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Background This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1,n=6; cohort 2,n=14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3–84.7%) in cohort 1 and 14.3% (2.6–38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1,n=3; cohort 2,n=2). Median PFS (90% CI) was 32.1 (5.0–35.9) weeks in cohort 1 and 6.1 (5.7–6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4–49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier NCT01316263.

Background: The Wee1 tyrosine kinase is activated upon DNA damage and regulates the G2-M cell cycle checkpoint Inhibition of Wee1, in conjunction with additional genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, being an attractive approach for treating cancer Debio 0123 is a potent and highly specific WEE1 inhibitor with an IC50 in the low nanomolar range Debio 0123 was demonstrated to inhibit phospho-CDC2 which translated into an increase in DNA damage and premature entry into mitosis (AACR 2019, abstract 4423) Debio 0123 combination with carboplatin (CbPt) was synergic in vitro In vivo, Debio 0123 was demonstrated to increase antitumoral activity of cbPt in models where neither agent was active alone Trial design: Methods This is a phase I, multi-center, open-label, dose escalation study of Debio 0123 as monotherapy (first cycle only) and in combination with CbPt, from cycle 2 in subjects with advanced solid tumors that recurred or progressed following prior platinum therapy Primary objective: determination of the recommended phase II dose (RP2D) of Debio 0123 when administered in combination with CbPt using a modified Continual Reassessment Method (mCRM) Patients receive Debio 0123 orally once daily for the first 3 days of a 21 day-cycle as monotherapy during first cycle and in combination with CbPt in following cycles Secondary objectives: includes determination of occurrence of dose-limiting toxicities (DLT) and characterization of the pharmacokinetics of Debio 0123 and its active metabolite, which are evaluated after single and repeated administration when administered alone or in combination with CbPt Potential risk of QTc prolongation is evaluated by exposure-response modeling Pharmacodynamics biomarkers including phospho-CDC2 are explored in pre- and post-treatment tumors and skin biopsies Recruitment started in July 2019 Cohort 2 has been completed Start of enrollment into cohort 3 is currently unknow due to COVID-19 but will begin as soon as possible Clinical trial identification: NCT03968653 Legal entity responsible for the study: Debiopharm Interbational S A Funding: Debiopharm International S A Disclosure: V Nicolas: Full/Part-time employment: Debiopharm AS A Vaslin: Full/Part-time employment: Debiopharm AS K Tobal: Full/Part-time employment: Debiopharm AS D Purcea: Full/Part-time employment: Debiopharm AS S F van Haren: Full/Part-time employment: Debiopharm AS L Damstrup: Full/Part-time employment: Debiopharm International S A All other authors have declared no conflicts of interest

Background Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anti-cancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Methods We initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anti-cancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anti-cancer drugs are available. Results Here, we show an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 34% in the first 215 treated patients. This comprised 136 patients who received targeted therapies, and 79 patients who received immunotherapy. Overall median clinical benefit duration was nine months (95% CI 8 – 11 months), including 26 patients with ongoing clinical benefit at data cutoff. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab, and a cohort of colorectal cancer patients with relatively low mutational load with limited clinical benefit from immunotherapy. Conclusions The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Legal entity responsible for the study Netherlands Cancer Institute. Funding Hartwig Medical Foundation, Dutch Cancer Society, Barcode for Life, Roche, Novartis, MSD, GSK, Pfizer, AstraZeneca, BMS. Disclosure E.E. Voest: Research grant / Funding (self), Legally responsible for all contracts: All pharma. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Sanofi. M. Chalabi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Netherlands Cancer Institute. E.F. Smit: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Novartis ; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution), Research grant / Funding (institution): Roche Genentech; Honoraria (institution): Seattle Genetics. N. Mehra: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Cuppen: Honoraria (institution), Advisory / Consultancy: Illumina; Honoraria (self), Advisory / Consultancy: InteRNA Technologies; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. H.M.W. Verheul: Honoraria (institution), Advisory / Consultancy: Glycostem; Honoraria (institution), Advisory / Consultancy: Lava Therapeutics. H. Gelderblom: Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. All other authors have declared no conflicts of interest.

Background GIST in older adults and in children are well-known entities, but this is not the case for AYA patients with GIST. Typically, GIST in children (70% female) rarely show mutations in KIT or platelet-derived growth factor receptor (PDGFR) ( Methods AYA GIST patients (18-40 years at diagnosis) diagnosed between 2009-2019 and registered in the Dutch GIST Registry (DGR) were included. Patients without mutations in KIT/PDGFR/BRAF and SDH deficiency (by immunohistochemistry) were considered quadruple wildtype (WT). Overall survival (OS) was estimated using Kaplan-Meier method. Furthermore, two subgroups were compared: 18-29 years vs. 30-40 years (Chi-square, Fisher’s exact, Mann-Whitney U test). Results From 1011 patients in the DGR, 52 AYA patients (5%) were identified: 54% male, median age 35 years. Main primary tumor locations were stomach (46%) and small intestine (46%). Four AYA patients had a known genetic predisposition: 2 Neurofibromatosis 1 (NF1), 1 Carney Triad, 1 KIT exon 11 germline mutation. GIST genetic profiles were reported as KIT mutation 64%, PDGFR mutation 6%, KIT/PDGFR WT 6%, quadruple WT 8%, SDH deficient 6% and NF1 associated 4%. At diagnosis, 42% had high-risk GIST and 13% metastatic disease. With a median follow-up of 43 months (0-113), median OS for all patients was 8.9 years with a 5-year survival of 85%. No significant differences were found between the two subgroups with regard to gender, location, size, morphology, risk classification and mutation status. Conclusions GIST presenting at AYA age is rare. AYA GIST differ from the well-known paediatric GIST, but are also not fully similar to the typical adult GIST. In our series a remarkable high percentage of small intestine GIST and high-risk tumours were observed, 30% non-KIT/PDGFR mutations and a relatively good survival. Legal entity responsible for the study The Netherlands Cancer Institute. Funding An unrestricted research grant for the Dutch GIST Registry was received from Novartis, Bayer and Pfizer. Disclosure I.M.E. Desar: Research grant / Funding (institution): Novartis; Advisory / Consultancy, advisory board: Eisai; Advisory / Consultancy, advisory board: Lilly. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (institution), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merus. W.T.A. van der Graaf: Research grant / Funding (institution): Novartis; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Background Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK). Even though exposure has been linked to efficacy and toxicity for many of these drugs, they are still dosed using a one-size-fits-all approach. Consequently, individual patients (pts) have a high probability to be either underdosed or overdosed, potentially leading to decreased antitumor efficacy or increased toxicity. Therapeutic drug monitoring (TDM), which is personalised dosing based on measured drug levels, can be used to address these problems and thereby optimize treatment outcomes. Methods This prospective clinical study (www.trialregister.nl, NL6695) evaluates the feasibility, tolerability and efficacy of TDM of oral anticancer drugs. In total, 600 pts will be included for 23 different drugs. Pts starting regular treatment with one of these drugs at the approved dose are included. PK sampling is performed 4, 8, and 12 weeks after start of treatment and every 12 weeks thereafter. Drug concentrations are measured and trough concentrations (Cmin) are estimated. In case of Cmin below the predefined target and acceptable toxicity, a PK-guided intervention is recommended. This may include emphasizing compliance, adaptations in concomitant medication (due to drug-drug interactions), concomitant intake with food, splitting intake moments or dose increments. Results In total, 274 pts were included (trametinib (n = 43), abiraterone (n = 38), enzalutamide (n = 35), imatinib (n = 33), pazopanib (n = 23), other (n = 102)), of whom 246 pts had available PK data. 83 pts (34%) were underdosed and had ≥ 1 PK samples below the predefined target. In 48 of 246 pts (20%) a PK-guided intervention was performed, which was successful (i.e. target attainment without additional toxicities) in 39 pts (81%). In 35 pts, a PK-guided intervention could not be performed, due to toxicity (17 pts), logistical reasons (13 pts) or lack of physician adherence (5 pts). Conclusions This prospective study shows that PK-guided dose optimization of oral anticancer drugs is feasible in clinical practice. A PK-guided intervention was recommended in 20% of the patients and resulted in target attainment without additional toxicities in 81% of these patients. Clinical trial identification NL6695; release date: 6 December 2017. Legal entity responsible for the study Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital. Funding Unrestricted research grant of Novartis, Pfizer and Roche. Disclosure S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. D.J.A.R. Moes: Advisory / Consultancy: Sandoz; Advisory / Consultancy, Research grant / Funding (institution): Chiesi Pharmaceuticals. I.M.E. Desar: Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Eisai. D.J. Touw: Advisory / Consultancy: Sanguin; Research grant / Funding (institution): Chiesi Pharmaceuticals. N.P. van Erp: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Gilead. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (institution), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.

Background Around half of patients with intermediate or high-grade soft tissue sarcomas (STS) will develop advanced disease. The mainstay of treatment for advanced STS is chemotherapy. Although treatment intent is usually palliative, the degree to which chemotherapy affects symptoms of disease, patient functioning and health-related quality of life (HRQoL) is rarely measured nor incorporated into clinical trials. Radiological response rates, time to progression and survival are traditionally used to measure treatment benefit. Therapeutic decisions are often challenging due to modest response rates and treatment-related adverse events. HRQoL is perceived by some patients as of equal- or greater importance than survival. Clinicians should be able to provide HRQoL data to patients to enhance the shared decision-making process and encourage a holistic approach to care. The aim of this study is to assess HRQoL in patients with advanced STS treated with 1st line chemotherapy, explore the decision-making process and evaluate patient post-treatment reflection. Trial design This is a longitudinal cohort study for patients aged ≥18 years with advanced STS (n = 132) who are treated with 1st line chemotherapy. Patients from 8 centres (United Kingdom 3, The Netherlands 5) are invited to complete questionnaires at baseline, each cycle of chemotherapy and three-monthly during follow-up. Data collection will be done within PROFILES, an established international registry for cancer patient reported outcomes. Questionnaires include patient demographics, decisional conflict scale, control preferences scale, quality-quantity questionnaire, treatment expectations, EORTC-QLQ-C30, FACT-G (2 items), work-ability index, financial toxicity and decisional regret scale. Clinical details, such as STS histology, will be collected from patient records and linked to questionnaire data. The primary endpoint is change in global HRQoL from baseline to Cycle 4 of chemotherapy. Exploratory endpoints include HRQoL functioning scales and symptoms. Recruitment started February 2018; 57 patients have completed (at least) the baseline questionnaire. (May 2019). Clinical trial identification NCT03621332. Legal entity responsible for the study Institute of Cancer Research, London, United Kingdom and Radboud UMC, Nijmegen, Netherlands. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Our aim was to investigate severe toxicity in DPYD variant allele carriers receiving CRT. Methods Medical records of 828 patients who received FP-based CRT were reviewed from three centres. Severe (grade ≥III) toxicity in DPYD variant allele carriers receiving upfront FP dose reductions according to pharmacogenetic dosing guidelines and DPYD variant allele carriers not receiving FP dose reductions was compared with DPYD wild-type patients receiving standard dose of FPs in CRT. Results DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, confidence interval [CI] = 1.02–6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, CI = 1.32–13.25, P = 0.015) toxicity compared with wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity compared with wild-type patients, but more (not statistically significant) severe haematological toxicity. Hospitalisations for all DPYD variant allele carriers were comparable, independent of dose adjustments; however, the mean duration of hospitalisation was significantly shorter in the dose reduction group (P = 0.010). Conclusions Standard FP dosages in CRT resulted in an increased risk of severe toxicity in DPYD variant allele carriers. We advise to apply FP dose reductions according to current guidelines in DPYD variant allele carriers starting CRT.

Background: Many adverse events (AEs) associated with aromatase inhibitors (AIs) involve symptoms related to the depletion of circulating estrogens, and may be related to efficacy. We assessed the relationship between specific AEs [hot flashes (HF) and musculoskeletal AEs (MSAE)] and survival outcomes in Dutch and Belgian patients treated with exemestane (EXE) in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Additionally, the relationship between hormone receptor expression and AEs was assessed. Methods: Efficacy end points were relapse-free survival (RFS), overall survival (OS) and breast cancer-specific mortality (BCSM), starting at 6 months after starting EXE treatment. AEs reported in the first 6 months of treatment were included. Specific AEs comprised HF and/or MSAE. Landmark analyses and Cox proportional hazards models assessed survival differences up to 5 years. Results: A total of 1485 EXE patients were included. Patients with HF had a better RFS than patients without HF [multivariate hazard ratio (HR) 0.393, 95% confidence interval (CI) 0.19–0.813; P= 0.012]. The occurrence of MSAE versus no MSAE did not relate to better RFS (multivariate HR 0.677, 95% CI 0.392–1.169; P = 0.162). Trends were maintained for OS and BCSM. Quantitative hormone receptor expression was not associated with specific AEs. Conclusions: Some AEs associated with estrogen depletion are related to better outcomes and may be valuable

A comprehensive overview providing information on the management of kinase inhibitor-associated drug-drug interactions can be found on the OncologyPRO website which has been developed in in collaboration with the European Society for Medical Oncology (ESMO).

Background: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. Therefore, 2B3-101 has been developed as a brain-targeted doxorubicin product. In preclinical studies, 2B3-101 showed a 5-fold increased delivery of doxorubicin to the brain and improved survival of mice with HGG, compared to Caelyx®. Methods: This study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of 2B3-101 in pts with advanced solid tumors and BM or HGG. In phase 1, pts with BM or HGG received 2B3-101 (5-70 mg/m2 q21d) and breast cancer (BC) BM pts received 2B3-101 (40-50 mg/m2 q21d) with trastuzumab. In phase 2a, BCBM pts received 2B3-101 (50 mg/m2 q21d) alone or with trastuzumab, HGG pts received 2B3-101 (60 mg/m2 q28d); melanoma and SCLC pts received 2B3-101 (50 mg/m2 q21d) in exploratory arms. Results: Results up to March 2014 from pts treated with ≥40 mg/m2 are described. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a half-life of 69h (range 43-120h) independent of trastuzumab co-treatment. 203 cycles (range 1-10) of 2B3-101 alone or with trastuzumab were given to 68 pts. 2B3-101 alone or with trastuzumab was well tolerated up to a dose intensity of 15 mg/m2/wk. Cycle 1 MTD was not reached. Phase 2a doses were selected based upon tolerability after repeated dosing. Most frequent reported treatment emergent AEs ≥ grade 2 were: neutropenia (36%), PPE (34%), fatigue (32%), stomatitis (19%), and infusion reaction (18%). All were transient and manageable with standard treatment. 2B3-101 showed no CNS- or cardiotoxicity. In evaluable BCBM pts (n = 19), 11% had PR and 53% SD as overall best response, including 4 pts with intracranial (IC) response of ≥ 20% with 3-months PFS rate of 58%. In evaluable HGG pts (n = 24), 54% had SD as best response, including 3 pts with IC response of ≥ 20% and a 3-months PFS rate of 33%. Conclusions: 2B3-101 is safe and well tolerated and shows activity in advanced BCBM and HGG pts, diseases with limited treatment options. Results warrant further randomized, controlled Phase 2b studies, with initial focus on (HER2+) BCBM. ClinicalTrials.gov NCT01386580, sponsored by to-BBB technologies BV. Disclosure: B. Milojkovic Kerklaan: research grant; W. Gladdines: employee; F. Lonnqvist: employee. All other authors have declared no conflicts of interest.

Background The highest rates of gastric cancer occur in Eastern Asia. Fluoropyrimidine-based therapy is used initially in unresectable and metastatic disease, following progression, 60–70% of patients in Asian countries subsequently receive second-line chemotherapy. However, there is no standard treatment in this setting. Ixabepilone, an epothilone B analog, is a non-taxane microtubule-stabilizing agent with clinical anti-tumor activity across multiple tumor types. We evaluated the efficacy and safety of single-agent ixabepilone as a second-line chemotherapy in Asian patients. Methods Asian patients with unresectable or metastatic gastric adenocarcinoma who had failed previous fluoropyrimidine-based chemotherapy received ixabepilone 40 mg/m2 by 3-hour intravenous infusion every 3 weeks. The primary end point was objective response rate (ORR). In this study, an ORR ≤8% was not of clinical interest, and an ORR ≥20% was of strong clinical interest. The test had 80% power to reject the null hypothesis at a significance level of 5% if the true ORR is 20%. Results This phase II was conducted at 9 sites in the Asian-Pacific region including Japan, Korea, Taiwan, Hong Kong and Singapore from November 2009 to June 2011. Fifty-two patients were treated (65.4% male; median age: 56.5 years). Ixabepilone was administered for a median of 3.5 courses (range: 1–10). Of the 45 patients who received at least two courses. The ORR was 15.4% (95% CI: 6.9–28.1), with 8 patients achieving partial responses for a median duration of 3.1 months (95% CI: 2.6–4.1 months). Twenty-six patients (50.0%) had stable disease, and therefore the disease control rate was 65.4% (95% CI: 50.9–78.0). Median progression-free survival was 2.8 months (95% CI: 2.1–3.5 months). The most common grade 3 non-hematological toxic effects were fatigue (9.6%), decreased appetite (7.7%), and peripheral sensory neuropathy (5.8%). Grade 3/4 neutropenia occurred in 46.2% of patients, with febrile neutropenia in 7.7%. There was no treatment-related death. Conclusion Ixabepilone showed a modest efficacy in Asian patients with advanced gastric cancer following prior fluoropyrimidine-based therapy, and has a predictable and manageable safety profile consistent with that seen in other tumor types.

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and...

Methods Patients (pts) with locally advanced or metastatic, grade 2 or 3 STS aged up to 60 yrs, were randomised to receive either single agent D (75 mg/m2) or D (75 mg/m2) with I (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by performance status (0 or 1), age ( Results 455 pts from 38 centres were randomised to D (n = 228) or D-I (n = 227). With median follow-up of 56 months, OS at 1 yr was slightly greater with D-I at 60% (95.5% CI 53 – 66) vs 51% (95.5% CI 44 – 58) with D alone, but the difference was not statistically significant (HR 0.82, 95.5% CI 0.66 – 1.01, stratified log rank test p = 0.061). No difference was seen in the 2-yr OS rate which was 31% (95.5%CI 25 – 38) for D-I vs 28% (95.5%CI 22 – 34) for D. Median PFS was significantly increased at 7.4 months (95% CI 6.6 – 8.3) for D-I vs 4.6 months (95% CI 2.9 – 5.6) for D (HR 0.72, 95% CI 0.59 – 0.88, stratified log rank test p = 0.002). Responses were CR: D = 1, D-I = 4; PR: D = 30 (13.2%), D-I = 56 (24.7%); SD: D = 105 (46.1%), D-I = 114 (50.2%). Febrile neutropenia was more common with D-I (45.9% vs 13.6%) as was anaemia (35.3% vs 4.6%). Conclusions The lack of a significant improvement in OS does not support the routine use of this intensive combination of D + I for STS in the palliative setting. The higher response rate suggests that D-I might be justified in selected pts age Disclosure All authors have declared no conflicts of interest. The EORTC 62012 trial was initiated to address concerns that previous studies comparing single agent doxorubicin (D) versus (vs) doxorubicin plus ifosfamide (I) in soft tissue sarcomas (STS) had used suboptimal doses of I. Non-randomised data suggested that a higher dose of I could increase response rate and progression free survival (PFS).

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.