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e14557 Background: YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody under evaluating its safety and efficacy in phase I clinical trial. We have reported interim analysis of dose escalation cohort which showed a tolerable safety profile. Here, we present the updated clinical activity of YBL-006 in dose escalation and expansion cohorts. Methods: Dose escalation (0.5, 2, 5, 10 mg/kg) and dose expansion (flat doses of 200 mg every 2 weeks [Q2W] and 300 mg every 3 weeks [Q3W]) cohorts explored the safety, pharmacokinetics (PK) and objective response rate (ORR) in the patients with advanced solid tumors who failed or were ineligible to the standard of care. Adverse events (AEs) were graded using the CTCAE v5. ORR was assessed using the RECIST (v1.1). Lunit SCOPE IO, an H&E analysis tool, was applied as an exploratory biomarker, and samples with “Immune inflamed phenotype” were defined as those with high intratumoral TIL density in ≥ 20% of the tumor microenvironment. The cut-off date for analysis was Jan 4th, 2022. Results: A total of 67 patients (safety set) with advanced solid tumors were enrolled in the study. Median follow-up duration of the safety set was 1.6 months (range 0.2-16.8). There was no dose-limiting toxicity during dose escalation phase. Most frequent AEs were grade 1 or 2; fatigue (19.4%), pruritus (10.4%), and fever (7.5%), and two hypothyroidism (3.0%), one pneumonitis (1.5%), and one cytokine-releasing syndrome (1.5%) were observed. One subject experienced grade 3 diarrhea in the safety set. PK study showed that half-life was 8.0 days, and mean Cmax and AUC0-inf were 4.15 x 104 ng/ml and 1.12 x 107 ng/ml*h for 200 mg dose, and 6.26 x 104 ng/ml and 1.53 x 107 ng/ml*h for 300 mg dose, respectively. A total of 52 patients were evaluable for efficacy. ORR was 15.4%, including 1 complete response (penile squamous cell carcinoma [SqCC]), and 7 partial responses (two gastric adenocarcinomas, anal SqCC, paranasal sinus SqCC, nasopharyngeal carcinoma, neuroendocrine carcinoma, and thyroid Hurthle cell carcinoma). Durable responses were seen in 2 patients for over 12 months. Median duration of response was 4.9 weeks (range 1-65). Among efficacy set, 32 samples were available for Lunit SCOPE IO. ORR was significantly higher in inflamed immune phenotype compared to non-inflamed samples (62.5% vs 8.3% p = 0.005). Conclusions: Interim analysis of phase I trial of YBL-006 shows a tolerable safety profile and clinical activity. Notable anti-tumor efficacy was observed in inflamed immune phenotype. Clinical trial information: NCT04450901.

Complementary and Alternative Medicine (CAM) is widely used among cancer patients worldwide. This prospective observational study aimed to show the effect of CAM use on chemotherapy delivery in Thai patients.During March 2014 to February 2015, the patients with breast, lung or colorectal cancer receiving first cycle chemotherapy at King Chulalongkorn Memorial Hospital were enrolled. The correlation between CAM using and chemotherapy schedule delay and dose reduction, dose intensity, quality of life and adverse event rates were analyzed.There were 80 (44.20%) patients using CAM among 181 enrolled patients. Seventy six CAM users and 97 non-CAM users receiving 2nd cycle of chemotherapy were included for primary analysis. The chemotherapy schedules were delayed and/or reduced in 40 (52.6%) and 48 (49.5%) in CAM users and non-CAM users, respectively, p =0.681. The mean relative dose intensity (RDI) were 92.4% and 94.1% in CAM and non-CAM users, respectively, p=0.244. However, there were significantly more CAM users receiving chemotherapy less than 90% RDI (34.8% vs 19.8%, p=0.033). As compared to first cycle, at third cycle, the mean QOL score changes were -4.63 (95% CI -2.49-9.27) and -8.02 (-2.36- 9.142) in CAM user and non-CAM user, respectively (p=0.255). There were significantly higher rates of grade 3 or 4 anemia (5.1% vs 0%, p=0.024), and grade 2 malaise (19.0% vs 5.1%, p=0.004) in CAM users.There were similar overall rates of chemotherapy schedule delay and dose reduction between CAM- and non-CAM users. However, there were less CAM-users achieving 90% chemotherapy RDI.

Introduction In the phase 3 ASCEND-4 study, ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. Methods Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5–6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. Results Of 376 randomized patients, 158 (42.0%) were Asian (ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5–34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6–not estimable) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41–1.05) in the ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. Conclusion Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.

Background Cosibelimab is a high affinity, fully-human IgG1 monoclonal antibody that directly binds to programmed death ligand-1 (PD-L1) and blocks its interaction with the programmed death receptor-1 (PD-1) and B7.1 receptors to restore an anti-tumor immune response. Cosibelimab has the additional benefit of a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against tumor cells. Study CK-301–101 is a global, multicenter, multicohort trial that is enrolling patients (pts) with select advanced cancers, including pivotal cohorts of pts with metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) and a cohort of pts with previously untreated advanced non-small cell lung cancer (NSCLC). Methods Eligible pts were aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1. The cSCC cohorts enrolled pts with histologically confirmed metastatic or locally advanced cSCC not amenable to local therapy. The NSCLC cohort enrolled previously untreated NSCLC pts with advanced disease and a PD-L1 tumor proportion score of at least 50%. Pts received a fixed dose of 800 mg cosibelimab administered intravenously every two weeks. Anti-tumor activity was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and were conducted every 8 weeks for the initial 32 weeks on study, and every 12 weeks thereafter. Results As of August 2020, 114 pts (73M/41F, median age 66 years) with diverse tumor types have been enrolled and treated with cosibelimab. Among these pts, 103 (90%) experienced ≥1 treatment-emergent adverse event (AE), 42 (37%) experienced a grade ≥3 AE, and 6 (5%) experienced a grade ≥3 drug-related AE. The most common AEs were fatigue (25%), anemia (21%), rash (18%) and nausea (16%) and the most common drug-related AEs were fatigue (15%) and rash (14%). In 42 cSCC pts evaluable for response, ORR based on investigator assessment of tumor response was 55% (95% confidence interval [CI]: 39, 70), including 5 (12%) complete responses, with 20/23 (87%) responses ongoing and 10 responses ≥6 months in duration as of data cutoff. In 25 NSCLC pts evaluable for response, ORR based on investigator assessment was 44% (95% CI: 24, 65), with 5/11 (45%) responses ongoing and 10 responses ≥6 months in duration. Conclusions Cosibelimab has a predictable and manageable safety profile and demonstrated robust clinical activity in cSCC and NSCLC pts, including durable complete and partial responses. Updated results will be presented. Trial Registration NCT03212404 Ethics Approval The study was approved by an appropriate ethics committee for each participating institution. Informed consent was obtained for all subjects. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Background This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib. Methods Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory. Results 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months. Conclusions Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations.

The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population.In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/mCrizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients.First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.

Background: The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response. Methods: This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC. Results: A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules ( n = 8), and in the expansion, patients received 600 mg BID capsules ( n = 28) or 400 mg BID tablets ( n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)]. Conclusions: Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC. Trial registration: ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827

Background: East Asian, including Thailand, lung cancer population may have a relatively lower prevalence of KRAS mutations than Caucasians. We investigated the prevalence and clinical characteristics of KRAS-driven non-small cell lung cancer (NSCLC) patients and the expression of cyclin D1, one of the KRAS downstream targets. Methods: Lung cancer patients who received treatment at the King Chulalongkorn Memorial Hospital between January 2015 and July 2017 were enrolled. We identified KRAS mutations using allele specific PCR KRAS mutation testing. Cyclin D1 expression was determined using immunohistochemistry. Results: After excluding 376 EGFR mutations and inadequate samples, we enrolled 95 patients eligible for KRAS mutation testing. KRAS mutations were identified in 28 out of 95 patients. There were 26 patients with KRAS codon 12/13 and 2 patients with KRAS codon 61 mutations. The prevalence of KRAS mutations among informative samples was 28 out of 357 (7.8%) which was relatively lower than that reported in Caucasian population. Smoking and male were significantly associated with KRAS mutations. The prognosis of KRAS-mutant NSCLC patients in particular codon 61 mutations was worse than that found in KRAS- and EGFR-wild-type (KRAS WT/EGFR WT) NSCLC patients (P=0.048). The levels of cyclin D1 expression in KRAS-mutant NSCLC were significantly higher than those in KRAS WT/EGFR WT NSCLC (P=0.02). A better prognosis of KRAS-mutant NSCLC patients with low cyclin D1 expression was observed when compared with those with high cyclin D1 expression (median overall survival 41.7 vs. 3.5 months, P=0.037). Conclusions: We found a moderate prevalence of KRAS mutations in lung cancer in Thailand. Clinical characteristics were similar to those of Caucasian population. Most KRAS-mutant NSCLC had high cyclin D1 expression. Cyclin D1 expression may serve as a useful prognostic biomarker in KRAS-mutant lung cancer. Validation of this finding in larger cohort is required.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781

Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid’s adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions. Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected. Eighty-one of 85 patients who did not undergo infusion HSR after 2 cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51 years (range 27–74 years). Only 16% of the patients had a BMI greater than 30 kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I–II HSR (6.25%), which occurred mostly during the first 6 cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients. Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

Purpose This study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations. Patients and methods One hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal-Wallis or Mann-Whitney U test, including the simple main effects analysis. Results The patients had stage 0-IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype. Conclusion CYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

Background Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Methods Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Results Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3–4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3–4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Conclusion Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities.

Background Stomatitis is the most frequent adverse event reported in trials of mTOR-inhibitors, including EVE. In the pivotal phase 3 BOLERO-2 study, stomatitis incidence in the EVE + exemestane (EXE) arm was 59%. The BOLERO-4 study (NCT01698918) evaluated the efficacy and safety of first-line EVE + LET in postmenopausal pts with HR+, HER2− metastatic or locally advanced breast cancer (ABC). BOLERO-4 also assessed the effectiveness of an alcohol-free dexamethasone (0.5 mg/ 5ml; DEX) oral rinse for treating stomatitis in a subset of pts (USA). Methods Postmenopausal pts with HR+, HER2− ABC previously untreated for advanced disease received EVE (10 mg/day) + LET (2.5 mg/day).At disease progression, pts were offered EVE (10 mg/day) + EXE (25 mg/day). Pts who had at least one episode of stomatitis received oral stomatitis daily questionnaire (OSDQ), which is a 6 question pt-reported outcome (PRO) survey (Stiff et al, JCO. 2006). A subset of these pts (USA) was randomized (1:1) to receive DEX or standard of care (SOC). The primary objective of investigator-assessed progression-free survival in the first-line setting for ABC was presented previously. A secondary objective was to evaluate the effectiveness of the DEX oral rinse in reducing the severity and duration of stomatitis, using OSDQ data. Results Of the total 202 pts enrolled in this study, 52 pts were enrolled in USA, of which, 24 (46.2%) were randomized to receive DEX (n=11) or SOC (n=13), upon confirmation of stomatitis. The median duration of first stomatitis episode was longer per OSDQ (DEX, not estimable vs SOC, 13.7 wk) compared with physician-reported duration (DEX, 1.6 wk vs SOC, 1.9 wk). PRO OSDQ results were similar in both arms. Among the 202 pts enrolled, 89 (44.1%) filled the OSDQ at their first stomatitis episode. The median time from treatment initiation to first stomatitis episode was 1.7 wk; median duration of stomatitis was 13.7 wk (OSDQ) vs 2.1 wk (physician reported). The majority of pts experiencing stomatitis had moderate/little/no soreness, moderate/low/no pain, and stomatitis had low/no effect on daily activities (Table 1). Table 1. OSDQ Key Results (N=87)Questions (Score)First Day of Stomatitis Episode, n (%)End of First Stomatitis Episode, n (%)Overall healthPoor (0-4)20 (23.0)23 (26.4)Moderate (5-7)40 (46.0)32 (36.8)Perfect (8-10)27 (31.0)32 (36.8)Mouth and throat sorenessNo/a little/moderate (0-2)64 (73.6)84 (96.6)A lot or extreme (3-4)23 (26.4)3 (3.4)Mouth pain severityNo/low/moderate (0-4)51 (58.6)73 (83.9)Severe (5-7)24 (27.6)10 (11.5)Unbearable (8-10)12 (13.8)4 (4.6)Effect on daily activitiesNo/low (0-4)70 (80.5)78 (89.7)Moderate (5-7)11 (12.6)4 (4.6)High (8-10)6 (6.9)5 (5.7) Conclusions Overall, patient-reported median duration of stomatitis was longer than that reported by physicians, most likely due to differences in perceptions and the challenges in collecting and cleaning PRO data. Overall good health score was maintained in the majority of pts experiencing stomatitis and stomatitis had low/no effect on daily activities. However, these results, especially in the randomized subset need to be interpreted with caution owing to the small sample size, missing data and lack of commercially available DEX in most countries. Citation Format: Villanueva C, Tsugawa K, Toyama T, Noh W, Jeong J, Cardoso F, Sriuranpong V, Srimuninnimit V, Ozguroglu M, Kendall S, Falkson C, Cianfrocca M, Manlius C, Lin JCJ, Ringeisen F, Ridolfi A, Royce M. Stomatitis in patients treated with first-line everolimus (EVE) plus letrozole (LET): Results from BOLERO-4 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-08.

Purpose: To compare incidences of hypersensitivity reaction (HSR) between original and generic taxanes including paclitaxel and docetaxel. Methods: We conducted a prospective study enrolling all patients receiving taxanes at King Chulalongkorn Memorial Hospital. Taxanes were infused accordingly to the step-wise rate escalation protocol at this hospital. Active surveillance for HSRs was performed. During the study period, there was only 1 generic brand used for each taxane. We primarily compared the incidences of HSR between original and generic drugs for each taxane. Results: During the period from January 1 to December 31, 2013, a total of 258 consecutive patients receiving taxanes were enrolled; 128 received paclitaxel, i.e. 65 and 63 in the original (Taxol) and generic arms, respectively, and 130 received docetaxel, i.e. 66 and 64 in the original (Taxotere) and generic arms, respectively. Premedication, including antihistamines and dexamethasone, was administered to all patients 30 min before taxane infusion. There were 26 (10.0%) HSR events including 24 grade 2 and 2 grade 3 HSRs. In the paclitaxel group, there were 9 (13.8%) and 7 (11.1%) HSRs in the original and generic arms, respectively (p = 0.791). In the docetaxel group, there were 9 (13.6%) and 1 (1.6%) HSRs in the original and generic arms, respectively (p = 0.017). No life-threatening symptoms or permanent discontinuation of taxanes occurred. Conclusions: In this prospective study, the incidences of HSR were similar with generic and original paclitaxel but significantly different with generic and original docetaxel.

Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.

Aim: The current study evaluated the efficacy and tolerability of second-line afatinib in patients with EGFR mutation-positive ( EGFRm+) non-small-cell lung cancer (NSCLC) following chemotherapy. Patients & methods: In this open-label, single-arm Phase IV study, patients with EGFRm+ (Del19/L858R) NSCLC who had progressed following platinum-based chemotherapy received afatinib (starting dose 40 mg/day). The primary end point was confirmed objective response. Results: 60 patients received afatinib for a median duration of 11.5 months. 50% of patients had a confirmed objective response, of median duration 13.8 months. Median progression-free survival was 10.9 months. The most common treatment-related adverse events were diarrhea (72%), rash (28%) and paronychia (23%). Conclusion: Our data support the use of afatinib (40 mg/day) as an effective and well-tolerated second-line treatment in EGFRm+ NSCLC.

Non-tumor-derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC), with unclear origination, is associated with prognosis. We hypothesized that a part of nt-cirDNA release from CD3 or CD8 tumor-infiltrating lymphocytes (TILs) could have clinical implications. To investigate the feasibility of T-cell-derived circulating DNA (T-cirDNA) detection, real-time PCR with Taqman assay-specific rearranged TCRβ CDR3 region was conducted in plasma of 103 advanced NSCLC. CD3 and CD8-specific immunohistochemistry from biopsy specimen, was reviewed by one blinded pathologist to the T-cirDNA results. Prognostic impact including demographic characteristics was integrated into the model. Circulating DNA was detectable in 100 patients with median of 4 ng ml−1, while median of plasma T-cirDNA was 1.71 pg ml−1. Median %ratio of T-cirDNA/cirDNA was 0.02%. T-cirDNA was categorized by %ratio of T-cirDNA/cirDNA as undetectable, low (≤ 1%) and high (> 1%). Paradoxical prognostic impact of T-cirDNA/cirDNA was observed. Undetectable and high T-cirDNA/cirDNA translated to independent favorable prognostic outcome, HR of 0.54 [95% CI 0.30–0.96] and 0.41 [95% CI 0.21–0.80], respectively. 43 patients were assessed for CD3/CD8 TILs and PD-L1. High intratumoral CD3/CD8 TILs but not stromal CD3 TILs was correlated with high T-cirDNA/cirDNA representing active T-lymphocyte activity to eliminate cancer cells. While the prognosis of undetectable T-cirDNA/cirDNA, represents inactivated naive T-cell, was determined by the presence of EGFR mutation and had long durable response of EGFR inhibitors. T-cirDNA could be a novel biomarker representing adaptive immune resistance in NSCLC patients. Further exploration as a predictive biomarker for EGFR inhibitors in setting of EGFR mutation might be warranted.

To evaluate the efficacy and safety of the addition of olanzapine to ondansetron and dexamethasone for chemotherapy-induced nausea vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy (HEC). In this randomized, double-blind, placebo-controlled, crossover study, we randomly assigned chemotherapy-naive patients receiving HEC to receive olanzapine or placebo in addition to ondansetron and dexamethasone. All subjects were crossed over to another treatment arm on second-cycle chemotherapy. The primary endpoint was complete response (CR) rate defined as no vomiting and no use of rescue drugs. At the first cycle, there were significantly more patients with CR in the olanzapine group than in the placebo group in overall phase (68.7% vs. 25.0%, p

Background Feasibility and safety of EUS-guided radiofrequency ablation (EUS-RFA) for unresectable pancreatic cancer (UPC) has been reported in only few small non-comparative studies. Aim Compare radiological response and pain medication used between EUS-RFA plus chemotherapy versus chemotherapy (CMT) alone as primary treatment of UPC in prospective comparartive study. Methods Patients with UPC with ECOG below 3 were recruited. Patients treated with EUS-RFA plus concurrent CMT were classified as group A. Control group was patients treated with CMT alone with matching clinical parameters (group B). All relevant parameters were compared (figure 1A). Results From July 2017 to August 2018, 28 patients (mean age 66.14?10years; M:F= 1:3) at King Chulalongkorn Memorial hospital were recruited. No statistical difference of baseline parameters (table 1). 34 EUS-RFA procedures were performed in 14 patients with median number of procedure 3 times (range 1–4 times), median total ablation time 270 seconds (range 90 - 962 seconds), and adverse event (AEs) rate 8.8% (3/34). Three AEs were post-procedure infection (length of stay (LOS) 7 days), bleeding puncture site (LOS 7 days) and mild pancreatitis (LOS 2 days). No delay of scheduled chemotherapy. 3 patients drop out due to disease progression in group A (n=11) and 1 patient loss to follow up in group B (n=13). Outcomes of both groups were compared (figure 1B). Morphine equivalent analgesia dose reduction was significantly better in group A, 22.5 mg/day (range 0–60) versus 0 mg/day (-20 to 30) (p=0.003), respectively, as well as median percentage dosage reduction (50% (0 to 100) versus 0% (-100 to 42.9), p=0.001), respectively. No enlargement of mean maximal target lesion diameter (mm) in group A (before vs. after; 61.37?20.1 vs 64.25?22.0 (P = 0.099), but significant increase in group B (50.1?21.1 vs. 55.4?18 (p=0.017), respectively).No significant difference of 6-month survival rate. Conclusions EUS-RFA plus concurrent CMT significantly reduce morphine dosage requirement than CMT in UPC. RFA additionally stabilized the tumor maximal target diameter whereas CMT failed.

Supplemental material, INC280X2201_HCC_Manuscript_Supplementary_Figure_S1 for A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma by Shukui Qin, Stephen Lam Chan, Wattana Sukeepaisarnjaroen, Guohong Han, Su Pin Choo, Virote Sriuranpong, Hongming Pan, Thomas Yau, Yabing Guo, Minshan Chen, Zhenggang Ren, Jianming Xu, Chia-Jui Yen, Zhong-Zhe Lin, Luigi Manenti, Yi Gu, Yongjian Sun, Ralph Tiedt, Lu Hao, Wenjie Song and Tawesak Tanwandee in Therapeutic Advances in Medical Oncology

9085 Background: In the Phase 3, EMPOWER-Lung 1 study, cemiplimab monotherapy provided significant survival benefit and an acceptable safety profile vs chemotherapy in patients with advanced NSCLC and PD-L1 ≥50%. EMPOWER-Lung 1 included patients with brain metastases at baseline who are typically underrepresented in clinical trials. Other published exploratory analyses in single-cohort studies suggest benefit from immunotherapy in this patient population. Here, we present subgroup analysis of patients with brain metastasis from EMPOWER-Lung 1. Methods: Patients were randomized 1:1 to cemiplimab 350 mg IV every 3 weeks or investigator’s choice of chemotherapy (NCT03088540). Patients with treated, clinically stable brain metastases (radiological stability not required) were eligible to enroll and are the focus of this subgroup analysis from the PD-L1 ≥50% population (n=563) of the EMPOWER-Lung 1 study. Results: A total of 68 of 563 (12.1%) cases had treated stable brain metastases at time of randomization. Patients were evenly distributed between cemiplimab (n=34) and chemotherapy (n=34), with similar median duration of follow-up (Table). Baseline characteristics were generally similar; median (range) age: 60.0 (45–76 ) vs 62.0 (48–77); male: 97.1% vs 85.3%; and non-squamous histology: 85.3% vs 76.5%; between cemiplimab vs chemotherapy, respectively. Per independent review committee, median overall survival (OS, 18.7 vs 11.7 months), median progression-free survival (PFS, 10.4 vs 5.3 months), and objective response rate (ORR, 41.2% vs 8.8%) were superior with cemiplimab vs chemotherapy (Table). After baseline, central nervous system (CNS) disease progression occurred in 2 (5.9%) patients with cemiplimab vs 4 (11.8%) patients with chemotherapy; extra-CNS disease progression occurred in 9 (26.5%) patients with cemiplimab vs 15 (44.1%) patients with chemotherapy. Conclusions: 1L cemiplimab monotherapy improved OS, PFS, and ORR vs chemotherapy, in patients with advanced NSCLC with PD-L1 ≥50%, and clinically stable brain metastases at baseline. Cemiplimab monotherapy represents a suitable option for this subgroup of patients. Clinical trial information: NCT03088540. [Table: see text]

9039 Background: Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, 10-20% of de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) in the presence of EGFR mutation remains the issue of concern. Methods: We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 year). Results: Uncommon EGFR mutation subtype was a significant variable in de novo resistance vs. IRs and LTRs with odd ratios of 6.83 ([95% CI 2.36 – 19.80], p-value < 0.001) and 16.84 ([95%CI 1.66 – 171.45, p-value 0.02), respectively. The remaining sensitizing EGFR mutation subtype (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6×10-4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4 /6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value < 0.001]. Conclusions: The presence of CDK4 /6 amplification in pretreatment specimen serve as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.

12100 Background: Prevention of chemotherapy-induced nausea and vomiting (CINV) is vital in cancer treatment. Here, we compared the efficacy of netupitant-containing regimen; composed of NEPA, dexamethasone, and olanzapine (NEPAs), which is recommended for preventing CINV from high-emetogenic chemotherapy (HEC) to standard 3-drugs; ondansetron, dexamethasone, olanzapine for preventing CINV from high-dose cisplatin (≥75 mg/m2). Methods: This randomized, double-blind, placebo-control trial randomly assigned untreated patients who were received high-dose cisplatin in a 1:1 ratio to either NEPAs or standard 3-drugs combination regimen. Dose of dexamethasone in NEPAs regimen was modified after preplanned interim safety analysis to increase from 4 to 8 mg per day on days 2-4. The stratification factors were concurrent treatment with radiation and sex. The primary endpoint was the overall complete response (CR) rate defined as no vomiting and no use of rescue antiemetic drugs. The protocol allowed crossover to NEPAs for those who received standard 3-drugs and did not reach CR in the first cycle. We collected outcome in the first 2-cycle of treatment. Results: Between January 2019 and December 2020, hundred patients were randomly assigned to either NEPAs (n = 51) or in-house standard 3-drugs (n = 49). Demographic characteristics were well-balanced in both arms. Total events in both arms were 101 events for NEPAs and 78 events for standard 3-drug. Overall CR rate were 70% and 69% in NEPAs and standard 3-drugs, ( p-value 0.87) respectively. According to emesis phase, CR in acute (0- 24 hrs.) and delay phase (24-120 hrs.) were not different in both arms; 91% vs. 89% and 72% vs. 71% in NEPAs and standard 3-drugs respectively. However, mean nausea VAS score was significantly lower in NEPAs (1.63 vs. 2.02, p-value = 0.001). The ad hoc subgroup analysis shown similar efficacy between before and after protocol amendment of NEPAs regimen in term of delay emesis CR rate; 70.9% vs. 73.9% ( p-value 0.73). Conclusions: The NEPA-containing regimen did not show superiority compare to standard 3-drug in terms of complete response rate for CINV prevention among patients receiving high-dose cisplatin. Furthermore, the dexamethasone dosage of 4 vs. 8 mg per day might not affect the efficacy of delay emesis of the NEPAs regimen. Clinical trial information: TCTR20190508001. [Table: see text]

Background Tamoxifen (TAM) is used in breast cancer treatment, but interindividual variabilities in TAM-metabolizing enzymes exist and have been linked to single nucleotide polymorphisms in the respective encoding genes. The different alleles and genotypes of these genes have been presented for Caucasians and Asians. This study aimed to explore the prevalence of the incomplete functional alleles and genotypes of the CYP2D6 and CYP3A5 genes in Thai breast cancer patients undergoing TAM treatment. Patients and methods In total, 134 Thai breast cancer patients were randomly invited to join the Thai Tamoxifen Project. Their blood samples were collected and extracted for individual DNA. The alleles and genotypes were determined by real-time polymerase chain reaction with TaqMan(®) Drug Metabolism Genotyping Assays. Results The patients were aged from 27.0 years to 82.0 years with a body mass index range from 15.4 to 40.0, with the majority (103/134) in the early stage (stages 0-II) of breast cancer. The median duration of TAM administration was 17.2 months (interquartile range 16.1 months). Most (53%) of the patients were premenopausal with an estrogen receptor (ER) and progesterone receptor (PR) status of ER+/PR+ (71.7%), ER+/PR- (26.9%), ER-/PR+ (0.7%), and ER-/PR- (0.7%). The allele frequencies of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP3A5*1, and CYP3A5*3 were 72.9%, 3.2%, 1.1%, 22.8%, 37.3%, and 62.7%, respectively, while the genotype frequencies of CYP2D6*1/*1, CYP2D6*1/*2, CYP2D6*2/*2, CYP2D6*4/*4, CYP2D6*1/*10, CYP2D6*2/*10, CYP2D6*4/*10, CYP2D6*10/*10, CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 were 9.7%, 2.2%, 3.7%, 1.5%, 15.7%, 9.7%, 3.7%, 53.7%, 13.4%, 47.8%, and 38.8%, respectively. Conclusion The majority (97.8%) of Thai breast cancer patients undergoing TAM treatment carry at least one incomplete functional allele, including 20.9% of the patients who carry only incomplete functional alleles for both the CYP2D6 and CYP3A5 genes. This research indicates the high prevalence of these defective alleles that are involved in TAM-metabolic pathways that might further affect TAM treatment.

Background Premedication with dexamethasone is crucial to prevent hypersensitivity reactions (HSR) associated with administration of taxanes. However, high dose and prolonged exposure to dexamethasone may cause adverse effects. Objectives To determine the incidence of HSR in patients with early breast cancer who did or did not receive dexamethasone prophylaxis for weekly paclitaxel infusions. Methods We retrospectively reviewed the records of a cohort of patients with early breast cancer who received paclitaxel weekly from January 2012 through March 2015 at King Chulalongkorn Memorial Hospital. All patients received a standard premedication protocol including dexamethasone before their first paclitaxel infusion. Dexamethasone was omitted in later cycles in some patients at the discretion of the attending physician. Data concerning the baseline characteristics of the patient, details of the premedication protocol, including dose and schedule of dexamethasone, and HSR events were collected in this observational study. Results Data were drawn from 86 breast cancer patients (median age 52.6 years) treated with a total of 984 cycles of paclitaxel chemotherapy. No patient had any history of allergy or HSR to taxanes. Dexamethasone was omitted in 617 later cycles. Six patients had grade II-III HSR (7.0%), which occurred mostly during the first 6 cycles (5/6, 83.3%). The incidence of HRS was 3/367 cycles (0.82%) with dexamethasone premedication (P = 0.99) and 5/617 (0.81%) without. Conclusions Withholding dexamethasone premedication for paclitaxel chemotherapy was feasible, and did not result in a higher incidence of HSR. However, an optimal schedule for dexamethasone warrants investigation in a prospective manner.

Tamoxifen is a pharmacological estrogen inhibitor that binds to the estrogen receptor (ER) in breast cells. However, it shows an estrogenic effect in other organs, which causes adverse drug reactions (ADRs). The sulfotransferase 1A1 (SULT1A1) enzyme encoded by the SULT1A1 gene is involved in estrogen metabolism. Previous research has suggested that the SULT1A1 copy number is linked with the plasma estradiol (E2) concentration. Here, a total of 34 premenopausal breast cancer patients, selected from the Thai Tamoxifen (TTAM) Project, were screened for their SULT1A1 copy number, plasma E2 concentration and ADRs. The mean age was 44.3±11.1 years, and they were subtyped as ER+/ progesterone receptor (PR) + (28 patients), ER+/ PR- (5 patients) and ER-/PR- (1 patient). Three patients reported ADRs, which were irregular menstruation (2 patients) and vaginal discharge (1 patient). Most (33) patients had two SULT1A1 copies, with one patient having three copies. The median plasma E2 concentration was 1,575.6 (IQR 865.4) pg/ml. Patients with ADRs had significantly higher plasma E2 concentrations than those patients without ADRs (p = 0.014). The plasma E2 concentration was numerically higher in the patient with three SULT1A1 copies, but this lacked statistical significance.

e21033 Background: Prognostic biomarker in early-stage lung cancer is less well defined. Despite early detection, one-third of patients with completely resected early-stage lung cancer without lymph node involvement have a recurrence. Our main objective is to investigate potential biomarkers useful in classification and predicting prognosis of this early-stage lung cancer, particularly in lymph node-negative subgroup. Methods: In discovery phase, we performed proteomic profiling on 60 lung cancer tissues to distinguish solid versus non-solid adenocarcinoma. Relative protein quantification was analyzed using Tandem Mass Tag mass spectrometry. In validation phase, tumor tissues from an additional cohort were analyzed by immunohistochemistry in conjunction with quantitative image analysis to confirm the differential expression of significantly altered proteins, including MCM2, MCM4, MCM6, SCAMP3, DPP4 and MYH11. Prognostic potentials of each biomarker were analyzed with univariate and multivariate analyses. Results: Quantitative proteomic analysis of predominantly solid versus non-solid adenocarcinoma tissues showed 30 differentially expressed proteins consisting of 13 increased and 17 decreased proteins found in solid compared with non-solid adenocarcinoma. Four most increased proteins (MCM2, MCM4, MCM6, and SCAMP3) and two most decreased proteins (DPP4 and MYH11) were selected for immunostaining in the validation cohort of 204 patients with resected adenocarcinoma without lymph node involvement. 57 out of 204 (27.9%) patients had recurrent disease. The high expression level of MCM4 was the strongest signature for disease recurrence (HR 4.85, 95%CI 2.78-8.47, p < 0.0001) and remained significant under multivariate analyses adjusted for TNM stage, histologic subtypes, lymphovascular invasion, tumor necrosis, and adjuvant chemotherapy. Recurrence-free survival (RFS) was significantly shorter in patients with high MCM4 compared with low MCM4 (5-y RFS 50% vs 84%, p < 0.0001) and remained highly significant within stage IA (5-y RFS 69% vs 93%, p < 0.0001), or stage IB and II (5-y RFS 36% vs 69%, p = 0.001). High expression of MCM4 correlated with other poor prognosis factors including smoking (p = 0.001), stage (p = 0.003), lymphovascular invasion (p = 0.036), visceral pleural invasion (p = 0.005), tumor necrosis (p < 0.0001) and solid histology (p < 0.0001). Conclusions: High MCM4 expression serves as an important prognostic biomarker predicting recurrence in early-stage node-negative lung adenocarcinoma.

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.

Background In MYSTIC, an open-label, phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs CT, while not statistically significant, a clinically meaningful improvement in overall survival (OS) was seen with D vs CT in patients with tumour cell PD-L1 expression ≥25% (TC ≥ 25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02]; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17]). Here we report results in a subpopulation of Asian patients. Methods Immunotherapy/CT-naive patients with metastatic NSCLC were randomized (1:1:1) to D (20 mg/kg q4w); D (20 mg/kg q4w) + T (1 mg/kg q4w ≤4 doses); or CT. In this analysis in a subpopulation of Asian patients, efficacy outcomes were evaluated in patients with PD-L1 TC ≥25%; safety was evaluated in all treated patients (regardless of PD-L1 expression). Results Of the 488 patients in the primary analysis population (PD-L1 TC ≥25%), 156 (32%) were Asian (D, 59; D+T, 50; CT, 47). Baseline characteristics in the Asian population were balanced between treatment arms. OS was improved in Asian patients (PD-L1 TC ≥25%) with D vs CT (HR 0.69 [95% CI 0.43–1.09]) and D+T vs CT (HR 0.64 [95% CI 0.40-1.03]); more patients receiving D or D+T remained in response at 6 months vs CT (Table). Grade ≥3 treatment-related adverse events (TRAEs) and any grade TRAEs leading to discontinuation occurred in 19.7% and 9.0% (D); 23.9% and 14.5% (D+T); 23.4% and 7.2% (CT) patients in the Asian subpopulation, respectively.Table474OTableDurvalumabDurvalumab + tremelimumabChemotherapyOverall (n = 163)Asian (n = 59)Overall (n = 163)Asian (n = 50)Overall (n = 162)Asian (n = 47)Median OS, mo16.3 (12.2–20.8)18.8 (9.2–28.4)11.9 (9.0–17.7)17.7 (11.6–27.3)12.9 (10.5–15.0)10.6 (7.0–14.6)24-mo OS rate, %38.343.835.442.022.722.3OS HR vs CT (95% CI)0.76 (0.56–1.02)*0.69 (0.43–1.09)0.85 (0.61–1.17)†0.64 (0.40–1.03)––ORR, n (%)58 (35.6)19 (32.2)56 (34.4)18 (36)61 (37.7)17 (36.2)Patients remaining in response (%) at6 mo66.968.467.652.732.434.312 mo61.362.254.926.318.0NROverall and Asian populations include patients with PD-L1 TC ≥25%;.*97.54% CI; †98.77% CI; ORR occurred on June 1, 2017; DoR, duration of response; NR, not reached; ORR, objective response rate; OS, overall survival. Conclusions Durvalumab resulted in a favourable HR for OS compared to CT in patients with PD-L1 TC≥25% in the Asian subpopulation, which was consistent with the primary analysis population. OS HR for D+T vs CT appeared to be more favourable in the Asian subpopulation compared to the primary analysis population, although results should be interpreted with caution due to small sample sizes. The safety profile of D±T in the subpopulation of Asian patients was manageable and consistent with the primary analysis population. Clinical trial identification NCT02453282. Editorial acknowledgement Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Beena John, PhD of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure B.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Champions Oncology; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K.H. Lee: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. S. Lucien Geater: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Samsung. T.V. Ngoc: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Novartis. S. Clarke: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. S. Kuyama: Speaker Bureau / Expert testimony, Lecture fees: AstraZeneca; Speaker Bureau / Expert testimony, Lecture fees: Pfizer; Speaker Bureau / Expert testimony, Lecture fees: Eli Lilly; Speaker Bureau / Expert testimony, Lecture fees: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Lecture fees: MSD; Speaker Bureau / Expert testimony, Lecture fees: Taiho; Speaker Bureau / Expert testimony, Lecture fees: Chughai. K. Nakagawa: Honoraria (institution), Research grant / Funding (institution): MSD / Takeda / SymBio Pharmaceuticals / Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): Taiho /Ono / Chughai; Honoraria (self), Research grant / Funding (institution): AstraZeneca / Astellas Pharma / Novartis / Nippon Boehringer Ingelheim / Pfizer Japan; Research grant / Funding (institution): Merck Serono / ICON Japan /PAREXEL / IQVIA Services Japan / A2 Healthcare / AbbVie; Research grant / Funding (institution): EP-CRSU / Linical / Otsuka Pharmaceuticals / EPS International / Quintiles / CMIC Shift Zero / Eisai / Kissei Pharmaceutical ; Research grant / Funding (institution): Kyowa Hakko Kirin / EPS Corporation / Bayer Yakuhin / inVentiv Health Japan / Gritstone Oncology / GSK / Yakult Honsha / Covance ; Honoraria (self): Kyorin Pharmaceutical / CareNet / Nichi-Iko Pharmaceutical / Hisamitsu Pharmaceutical / Yodosha / Clinical Trial / Reno Medical / Nanzando / Medical Review; Honoraria (self): Medicus Shuppan / Ayumi Pharmaceutical / Thermo Fisher Scientific / Yomiuri Telecasting Corporation / Nikkei Business Publications. F. Liu: Full / Part-time employment, Full-time employee: AstraZeneca. D. Clemett: Full / Part-time employment, Full-time employee: AstraZeneca. U. Scheuring: Full / Part-time employment, Full-time employee: AstraZeneca. S. Peters: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca / Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer / Seattle Genetics and Takeda; Honoraria (self), Advisory / Consultancy: Biocartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Clovis; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo / Regeneron / Sanofi; Honoraria (self), Advisory / Consultancy: Debiopharm; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): F Hoffmann-La Roche; Honoraria (self), Advisory / Consultancy: Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Illumina; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pharma Mar. N. Rizvi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Janssen; Leadership role, Shareholder / Stockholder / Stock options: ARMO BioSciences; Shareholder / Stockholder / Stock options: Gritstone Oncology. All other authors have declared no conflicts of interest.

Background In global phase III ASCEND-4 study (NCT01283516), ceritinib 750 mg/day (fasted), demonstrated statistically significant and clinically meaningful improvement in PFS by BIRC (median, 16.6 mos [95% CI: 12.6, 27.2] vs 8.1 mos [95% CI: 5.8, 11.1]; HR = 0.55; p Methods Pts with stage IIIB/IV, ALK + (centrally tested IHC), nonsquamous NSCLC, ≥1 measurable lesion per RECIST v1.1, and WHO PS 0–2 were eligible. Efficacy and safety were evaluated in Asian pts who had not received prior systemic anticancer therapy except neo-/adjuvant therapy. Data cutoff: June 24, 2016. Results Among 376 pts randomized (1:1) in the study, 158 pts were Asian, with 76 in ceritinib arm and 82 in chemotherapy arm. Of these, 25 pts (32.9%) in ceritinib arm and 21 (25.6%) in chemotherapy arm had brain metastases at baseline. Median duration of treatment exposure: 64.5 wks (ceritinib, N = 76) and 35.0 wks (chemotherapy, N = 75). Median duration from randomization to data cutoff: 18.3 mos. Ceritinib demonstrated superior PFS by BIRC (median, 26.3 mos; 95% CI: 8.6, NE; HR = 0.66) compared to chemotherapy (Table). Most common (≥50%; all grades; all-causality) AEs in ceritinib arm: diarrhea (85.5%), ALT increased (73.7%), vomiting (73.7%), AST increased (69.7%), and nausea (69.7%). Incidence of grade 3/4 AEs was Table . 1473P By BIRC (N * =158) Ceritinib 750mg N = 76 Chemotherapy N = 82 Overall response rate (ORR), % [95% CI] 65.8 [54.0, 76.3] 29.3 [19.7, 40.4] Best overall response, n (%) Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-CR/Non-PD Unknown 0 50 (65.8) 11 (14.5) 11 (14.5) 2 (2.6) 2 (2.6) 0 24 (29.3) 38 (46.3) 6 (7.3) 3 (3.7) 11 (13.4) Disease control rate (DCR), % [95% CI] 82.9 [72.5, 90.6] 79.3 [68.9, 87.4] M ‡ =50 M ‡ =24 Median DOR, months [95% CI] NE [24.7, NE] 16.4 [7.8, NE] n/N (%) 14/50 (28.0) 8/24 (33.3) % Event-free probability estimates [95% CI] 9 months 81.2 [67.0, 89.8] 76.1 [48.0, 90.4] 12 months 79.0 [64.5, 88.1] 50.8 [22.5, 73.5] 15 months 70.4 [54.0, 81.9] 50.8 [22.5, 73.5] Median PFS, months [95% CI] 26.3 [8.6, NE] 10.6 [6.7, 15.0] n/N (%) 32/76 (42.1) 45/82 (54.9) % Event-free probability estimates [95% CI] 9 months 61.0 [48.4, 71.5] 54.7 [41.8, 65.8] 12 months 61.0 [48.4, 71.5] 49.8 [37.1, 61.2] 15 months 55.9 [43.2, 66.9] 39.0 [26.9, 51.0] * Total number of patients included in the full analysis set. ‡ Total number of patients with confirmed complete response or partial response. n: Total number of events included in the analysis. N: Total number of patients included in the analysis. Conclusions In Asian pts with ALK+ NSCLC, ceritinib demonstrated durable and clinically meaningful efficacy and a safety profile consistent with overall ASCEND-4 study results. Clinical trial identification NCT01828099. Editorial acknowledgement Shilpa Garg, Novartis Healthcare Pvt Ltd. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure D.S. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant / Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer; Travel / Accommodation / Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda. S. Geater: Advisory / Consultancy: Boehringer Ingelheim; Honoraria (institution): AstraZeneca, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche, Novartis, Boehringer Ingelheim; Full / Part-time employment: Prince of Songkla Univerisity. C.J. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. T.C. Hsia: Advisory / Consultancy: Norvatis, Lilly, AZ, Roche local speaker. M.C. Lin: Advisory / Consultancy: AZ, Novartis, BI, Roche. V. Sriuranpong: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Novartis, Roche, Pfizer, Eisai, Boehringer, Taiho, MSD, BMS, Amgen; Research grant / Funding (institution): AstraZeneca, Novartis, Roche, Pfizer, Boehringer, Eisai, Taiho, Lilly, MSD. P. Sen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Y.L. Wu: Honoraria (self): AZ, Roche, Eli Lilly, Pfizer, MSD, BMS, BI; Advisory / Consultancy: AZ, Roche, BI; Research grant / Funding (institution): AZ, Roche. All other authors have declared no conflicts of interest.

Background: Most patients (pts) with NSCLC present with advanced disease at diagnosis. Systemic therapy with platinum-based doublet chemotherapy regimens has been the standard first-line treatment for pts with advanced NSCLC whose tumours do not have EGFR, ALK, or ROS 1 mutations, but there is a need for effective treatments to improve long-term survival. With the recognition that NSCLC tumours express PD-L1, checkpoint inhibitors are being investigated in several clinical trials. There is currently only one PD-1 inhibitor approved as monotherapy in first-line treatment of NSCLC with PD-L1 expression ≥50%. In a phase 1 dose escalation and NSCLC expansion cohort, cemiplimab (REGN2810), a human monoclonal anti-PD-1, has demonstrated antitumour activity with an acceptable safety profile in anti-PD-1 naive, pre-treated pts with NSCLC. Trial design: This is a randomised (1:1), multicentre, open-label, phase 3 study of cemiplimab versus platinum-based doublet chemotherapy in systemic treatment-naive pts (≥18 years) with stage IIIB, IIIC or IV squamous or non-squamous NSCLC whose tumours express PD-L1 in ≥ 50% of tumour cells (NCT03088540).

Purpose This study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations. Patients and methods One hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis. Results The patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype. Conclusion CYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

Aims Currently, the only standard systemic treatment for advanced hepatocellular carcinoma is sorafenib monotherapy. The study was conducted to assess the efficacy and safety of the novel combination of sorafenib and gemcitabine in the treatment of advanced hepatocellular carcinoma. Methods Between March 2008 and October 2010, patients with advanced pathologically proven hepatocellular carcinoma who had not received previous systemic therapy and had Child–Pugh liver function class A or B received sorafenib plus gemcitabine. Treatment included 4-week cycle of gemcitabine (1000 mg/m2 days 1, 8, 15) to the maximum of six cycles together with sorafenib (400 mg twice daily). Patient continued sorafenib until disease progression or withdrawal from other reasons. The primary end point is progression-free survival. Results Forty-five patients were enrolled in this study. The median progression-free survival was 3.7 months (95% CI 3.5–3.8). The overall response rate was 4% with no complete responses and the disease control rate was 66%. The median overall survival (OS) was 11.6 months (95% CI 7.4–15.9). The median time to progression was 3.6 months (95% CI 3.4–3.7). The most frequently reported grade 3/4 treatment-related adverse events included thrombocytopenia 33%, neutropenia 16% and hand-foot skin reaction 13%. The study regimen was well tolerated. Conclusion The combination of sorafenib and gemcitabine in advanced hepatocellular carcinoma is generally well tolerated and has modest clinical efficacy. The median OS is up to 1 year. However, well-designed randomized controlled trials with a sorafenib alone comparator arm are needed to confirm this finding.

Aims We evaluated and compared the safety and efficacy of sunitinib in Asian and non-Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program. Methods Previously treated and treatment-naive patients received open-label sunitinib at a starting dose of 50 mg/day for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Safety was assessed regularly, tumor measurements were performed per local practice, and survival data collected where possible. Results Data were available for 212 Asian patients from Asian sites (Asian-A), 113 Asian patients from non-Asian sites (Asian-O) and 4046 non-Asian patients. The most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia, hand–foot syndrome, diarrhea, asthenia and fatigue. The incidence of many adverse events was greater in Asian-A than in Asian-O or non-Asian patients. Sunitinib efficacy was comparable between Asian and non-Asian patients, with an objective response rate of 18% versus 14%; median progression-free survival of 8.7 versus 10.9 months; and overall survival of 18.9 versus 18.4 months, respectively. Conclusions Sunitinib demonstrated tolerable safety and similar efficacy in Asian and non-Asian patients. Geographic differences in the reported frequency of specific adverse events were noted across Asian patients.

Importance Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. Trial Registration clinicaltrials.gov Identifier:NCT02472964; EudraCT Identifier: 2011-001965-42

Background Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum‐based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Methods Data of patients with cT2‐cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Results Forty‐four patients were treated with intensity‐modulated radiation therapy, volumetric‐modulated arc therapy or three‐dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow‐up duration was 22.4 months and median survival was 25.6 months. Two‐year overall, progression‐free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3–4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3–4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Conclusion Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long‐term survival with low toxicities.