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550 Background: TOPAZ-1 (NCT03875235) is a double-blind, Phase 3 study of durvalumab (D), an immune checkpoint inhibitor (ICI), + gemcitabine and cisplatin (GC) in participants (pts) with advanced biliary tract cancer (BTC). D + GC improved overall survival (OS) in pts with advanced BTC versus placebo (PBO) + GC (Oh et al. NEJM Evid 2022). Use of antibiotics during ICI treatment has been correlated with poorer OS and progression-free survival (PFS; Jiang et al. Front Oncol 2022). Methods: Pts were randomized 1:1 to receive D (1500 mg) or PBO on Day 1 every 3 weeks (Q3W), + G (1000 mg/m2) and C (25 mg/m2) on Days 1 and 8 Q3W, for ≤8 cycles, followed by D or PBO monotherapy Q4W. This exploratory subgroup analysis of TOPAZ-1 assessed OS and PFS by systemic antibiotic use during the study (≥1 dose 14 days before first D/PBO dose to 14 days after last D/PBO dose). Hazard ratios (HRs) were estimated using an unstratified Cox proportional hazards model, adjusting for disease status (initially unresectable or recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer). Data cut-off at primary analysis was Aug 11, 2021. Results: The number (%) of pts using antibiotics during the study (D + GC, 167/341 [49.0%]; PBO + GC, 167/344 [48.5%]) was similar between treatment arms. In the D + GC arm, median OS (95% CI) was similar regardless of antibiotics use: 12.6 (9.7–14.8) months in pts with antibiotics use vs 13.0 (10.8–14.7) months in pts without (Table). In the PBO + GC arm, median OS (95% CI) was 10.3 (8.7–12.5) in pts with antibiotics use vs 12.1 (11.0–13.8) in pts without. OS HRs (95% CI) in D + GC vs PBO + GC were 0.78 (0.59–1.02) in pts with antibiotics and 0.81 (0.62–1.07) in pts without. Median PFS (95% CI) was 7.3 (6.5–7.7) months in pts with antibiotics use vs 7.2 (5.9–7.4) months in pts without in the D + GC arm and 5.7 (5.4–6.6) months vs 6.1 (5.6–7.3) months, respectively, in the PBO + GC arm (Table). PFS HRs (95% CI) were 0.70 (0.55–0.89) in pts with antibiotics use and 0.82 (0.65–1.03) in pts without. Conclusions: In the TOPAZ-1 study of D in BTC, no meaningful difference was found in OS or PFS for participants who received antibiotics during the study period compared with those who did not, and results were consistent with the primary analysis. These results support that people receiving D may be treated with antibiotics when clinically indicated. Clinical trial information: NCT03875235 . [Table: see text]

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

549 Background: Intermediate-stage HCC, as defined as Barcelona Clinic Liver Cancer (BCLC) Stage B, is a heterogeneous disease in terms of liver function and tumor load. REACH (NCT01140347) and REACH-2 (NCT02435433) investigated ramucirumab (RAM) in patients (pts) with HCC after prior sorafenib (SOR), with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: All pts had HCC (BCLC stage C or B disease refractory/not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or Placebo (P) Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was performed. Prognosis of BCLC staging in overall survival (OS) was evaluated by multivariate Cox PH model (adjusted for baseline AFP and treatment (trt) arm); Trt effects in BCLC stage B and C by Cox PH model; median OS/PFS were estimated by Kaplan-Meier method. Objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), and adverse events (AEs) were also reported by BCLC. Liver function was assessed at baseline and prior to each trt with the Albumin-Bilirubin (ALBI) linear predictor. Results: Baseline characteristics were generally balanced between trt arms in each BCLC stage. BCLC staging trended as an independent prognosis factor for OS [B v C; HR = 0.756 (0.546, 1.046)]. A consistent trt benefit for RAM v P was observed across staging (Table). Grade ≥3 AEs were consistent with observations from both individual studies; hypertension was the most frequent grade ≥3 AE. No difference in liver function, as measured by ALBI, was observed between trt arms in either BCLC stage. Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit irrespective of BCLC stage. RAM was well tolerated and did not alter liver function compared to P. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]

4073 Background: Oral multikinase inhibitors that have shown improvements in overall survival (OS) in HCC are associated with clinically important toxicities that commonly require dose adjustment or discontinuation (D/C) due to intolerance. REACH and REACH-2 studied RAM in patients (pts) with HCC who progressed on or were intolerant to sorafenib (SOR), and REACH-2 only enrolled pts with baseline AFP ≥400 ng/mL. In REACH-2 RAM treatment (trt) improved OS compared to placebo (P), supporting findings in REACH pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by reason for D/C of SOR was performed. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or P Q2W. A pooled independent pt data analysis (stratified by study) of REACH-2 and REACH pts (AFP ≥400 mg/mL) was performed. Results are reported by reason for SOR D/C (intolerance or disease progression). OS and PFS were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR) and safety are reported. Results: Baseline characteristics in the pooled population were generally balanced between trt arms in each subgroup. Median durations of prior SOR were 2.5 mo for SOR intolerant (n = 70) and 4.0 mo for SOR progressors (n = 472). Median OS (RAM v P) was 10.2 v 6.7 mo for SOR intolerant and 8.0 v 4.7 mo for SOR progressors (Table). Rates of D/C due to trt-related adverse events (AEs) (Table) (7% in each subgroup), and Grade ≥3 AEs (most frequently hypertension) were consistent with those observed in each study. Conclusions: Acknowledging limitations of sample size, the RAM trt benefit in SOR intolerant pts was consistent with that in the ITT population. RAM was well tolerated in SOR intolerant pts with low rates of D/C due to related-AEs. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]

326 Background: REACH-2 (NCT02435433) demonstrated a significant survival benefit with RAM vs placebo in the second-line treatment of patients with advanced HCC and AFP ≥ 400 ng/mL. This analysis investigated changes in AFP during treatment, as well as potential relationships with survival or progression. Methods: Patients were randomized (2:1) to RAM 8 mg/kg IV or placebo Q2W plus best supportive care until disease progression or unacceptable toxicity. Serum AFP levels were measured at baseline and every 3 cycles. Percent change in AFP from baseline was analyzed at each time point up to Cycle 12 with descriptive statistics and Wilcoxon rank sum test between treatment arms. AFP response was defined as ≥ 20% decrease from baseline. The association between AFP progression and radiographic progression in each time interval was assessed by odds ratio [OR] and Fisher’s exact test. Time to AFP progression and time to radiographic progression (TTP) were evaluated by the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test. AFP progression was defined as ≥ 20% increase from baseline. Hazard ratio (HR) was generated using a stratified Cox regression model. Results: AFP response was significantly higher with RAM compared with placebo (42.1% vs 10.5%, p < 0.0001). Overall survival (OS) was longer in patients with AFP response (13.5 months) than in patients without (6.7 months), irrespective of treatment (HR 0.470, p < 0.0001). The median percent increase in AFP level from baseline was smaller in the patient population treated with RAM (0.4%, 6.1%, 15.4%, 10.8%) than with placebo (45.7%, 98.5%, 122.2%, 91.3%) at Cycles 3, 6, 9 and 12, respectively. Time to AFP progression (HR 0.422, p < 0.0001) and TTP (HR 0.427, p < 0.0001) favored a RAM benefit; subsequent analyses demonstrated a strong association between AFP progression and radiographic progression at 6 weeks (OR 2.44, p < 0.0084) and at 12 weeks (OR 1.89, p = 0.0430). Conclusions: Changes in AFP levels were associated with TTP and OS. RAM prolonged time to AFP progression and radiographic TTP, and slowed the rate of AFP increase during treatment. Clinical trial information: NCT02435433.

317 Background: In the phase 3 REFLECT study, lenvatinib (LEN) demonstrated a treatment effect on overall survival (OS) by statistical confirmation of non-inferiority to sorafenib (SOR) in patients (pts) with unresectable hepatocellular carcinoma (uHCC), who had not received prior treatment for advanced disease (Kudo M et al, Lancet 2018). Lenvatinib is approved in several major markets for the first line systemic treatment of uHCC. The most common adverse events (AEs) in pts treated with LEN were hypertension and diarrhea. In addition, LEN showed a different AE profile from that of SOR. Pts who received LEN experienced more instances of hypertension, proteinuria, dysphonia, and hypothyroidism than patients who received SOR. Recently, hypertension in LEN-treated pts with differentiated thyroid cancer was shown to be correlated with improved efficacy. Here we report the post hoc analysis exploring whether AEs associated with LEN were correlated with longer OS in REFLECT. Methods: 478 Pts were randomized to receive LEN (12 mg/d for actual body weight ≥ 60 kg or 8 mg/d for actual body weight < 60 kg). Subgroup analyses were conducted based on whether pts treated with LEN experienced any-grade AEs of interest (AEIs). OS was estimated by the Kaplan-Meier method. Results: The AEIs in pts treated with LEN were hypertension (42%), diarrhea (38%), proteinuria (24%), dysphonia (24%), and hypothyroidism (16%). OS was longer in pts who had several AEs of interest than in those who did not (table). Conclusions: In pts treated with LEN, the occurrence of hypertension, diarrhea, proteinuria, or hypothyroidism was generally associated with longer OS in pts with uHCC in this post hoc exploratory analysis. The potential confounding factors at baseline should be further investigated. Clinical trial information: NCT01761266. [Table: see text]

134 Background: Our preclinical studies showed that AUY922 treatment could induce downregulation of KIT protein and apoptosis in both imatinib-sensitive and -resistant GIST cells (Autophagy 2013). This prospective, phase II trial evaluated the efficacy and safety of AUY922 in patients with metastatic GISTs after failure or intolerance to imatinib and sunitinib in an Asian population. Methods: Based on the MTD defined in previous phase I study, infusion 70 mg/m2 of AUY922 was given once weekly, 4 weeks as a cycle. The primary endpoint was disease control rate (DCR, objective response + stable disease ≥ 16 weeks), assessed by computed tomography (CT) scan according to RECIST v1.1 every 8 weeks. Metabolic response was assessed by positron emission tomography (PET)-CT scans performed at baseline and after 4 weeks of treatment. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: Between 2011.10 and 2015.01, 25 evaluable patients were enrolled. DCR at 16 weeks was 20% but none had partial response. According to the EORTC-defined PET response criteria, ten patients (40%) had metabolic partial response ( > 25% decrease of SUV from baseline) at 4 weeks after AUY922 treatment. At a median follow-up time of 7.8 months (range, 2.0-33.4 months), median progression-free survival (PFS) was 2.4 months (95% confidence interval (CI), 1.6-3.2 months) and median overall survival was 9.6 months (95% CI, 0-21.1 months). Metabolic partial responders had a trend of better PFS (3.8 vs. 1.9 months in non-responders, P = 0.09). The common adverse events (AEs) were fatigue (82%), visual disturbances (70%), diarrhea (55%). Grade 3/4 AEs included visual field darkening (3.7%), blurred vision (7.4%) and diarrhea (7.4%). Treatment interruption and dose modification were frequently required (62%) in patients with more than 8 weeks of treatment because of grade 2-3 visual field darkening. Conclusions: AUY922 showed modest antitumor activity in heavily pretreated GIST patients. Clinical relevant ocular toxicity was unexpectedly high in current study cohort; its correlation with PK will be further explored. Clinical trial information: NCT 01389583.

77 Background: Cancer-related fatigue (CRF) is common symptom in cancer patients. However, there is no study related to occurrence, severity and impact of CRF in Taiwan. The aim of this study was to report the occurrence and severity of CRF, and its impact on quality of life in cancer inpatients and outpatients in Taiwan. Methods: A national survey with cross-sectional study design was used. Patients were recruited from 20 hospitals with inpatients unit (n = 574) and outpatients clinics (n = 633) in Taiwan. The structured questionnaire was used to assess patients’ demographic, clinical, and CRF characteristics among Taiwanese cancer patients. The CRF were assessed by International Classification of Diseases 10th Revision (ICD-10) and Brief Fatigue Inventory–Taiwan Form (BFI-T). Quality of life (QOL) was assessed by FACT-general. Descriptive statistics and bivariate correlations were used to compare the occurrence, severity, and impacts on quality of life of CRF between cancer inpatients and outpatients. Results: Overall, the occurrence was 23.36% based on ICD-10 CRF criteria and 31.9% and 15.6 for inpatients and outpatients, respectively. About94.4% of inpatients and 89.7% of outpatients experienced fatigue. Inpatients had significant higher fatigue severity (current fatigue, general fatigue, and worst fatigue) during the past 24 hours compared to the outpatients. Enjoyment of life was the most interfered by fatigue in both inpatients and outpatients. The mean levels of current fatigue, general fatigue and worst fatigue were moderate in inpatients, and they were mild to moderate in outpatients. The mean score of FACT-general was 17.57 in overall with the lowest level of functional well-being, and 15.68 and 19.29 in inpatients and outpatients. Conclusions: The occurrence based on the ICD-10 CRF criteria was relative low compared to self-report. Fatigue interfered patients’ enjoyment of life and the patients had the lowest level of quality of life in functional well-being. Healthcare providers should pay attention on how to decrease cancer patients’ fatigue in order to improve their QOL, especially in inpatients.

e13588 Background: MM-398 is a nanoliposomal irinotecan (nal-IRI). This study characterized the population PK and exposure–response with MM-398 in patients with solid tumors. Methods: Population PK...

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

4103 Background: Sorafenib (S) is the only approved systemic treatment for unresectable HCC. Nevertheless, there remains an unmet medical need for more effective treatment options for this disease. BAY 86-9766 (B) is an oral, allosteric inhibitor of MEK, a key component of the MAP kinase pathway. This study evaluated the efficacy and safety of a combination therapy with B plus S in patients (pts) with HCC. Methods: This is a single arm, open-label, phase 2 study. Eligible were pts with unresectable HCC, Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no hand-foot skin reaction, fatigue, or gastrointestinal toxicity ≥ grade 2, S was escalated to 400 mg bid from Cycle 2 on. Treatment continued until progression or withdrawal criteria were met. Tumor assessment was performed every 6 weeks during treatment. Safety was evaluated every week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts from Asia started study treatment. Pts were predominantly male (86%); median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV (17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%) had confirmed partial response and 25 pts (38%) had prolonged stable disease (≥10 weeks), with a disease control rate of 43%. Median time-to-progression was 4.1 months. Survival data are not mature, yet. The most frequent drug-related adverse events (AEs) were rash (60%), diarrhea (59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation (26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown cause, respectively). Dose modifications due to AEs were necessary in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg for S, respectively. Conclusions: B in combination with S showed antitumor activity in pts with HCC. However, frequent dose modifications due to AEs might have limited the treatment effect of this combination.

e14576 Background: Based on the results of ToGA (Trastuzumab for Gastric Cancer) study, trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with hum...

4266 Background: The aim of this dosing-finding study was to determine the maximum- tolerated dose (MTD), the dose-limiting toxicities (DLTs) and to define the recommended dose of biweekly oxalipla...