in 7 (23%) pts and off-target mutations (mut) at resistance in 9 (29%, 2 KRAS, 2 JAK2, 1 PIK3CA, and 1 MET). Median PFS to EGFR TKI was 17 months (mo) for the pts with p.T790M as the only resistance mechanism vs 8 mo for the other resistance profiles (HR 2.42 [95% CI, 1.04-5.65]; p = 0.028). In the post 3rd G cohort (31 pts), acquired resistance alterations were mostly on-target (n = 12, 39%): 9 p.C797S, 2 p.L718Q and 1 EGFR amp. Off-target resistance alterations were found in 11 (35%) tumors: 5 fusions involving oncogenes (16%, RET, BRAF, ALK, and FGFR3), 2 BRAF p.V600E (6%), then MET amp, HER2 amp, KRAS mut, and PIK3CA mut in 1 pts (3%). p.T790M loss (54%) was associated with a shorter time to osimertinib discontinuation vs maintained (median 13 vs 22 mo; HR 2.16 (95% CI, 1.00-4.73); p = 0.046). More than one resistance mechanism was found in 12 (39%) and 14 (45%) pts in the post 1st-2nd and 3rd G cohort, respectively. Conclusions Genetic alteration landscape at EGFR TKIs progression is complex and heterogeneous since more than one resistance alteration was recognized in 42% of pts. Combination strategy might be needed. Legal entity responsible for the study Gustave Roussy, Cancer Campus. Funding Gustave Roussy, Cancer Campus. Disclosure Y. Loriot: Honoraria (self): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Pfizer; Honoraria (institution): Roche, MSD, Astellas, Janssen, AstraZeneca, BMS, Seattle Genetics, Sanofi, Clovis, Incyte, Pfizer; Research grant / Funding (institution): Roche, MSD, Sanofi; Travel / Accommodation / Expenses: Roche, MSD, Janssen, AstraZeneca, Seattle Genetics; Licensing / Royalties: Pending patent (USA 62/455211, Europe 17209098.7). D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck, Novartis, prIME Oncology, Pfizer. S. Michiels: Advisory / Consultancy, Punctual statistical advice : IDDI Belgium, Janssen Cilag France; Advisory / Consultancy, Data and Safety Monitoring Member: Hexal, J&J, Ipsen, Neovacs, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis. C. Massard: Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion; Principal/sub-Investigator of Clinical Trials for AbbVie, Agios Pharmaceuticals, Amgen, Argen-X; Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. J-C. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: AstraZeneca and Gritstone. F. André: Research grant / Funding (institution): NVS, AZ, Roche, Daiichi, Lilly, Pfizer. G. Vassal: Advisory / Consultancy, Non-remunerated activity/ies: AstraZeneca, Bayer, BMS, Celgene, Incyte, Ipsen, Lilly, MSD, Merck, Pierre-Fabre, Novartis, Pfizer, Roche/Genentech, Servier, Takeda. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, Ipsen, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]