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This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia.

Historically, the majority of oncology clinical trials are conducted in Western Europe and North America. Globalization of drug development has resulted in sponsors shifting their focus to the Asia-Pacific region. In Malaysia, implementation of various government policies to promote clinical trials has been initiated over a decade ago and includes the establishment of Clinical Research Malaysia, which functions as a facilitator and enabler of industry-sponsored clinical trials on a nationwide basis. Although oncology clinical trials in Malaysia have seen promising growth, there are still only a limited number of early phase oncology studies being conducted. Hence, the Phase 1 Realization Project was initiated to develop Malaysia's early phase clinical trial capabilities. In addition, the adaptation of good practices from other countries contribute to the effective implementation of existing initiatives to drive progress in the development of early phase drug development set up in Malaysia. Furthermore, holistic approaches with emphasis in training and education, infrastructure capacities, strategic alliances, reinforcement of upstream activities in the value chain of drug development, enhanced patient advocacy, coupled with continued commitment from policy makers are imperative in nurturing a resilient clinical research ecosystem in Malaysia.

Context Cancer pain prevalence is high despite well-established international guidelines on pain management and improved accessibility to treatment. Inadequate cancer pain management can be attributed to barriers related to patients, health care professionals, and health care system. Objectives To identify patient-related barriers to effective cancer pain management in a diverse multicultural developing country. Design A cross-sectional survey study was carried out using Brief Pain Inventory—Short Form to measure effectiveness of pain management and Barriers Questionnaire II to explore patient-related barriers to effective pain management. Setting/Participants Patients on strong opioids treated in a comprehensive cancer unit of a public hospital in Sarawak, Malaysia. Results Among 133 subjects surveyed, 66% reported no pain or mild pain, 34% moderate pain, and 10% severe pain. Despite good pain control, 71% of patients still reported moderate-to-severe interference with daily activities. Fatalism scored the highest median Barriers Questionnaire II score among the four domains of patient-related barriers followed by harmful effects, physiological effects, and communication factor. Conclusion Cancer pain is generally well controlled with more than half of patients reporting mild pain. However, degree of interference with daily activities is still high despite good cancer pain control. Fatalistic mentality need to be addressed for effective cancer pain management. Further studies on health care professional-related barriers and health system-related barriers are urgently needed to provide a comprehensive approach of holistic pain management.

BackgroundIdentifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming.MethodsThe Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.ResultsOncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms.ConclusionThe MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.

BackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .

Purpose Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non–small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial.Materials and Methods Key efficacy endpoints were blinded independent review committee (BIRC)–assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events.Results At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively.Conclusion Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

Summary Background In the global phase 3 RAINBOW study, ramucirumab plus paclitaxel significantly improved overall survival compared with placebo plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. RAINBOW-Asia, a bridging study with similar design to RAINBOW, aimed to evaluate the efficacy and safety of ramucirumab plus paclitaxel for advanced gastric or GEJ adenocarcinoma in Asian, predominantly Chinese, patients. Methods RAINBOW-Asia was a randomised, double-blind, placebo-controlled, phase 3 trial done at 32 centres in China, Malaysia, the Philippines, and Thailand. Adult patients (≥18 years) with metastatic or locally advanced, unresectable gastric or GEJ adenocarcinoma who previously received fluoropyrimidine–platinum-based chemotherapy were randomly assigned with a centralised interactive web response system in a 2:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15 plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of every 28-day cycle. Randomisation was stratified by Eastern Cooperative Oncology Group performance status and presence of peritoneal metastases. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done in the intention-to-treat population, and safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT02898077 , and has been completed. Findings Between March 2, 2017, and June 30, 2020, 440 patients were randomly assigned to receive ramucirumab plus paclitaxel (n=294) or placebo plus paclitaxel (n=146). Median progression-free survival was 4·14 months (95% CI 3·71–4·30) in the ramucirumab plus paclitaxel group compared with 3·15 months (2·83–4·14) in the placebo plus paclitaxel group (hazard ratio [HR] 0·765, 95% CI 0·613–0·955, p=0·0184). Median overall survival was 8·71 months (95% CI 7·98–9·49) in the ramucirumab plus paclitaxel group and 7·92 months (6·31–9·10) in the placebo plus paclitaxel group (HR 0·963, 95% CI 0·771–1·203, p=0·7426). The most common grade 3 or worse treatment-emergent adverse events were decreased neutrophil count (159 [54%] of 293 patients in the ramucirumab plus paclitaxel group vs 56 [39%] of 145 in the placebo plus paclitaxel group), decreased white blood cell count (127 [43%] vs 42 [29%]), anaemia (46 [16%] vs 24 [17%]), hypertension (21 [7%] vs nine [6%]), and febrile neutropenia (18 [6%] vs one [ Interpretation These findings, along with the results from RAINBOW, support the use of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma. Funding Eli Lilly and Company, USA. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Objective To examine the results of the Malaysian Advanced Prostate Cancer Consensus Conference (MyAPCCC) 2018, held for assessing the generalizability of consensus reached at the Advanced Prostate Cancer Consensus Conference (APCCC 2017) to Malaysia, a middle-income country. Methods Six key sections were chosen: (1) high-risk localized and locally advanced prostate cancer, (2) oligometastatic prostate cancer, (3) castration-naive prostate cancer, (4) castrate resistant prostate cancer, (5) use of osteoclast-targeted therapy and (6) global access to prostate cancer drugs. There were 101 consensus questions, consisting of 91 questions from APCCC 2017 and 10 new questions from MyAPCCC 2018, selected and modified by the steering committee; of which, 23 questions were assessed in both ideal world and real-world settings. A panel of 22 experts, comprising of 11 urologists and 11 oncologists, voted on 101 predefined questions anonymously. Final voting results were compared with the APCCC 2017 outcomes. Results Most voting results from the MyAPCCC 2018 were consistent with the APCCC 2017 outcomes. No consensus was achieved for controversial topics with little level I evidence, such as management of oligometastatic disease. No consensus was reached on using high-cost drugs in castration-naive or castration-resistant metastatic prostate cancer in real-world settings. All panellists recommended using generic drugs when available. Conclusions The MyAPCCC 2018 voting results reflect the management of advanced prostate cancer in a middle-income country in a real-world setting. These results may serve as a guide for local clinical practices and highlight the financial challenges in modern healthcare.

TPS6603 Background: Existing data demonstrate the impact of Immune checkpoint modulators (ICMs) on Health-Related Quality of Life (HRQOL), but this was from studies that used HRQOL tools developed for patients treated with chemotherapy and/or radiation. To address this gap, we developed a toxicity subscale to cover important immune-related adverse events (irAEs) to combine this subscale with the generic FACT-G to measure HRQOL in patients treated with ICMs, the FACT-ICM. This trial proposes to validate the use of the FACT-ICM as a tool for HRQOL measurement and simultaneously to assess the benefit of remote symptom monitoring and management using a new electronic platform developed specifically for patients receiving ICMs. Methods: Participants will be randomized (1:1) before starting their standard of care ICM therapy to either usual care or the monitoring arm. The ME-Q platform uses a web-based application to enable remote monitoring of patient symptoms and HRQOL, allowing all participants enrolled in both the usual care or monitoring arms to complete the FACT-ICM and other questionnaires (DART, Health Resource Utilization, Decision regret scale, post-study system usability questionnaire) at set time points. Patients on the monitoring arm will have their electronic responses sent automatically, and new or significant worsening symptoms of clinical concern will generate an alert to the advanced practicing nurse (APN) responsible for replying to the patient and acting on responses. Via phone or a video teleconference, the nurse will perform a targeted assessment and provide standardized clinical advice and interventions based on well-established clinical algorithms and international guidelines for the management of irAEs. The APN will inform the patient's clinical team about the patient's responses and obtain the treating team's input and agreement on a proposed treatment plan. Patients enrolled in the usual care arm will respond to the questionnaires; however, their responses are not transmitted to their clinical team. The primary objective will be to validate the PRO tool for HRQOL measurement, and the secondary objective is to improve HRQOL in cancer patients receiving ICMs by remote monitoring and symptom management using the ME-Q electronic platform. We estimate that a total sample size of 266 patients (divided into two arms) achieves 90% power to detect an effect size of 0.4 in mean score changes (from baseline to 4 months) between arms using a two-sample t-test with a two-sided significance level of 0.05. Enrolment is to be completed in 2 years.

Immuno-oncology therapies have been approved for various solid tumors; however, the high cost of these treatments and their potential toxicities require a thorough assessment of their risks and benefits. Collection of data directly from patients through patient-reported outcome instruments can improve the precision and reliability of adverse event detection, assess tolerability of adverse events, and provide an evaluation of health-related quality of life (HRQOL) changes from immuno-oncology therapies. There is robust development in HRQOL tools specifically for patients treated with immuno-oncology agents. This review examines the history and basic concepts of HRQOL and patient-reported outcome assessments commonly used in oncological trials, highlighting the strengths and weaknesses of current approaches when applied to immunotherapies, as well as some of the current efforts to develop tools for this field and opportunities for future research. LAY SUMMARY: Immuno-oncology (IO) therapies are costly and carry potential toxicities known as immune-related adverse events. Evaluation of health-related quality of life (HRQOL) can impact the risk-benefit assessment of IO therapies. Integration of HRQOL end points and patient-reported outcome data for IO therapies are urgently needed. Ongoing robust development of patient-reported outcome tools specific to IO therapies are currently underway and will permit the evaluation of HRQOL for IO agents. Improvement in precision and reliability of HRQOL evaluation will enhance the ultimate true value of these expensive and effective drugs.

Identifying patients withThe Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant inThe MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.

Background Trametinib (Mekinist ®) is an oral bioavailable MEK 1/2 inhibitor that is FDA approved in combination with BRAF inhibitor Dabrafenib for BRAFV600 mutant solid tumors. The single agent recommended phase 2 dose (RP2D) is 2 mg daily (QD). No clinical data is available on recommendation of trametinib dosing in various degrees of hepatic dysfunction (HD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib as primary endpoints in patients (pts) with genomically unselected advanced solid tumors with various degrees of HD. Methods Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). NO group was enrolled as control subjects and was not evaluable for dose limiting toxicity (DLT). Trametinib was given QD on a 28-days cycle, with dose escalation based on a “3+3” design within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). Due to the long half-life of trametinib, PK samples were collected at days 15-16 in cycle 1. Differences in PK parameters among liver function groups were evaluated using analysis of variance (ANOVA). Results Out of 46 pts enrolled (2 pts ineligible), 44 (NO=17, ML=7, MD (1.5mg)=4, MD (2mg)=5, SV (1mg)=9, SV (1.5mg)=2) were evaluable for safety and 22 for PK analysis. The most common cancer type was GI-non CRC cancer (n=16, 36%). The most common all-grade treatment related adverse events (TRAEs) were acneiform rash (NO=53%, HD=48% of pts), nausea (NO=65%, HD=22%), diarrhea (NO=53%, HD=26%) and fatigue (NO=59%, HD=15%). Grade 3/4 TRAEs occurred in 27% (n=12) of pts (NO=8, 47%; HD=4, 15%). No treatment related deaths occurred. DLT was evaluable in 15 pts (ML=6, MD (1.5mg)=3, MD (2mg)=2, SV (1mg)=3 and SV (1.5mg)=1). One DLT (grade 3 acneiform rash) was observed in an SV pt (1.5mg). Dose interruptions or reductions due to TRAEs occurred in 15 pts (34%) [NO=9, 53%; ML=2, 29%; MD (1.5mg)=1, 33%; MD (2mg)=2, 33%; SV (1mg)=1, 11%; SV (1.5mg)=1; 50%]. Best response was stable disease in all HD groups (33 to 75%) and 54% in NO group. There were no significant differences for PK parameters of Cmax (p=0.18), Cmin (p=0.16), Cavg (p=0.62), or AUC0-24 (p=0.11) (NO vs ML, NO vs MD, NO vs SV, ML vs MD, ML vs SV, MD vs SV), when trametinib was normalized to 2 mg dose. However, only limited PK data were available for the MD (n=3) and SV (n=3) groups compared to NO (n=10) and ML (n=6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p=0.26). Conclusion RP2D for trametinib in ML pts is 2 mg QD. There are insufficient number of evaluable pts to declare RP2D for MD and SV HD groups. No DLTs were noted in the highest dose cohorts that reached 3 evaluable pts: 1.5 mg QD in MD group, and 1 mg QD in SV group. It may be appropriate for pts with MD and SV HD to start trametinib at 1.5 mg QD and 1 mg QD respectively, and monitored closely for toxicity. Citation Format: Pei Jye Voon, Eric X. Chen, Helen X. Chen, Albert C. Lockhart, Solmaz Sahebjam, Karen Kelly, Ulka N. Vaishampayan, Vivek Subbiah, Albiruni R. Razak, Daniel J. Renouf, Sebastien J. Hotte, Arti Singh, Philippe L. Bedard, Aaron R. Hansen, Ivy S. Percy, Lisa Wang, Lee-Anne Stayner, Lillian L. Siu, Anna Spreafico. A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P035.

TPS2670 Background: Immuno-oncology therapies, including immune checkpoint inhibitors (CPIs), are revolutionizing cancer treatment. However, primary and secondary resistance to CPIs remains a significant challenge. CPI resistance has been associated with reduced interferon (IFN) signaling, altered antigen presentation, and an immunosuppressive tumor phenotype. Stimulating innate immune cells to develop a proinflammatory tumor environment that activates IFN signaling and downstream adaptive antitumor immune mechanisms is predicted to overcome such resistance. Stimulator of Interferon Genes (STING) is a key mediator of type 1 IFN-dependent innate immune modulation. Most STING agonists evaluated clinically have required intratumoral administration, which has significant logistical challenges and excludes many pts whose tumors are not accessible for injection. TAK-676 is a novel STING agonist under clinical investigation as an IV administered systemic therapy in pts with solid tumors. Methods: The primary objective of this study is to determine the safety and tolerability of TAK-676 alone and in combination with pembrolizumab. Secondary objectives are to: determine the pharmacologically active dose and recommended phase 2 dose; characterize TAK-676 pharmacokinetics; assess preliminary antitumor activity; and assess STING agonism gene signature induction. An exploratory objective is to assess immune cell activation and clinical response. The study comprises a single-pt safety lead-in with single-agent (SA) TAK-676 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation will start in the combination arm when ≥2 dose levels in the SA arm have been evaluated and considered safe. In both arms, pts will receive TAK-676 on days 1, 8, and 15 in 21-day cycles for up to 1 year. In the combination arm, pts will also receive pembrolizumab 200 mg IV on day 1 of each cycle. Adult pts with histologically confirmed advanced or metastatic solid tumors who have no standard therapeutic options or are intolerant to them, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and ≥1 Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1- evaluable lesion are eligible; pts with tumors that have relapsed, are refractory or naïve to anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy are eligible for the combination arm. Planned enrollment is ̃76 pts; recruitment is ongoing. Clinical trial information: NCT04420884.

To study the surgical and oncological outcomes of endoscopic endonasal transpterygoid nasopharyngectomy (EETN) in salvaging locally recurrent nasopharyngeal carcinoma (NPC). This was a retrospective clinical record review study carried out at a tertiary centre from June 2013 until May 2017. A total of 55 locally recurrent NPC patients (rT1–rT4) underwent EETN performed by single skull base surgeon with curative intention with postoperative adjuvant chemotherapy but without postoperative radiotherapy. There were 44 (80.0%) males and 11 (20.0%) females, with mean age of 52.5 years. The mean operating time was 180 min (range 150–280 min). 85% (47/55) of patients achieved en bloc tumour resection. 93% (51/55) of patients obtained negative microscopic margin based on postoperative histopathological evaluation. Intraoperatively, one (1.8%) patient had internal carotid artery injury which was successfully stented and had recovered fully without neurological deficit. There were no major postoperative complications reported. During a mean follow-up period of 18-month (range 12–48 months) postsurgery, five patients (9.1%) had residual or recurrence at the primary site. All five patients underwent re-surgery. One patient at rT3 passed away 6 months after re-surgery due to distant metastasis complicated with septicaemia. The 1-year local disease-free rate was 93% and the 1-year overall survival rate was 98%. EETN is emerging treatment options for locally recurrent NPC, with relatively low morbidity and encouraging short-term outcome. Long-term outcome is yet to be determined with longer follow-up and bigger cohort study. However, a successful surgical outcome required a very experienced team and highly specialised equipment.

Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI-sensitizing mutations.Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety.The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively.In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.

FLAURA ClinicalTrials.gov number, NCT02296125 BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P

Background: Cerebral radiation necrosis (CRN) is a late, irreversible complication of radiation to the brain or its surrounding structures, especially debilitating for patients treated with curative intent. We report a case of advanced testicular nonseminomatous germ cell tumor (NSGCT) who developed CRN after palliative dose of whole brain radiotherapy (WBRT) for multifocal brain metastases. Case report: A 24-year-old gentleman presented with progressively painful left testicular swelling for 1 year. Testicular sonography revealed an enlarged left testicular mass measuring 5.6x8.8 cm. His serum AFP, LDH and b-HCG levels were elevated at 860 ng/ml, 392 U/L and 5490 IU/L respectively. He underwent a radical left orchidectomy which confirmed a mixed NSGCT with yolk sac (60%), immature teratoma (25%) and embryonal carcinoma (5%) components. Post orchidectomy, his serum AFP and LDH levels dropped but his b-HCG level quadrupled. Staging CT showed advanced disease with bilateral lung and nodal metastases. He developed severe headache with seizures and an urgent CT brain showed multiple hemorrhagic brain metastases. He received WBRT 20Gy/5 fractions over 1 week, followed by 4 cycles of Bleomycin/Etoposide/Cisplatin (BEP) chemotherapy. Upon treatment completion, he demonstrated good radiological response with normalization of tumor markers. Six months later, he developed bilateral homonymous quadrantanopia with no other neurological symptoms but his tumor markers remained normal. Repeated CT brain showed new bilateral occipital rim enhancing lesions with perilesional edema. MRI showed these lesions had irregular intralesional diffusion, increased diffusivity, and swiss cheese enhancement pattern. On spectroscopy, they demonstrated high lactate, low N-acetylaspartate and low creatine. PET/CT confirmed no FDG-avidity in these lesions and the radiological diagnosis of CRN was established. However, he declined open biospy for pathological confirmation. Four years later, he remains in remission with stable bilateral homonymous quadrantanopia. Conclusion: CRN remains a diagnostic and therapeutic challenge, and advancements these modalities are encouraged to improve long term patient outcomes.

Nasopharyngeal carcinoma (NPC) is endemic in many of East Asian countries. Epstein-Barr virus (EBV) infection, environmental factors and genetic predisposition are known risk factors for endemic form of NPC. We reported a retrospective epidemiological data of our newly diagnosed histologically confirmed NPC cases over 7 years. Total 1102 cases were identified. Ethnic Bidayuh has one of the highest crude rate in the world at 25.42 per 100,000 population. Eight and a quarter percent of the entire cohort had family history. There were 33 children and adolescent cases reported. Such high incidence was compounded by late presentation (85.1% were stage III to IV disease). Despite robust data on plasma EBV DNA in screening of at-risk populations, accessibility of such tests remains an issue in developing countries. Moreover, there are still limited approved treatment options available in addition to conventional multimodalities strategy with radiation and chemotherapy. Lack of strong data on targeted and immunotherapeutic options poses challenge in the management of this dismal tumor despite various ongoing studies. NPC is a huge health burden to high incidence areas especially in developing world. Better understanding of this intriguing tumor is essential in improving value-based treatment for developing countries.

Aims Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism. Methods We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics. Results Two previously reported AKR1C3 intronic variants, IVS4–212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4–212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 109 vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109 vs. 1.56 ± 2.80 × 109 l−1, P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2–55.8) vs. 31.0 (95% confidence interval 20.7–41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3–70.5) vs. 46.3 (95% confidence interval 35.1–57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4–212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration–time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4–212 C

Chylothorax is defined as the presence of chyle in the pleural cavity. Central vein thrombosis is an under-recognized cause of chylothorax in the adult population and is commonly related to central venous catheterization. Case 1 illustrates a patient with AIDS and disseminated tuberculosis with left chylothorax and central vein thrombosis after a month of antituberculosis therapy. Case 2 was a patient with advanced seminoma who presented with left chylothorax and central vein thrombosis while on chemotherapy. Chylothorax resolved with anticoagulation for both cases. Case 3 was a lymphoma patient with central vein thrombosis who developed chylothorax during chemotherapy. Chylothorax resolved with the continuation of anticoagulation and did not recur despite his progressive underlying lymphoma. There was no central venous catheterization in any of these three cases. These cases illustrate the unique association of central vein thrombosis and chylothorax and the importance of anticoagulation in its management.

Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics.Two previously reported AKR1C3 intronic variants, IVS4-212 CG and IVS4+218 GA, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 10(9) vs. 3.85 ± 3.42 × 10(9) l(-1) , P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 10(9) vs. 1.56 ± 2.80 × 10(9) l(-1) , P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 CG and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 TG correlated with OS. The AKR1C3 IVS4-212 CG genotype remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators.The AKR1C3 IVS4-212 GG genotype was associated with greater haematological toxicity and longer progression-free survival and overall survival after doxorubicin-based therapy, suggesting potential interaction of this variant with doxorubicin metabolism.

Personalising cancer treatment to optimise therapeutic efficacy while minimising exposure to the toxicities of ineffective drugs is the holy grail of medical oncology. Clinical parameters and conventional histopathological characterisations of cancers are no longer adequate to guide the practising oncologists in treatment planning. The explosion of knowledge in cancer molecular biology has led to the availability of tumour-specific molecules that serve as predictive and prognostic markers. In breast cancer, HER-2 positivity is a good predictor for success of anti-HER-2 trastuzumab monoclonal antibody therapy. K-ras mutational status predicts the likelihood of response to anti-EGFR monoclonal antibodies in advanced colorectal cancers. Similarly, EGFR mutational status in pulmonary adenocarcinoma is highly predictive for responses or otherwise to tyrosine kinase inhibitors. Notwithstanding our deeper understanding of tumour biology and the availability of predictive and prognostic laboratory tools, we are still far from achieving our dream of the perfect personalised cancer treatment, as each tumour in a particular patient is unique to itself. A much coveted, real-time, anti-tumour drug sensitivity testing in the future may one day pave the way for truly treating the right tumour with the right drug in the right patient. Key words: Personalised cancer treatment, Predictive markers, Prognostic markers

We read with great interest the recent article by Arcila and colleagues ([1][1]). We present a case of exon 20 insertion mutation (A763_764insFQEA), with documented clinical and radiologic response to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI). To our knowledge, this is the first report of

1060 Background: Continuous VEGFR-I use may ablate vasculature and impede chemotherapy delivery, failing to improve outcome; in contrast, low-dose, short-course VEGFR-I may normalize vasculature an...

1064 Background: Small molecule VEGFR inhibitors (VEGFR-I) have failed to improve outcome with chemotherapy in most solid tumors. Continuous administration of a potent VEGFR-I may destroy vasculature and impede drug delivery; in contrast, low-dose, short-course VEGFR-I before chemotherapy may normalize tumor vasculature and enhance drug delivery. Methods: We conducted a phase Ib followed by phase II randomized study in patients with measurable primary breast tumors using low-dose sunitinib (Su) for 1 week prior to doxorubicin/cyclophosphamide (AC) and measured tumor blood flow with DCE-MRI and microvessel density and pericyte recoverage with CD31 and α-smooth muscle actin (SMA) staining on tumor biopsies, at baseline, after 1 week of Su, and 2 weeks after cycle 1 AC. Patients in phase Ib received 12.5-25mg Su prior to AC; in phase II, patients were randomized to AC+/-12.5mg Su. Results: 21 patients have been enrolled, including 3 patients on 25mg Su+AC, 11 on 12.5mg Su+AC, and 7 on AC alone. After 1 week of 25mg Su, 2/3 patients had reduced tumor blood flow on DCE-MRI indicating anti-angiogenic effects. After 1 week of 12.5mg Su, significant increase in tumor fractional plasma volume (Vp) occurred (+28%±28%, p=0.025) suggesting increased perfusion, followed by decrease 2 weeks after AC (-33%±26%,p=0.035) corresponding to mean tumor size change of -17±15%, while no significant Vp changes occurred with AC alone (p=0.823); CD31 expression reduced (20.7 vs 15.7, p=0.173) while SMA/CD31 double staining increased (2.45 vs 7.34, p=0.046) indicating lower microvessel density and normalization of residual vasculature, which was not seen with AC alone (CD31, p=0.434; CD31/SMA, p=0.605). The main toxicity of Su+AC and AC alone was febrile neutropenia (29% vs 43%). 14 patients had surgery with pathological complete response in 1/6 patients who received 12.5mg Su+AC. Conclusions: 25mg Su for 1 week can reduce tumor blood flow, suggesting that concomitant standard dose Su may compromise drug delivery. Low dose 12.5mg Su for 1 week is sufficient to normalize tumor vasculature and increase tumor fractional plasma volume, and may potentially improve drug delivery and treatment outcome.

e13002 Background: CPT-11 has complex PK and PD; genotyping of UGT1A1 is recommended for higher doses in *28 carriers (Caucasian) and *6 carriers (Asian) because of a higher risk of toxicity. Raltegravir is mainly metabolized to raltegravir glucuronide by UGT1A1. CPT-11 is mainly eliminated by cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by esterase cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes to the inactive SN-38 glucuronide. We prospectively explored the correlation of midazolam and raltegravir PK with CPT-11 clearance (CL) and SN-38 levels respectively and toxicity in patients undergoing chemotherapy with CPT-11. Methods: Twenty-five Asian patients with advanced cancer received CPT-11 as a 2-weekly 90-minute infusion (180 mg/m2) as part of the FOLFIRI regimen. Subjects were administered raltegravir 400 mg orally (as a UGT1A1 probe) and intravenous midazolam 1 mg (as a CYP3A4 probe) one day before the first dose of their chemotherapy. Blood sampling for drug concentrations was performed for 2 days after probe drug administration. Non-compartmental PK analyses were performed using WinNonLin. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1*6. Results: One patient developed grade 3 diarrhea and 16 developed grade 3-4 neutropenia. The mean CPT-11 CL was 21.9 + 7.8L/h. SN-38G/SN-38 AUC ratio was highly correlated with Raltegravir glucuronide/ Raltegravir AUC ratio (r=0.784 p10Nadir Absolute Neutrophil Count (ANC) (r=-0.397 p10 Nadir ANC. Of the 24 patients with genotyping of UGT1A1*6 done, 17 were wild type (GG), 7 heterozygotes (AG) and 0 were mutant (AA). No differences in toxicity or SN38 pharmacokinetics were observed in the UGT1A1*6 variants. Conclusions: Raltegravir glucuronide ratio is a good predictor of SN-38 glucuronidation, and has potential to predict neutropenia from FOLFIRI treatment. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize CPT-11 therapy.

e19523 Background: There is currently limited data on the perceptions and attitudes of Asian cancer patients towards therapeutic clinical trials (CTs). Understanding this is crucial to their successful execution. Methods: From May to December 2011, we surveyed cancer outpatients at the National University Cancer Institute, Singapore, and collected data on patient demographics, tumor information, awareness, perceptions, and willingness to participate in CTs. Results: 240 patients were surveyed, including 85 (35%) who had previously participated, 141 (59%) who had never participated, and 14 (6%) who had refused participation in a CT. The majority was Chinese (78.8%) or Malay (16.7%), 57.5% was female and median age was 56 years (range 22-83). There were no differences in demographics between patients who had, had not or refused participation in a CT. 135 patients (56%) had prior awareness of CTs, and were more likely to be female (p=0.027) or had metastatic disease (p=0.002). 111 (46%) patients were willing to participate in CTs given the opportunity, and were more likely to have prior awareness of CTs (76.6% vs 38.8%, p

89 Background: Perioperative chemotherapy has been shown to improve outcomes among patients with locally advanced gastric adenocarcinoma. As docetaxel (D), cisplatin (C), and capecitabine (X) are active agents in gastric adenocarcinoma, we conducted a phase II trial to assess the efficacy and tolerability of preoperative DCX in patients with gastric adenocarcinoma. Methods: We enrolled patients with locally advanced gastric adenocarcinoma (clinical T3/4 or N positive) to preoperative DCX repeated every 21 days for three cycles, followed by surgery. The first cohort of 10 patients received docetaxel 35 mg/m2, cisplatin 35mg/m2 on days 1 and 8, with capecitabine 750 mg/m2 twice daily from day 1 to day 14. A subsequent cohort of another 11 patients had dose modifications for docetaxel and cisplatin, both to 30mg/ m2 on days 1 and 8. Results: Twenty-one patients were recruited. Median age was 61 years. Seventy-one percent of patients completed a total of 3 cycles of planned chemotherapy. Fourteen patients have successfully undergone surgery. R0 resection rate was 88%. Pathological complete response (pCR) and near complete response (pnCR) were both 17%. Preoperative radiological assessment showed a partial response rate of 65% after 2 cycles of treatment. Good pathological response (pCR and pnCR) was associated with better event-free survival (26 months vs 12 months, p=0.031). Common grade 3/4 toxicities were diarrhea (38%), neutropenia (30%), stomatitis (14%) and hypokalemia (14%). However, the diarrhea rate was reduced to 15% with dose modifications as mentioned above after 50% of the first cohort of 10 patients developed grade 3/4 diarrhea during the first cycle of chemotherapy. Febrile neutropenia rate was 14%. There was one treatment related death before surgery but no postoperative mortality. Conclusions: Preoperative DCX is highly active with modest toxicity in locally advanced gastric adenocarcinoma. DCX represents an attractive alternative regimen without the need for protracted infusional drug in perioperative chemotherapy for patients with locally advanced gastric adenocarcinoma. Good pathological response is associated with better outcome.