Citations

TPS4138 Background: Apatinib is an orally administered, highly selective tyrosine kinase inhibitor of VEGFR-2 that has been studied in many clinical trials, primarily in China, treating various solid tumors. Based on the results of the Chinese Phase 3 study, apatinib was approved in China for the treatment of advanced gastric cancer (GC), but apatinib has yet to be evaluated in a randomized placebo-controlled study in the rest of the world. ANGEL is a multinational, placebo controlled, Phase 3 study investigating the efficacy and safety of apatinib in advanced GC patients in North America, Europe, and Asia Pacific. Methods: Main eligibility criteria include patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction for whom at least 2 prior lines of standard chemotherapy had failed, ECOG performance status ≤ 1, and disease progression < 6 months after last chemotherapy treatment. Approximately 459 patients will be randomized in a 2:1 ratio to receive continuous 28-day cycles of apatinib 700 mg or a matched placebo daily with best supportive care until disease progression, intolerable toxicity or withdrawal of consent. Stratification factors include geographic region (Asia vs. North America/Europe), disease measurability, prior ramucirumab treatment, and treatment therapy line (3rd or 4th). Primary endpoint is overall survival (OS) in the intent-to-treat population, and secondary endpoints are progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. The primary analysis of OS will be conducted in intention-to-treat population using a stratified log-rank test at the two-sided alpha = 0.05 level of significance. If the primary analysis of OS is statistically significant, then PFS and ORR will be analyzed. All other secondary efficacy endpoints will be analyzed using two-sided tests at the alpha = 0.05 level of significance. Enrollment opened Feb 2017. Clinical trial information: NCT03042611.

4073 Background: Durvalumab and tremelimumab, investigational monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, respectively, have shown efficacy in monotherapy and offer promise in combination for patients (pts) with HCC. This is a phase I/II, open-label, randomized study of durvalumab combined with tremelimumab in unresectable HCC. Methods: Phase I part of this study is a safety run-in cohort treated at the recommended phase II doses of the durvalumab/tremelimumab combination (20 and 1 mg/kg IV Q4W respectively for 4 doses followed by 20 mg/kg Q4W durvalumab alone) in pts with unresectable HCC with or without concomitant HBV or HCV infection who progress on, are intolerant to, or have refused sorafenib therapy. Secondary objectives include evaluation of antitumor activity. Here we present results of a preplanned analysis from the completed phase I part of the study. Results: As of 10 January 2017, 40 pts have been enrolled (11 HBV+, 9 HCV+, 20 uninfected). 30% had no prior systemic therapy; 93% were Child Pugh Class A. 24 (60%) had ≥1 treatment-related AE; 20% had ≥1 grade ≥3 related AE. Most common (≥15%) treatment-related AEs: fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). Most common grade ≥3 related AE was asymptomatic increased AST (10%). 24 pts have discontinued treatment: 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (pt entered hospice care). 40 pts were evaluable for response at ≥16 weeks follow-up. Conclusions: No unexpected safety signals with durvalumab and tremelimumab were seen in this unresectable HCC population. Clinical activity observed predominantly in uninfected pts though interpretation limited by small subsets. Enrollment to the phase II portion of the study is ongoing. Clinical trial information: NCT02519348. [Table: see text]

4003 Background: Pembro has shown promising antitumor activity and manageable safety in a phase 1 study of pts with previously treated advanced gastric cancer. We conducted a global, multicohort, phase 2 study of pembro in pts with advanced gastric or gastroesophageal junction (G/GEJ) cancer (KEYNOTE-059;NCT02335411). Methods: Cohort 1 enrolled 259 pts, aged ≥18 y with measurable recurrent or metastatic G/GEJ adenocarcinoma who had progressed on ≥2 prior chemotherapy regimens and had ECOG PS 0-1. Pts received pembro 200 mg Q3W up to 2 y or up to disease progression, investigator/pt decision to withdrawal, or unacceptable toxicity. PD-L1+pts had expression in ≥1% tumor or stromal cells using IHC (22C3 antibody). Primary end points: ORR (RECIST 1.1, by central review), safety, and tolerability. Results: Of 259 pts in cohort 1, 76.4% were men; median age was 62.0 y. 51.7% and 48.3% received pembro as 3rd-line (3L) and 4L+ therapy, respectively. 57.1% had PD-L1+ tumors. At data cutoff (Oct 19, 2016), median duration of follow-up was 5.4 mo (range, 0.5 to 18.7). Overall ORR (CR + PR) was 11.2% (95% CI, 7.6-15.7); 1.9% of pts (95% CI, 0.6-4.4) had CR, 9.3% had PR (95% CI, 6.0-13.5), 17% (95% CI, 12.6-22.1) had SD, and 55.6% (95% CI, 49.3-61.7) had PD. Median DOR was 8.1 mo (range, 1.4+ to 15.1+). ORR was 14.9% (95% CI, 9.4-22.1) in 3L pts and 7.2% (95% CI, 3.3-13.2) in 4L+. In PD-L1+ pts, ORR was 15.5% (95% CI, 10.1-22.4) with 2.0% (95% CI, 0.4-5.8) CR and 13.5% (95% CI, 8.5-20.1) PR; in PD-L1– pts, ORR was 5.5% (95% CI, 2.0-11.6), with 1.8% (95% CI, 0.2-6.5) CR and 3.7% (95% CI, 1.0-9.1) PR. In 3L pts with PD-L1+ tumors, ORR was 21.3% (95% CI, 12.7-32.3), with 4.0% (95% CI, 0.8-11.2) CR; in 3L pts with PD-L1– tumors, ORR was 6.9% (95% CI, 1.9-16.7), with 3.4% (95% CI, 0.4-11.9) CR. Grade 3-5 treatment-related AEs (TRAEs) occurred in 43 pts (16.6%). TRAEs led to discontinuation in 2 pts (abnormal LFT, bile duct stenosis) and were fatal in 2 pts (acute kidney injury, pleural effusion). Conclusions: Pembro showed encouraging efficacy and manageable safety after ≥2 prior lines of therapy in pts with advanced G/GEJ cancer in this large phase 2 trial. Survival and additional biomarker data, including MSI status, will be presented. Clinical trial information: NCT02335411.

e12522 Background: Trastuzumab is widely used in management of HER2+ breast cancer patients. A known adverse effect of trastuzumab use is cardiac dysfunction, which can often be reversed with cessation of therapy. Our objectives were to 1) assess if trastuzumab can be safely administered to breast cancer patients with reduced cardiac function and 2) identify patient characteristics that predict susceptibility to trastuzumab-induced cardiac dysfunction. Methods: A retrospective analysis was performed on female patients seen at Mayo Clinic for HER2+ breast cancer and treated with trastuzumab for localized or metastatic disease between January 1, 2000 and August 31, 2015. Eligibility criteria included documentation of and results from at least one echocardiogram prior to and at least one after trastuzumab initiation. Left ventricular (LV) ejection fraction (EF) of 53% or more was considered normal. Any LVEF reduction of 10% or more was considered significant. Among patients with normal EF, age strata of < 45, 45-60, and > 60 at time of trastuzumab initiation were used to assess risk factors for clinically diagnosed cardiac dysfunction (defined as EF < 53 or abnormal strain and physical symptoms of heart failure (HF)). Results: We identified 335 women (mean age 53.3, with 25.3% age < 45, 44.5% age 45-60, and 30.1% age > 60) who had normal LVEF (median EF 64, range: 53-75) and 23 women (mean age 53.4, with 30.4% age < 45, 43.5% age 45-60, and 26.1% age > 60) who had low LVEF at baseline (median EF 52, range: 25-52). Approximately a third (34.3%) of women with normal LVEF prior to initiation of therapy had at least one subsequent echocardiogram showing a drop of 10% or a low LVEF ( < 53). Approximately a quarter (26%) of women with low LVEF at baseline had a 10% drop in LVEF. HF incidence increased with age. Predictive factors for trastuzumab-induced cardiac dysfunction were obesity and history of coronary artery disease (CAD) across all age strata, and chest irradiation (IR) for those aged 45-60 only. Conclusions: Our results suggest that trastuzumab can be administered in women with reduced cardiac function at no greater risk than in those with preserved cardiac function. Some women with no obesity, history of CAD, or history of chest IR may not need echocardiograms during trastuzumab therapy.

New integrated PET‐MRI systems potentially provide a complete imaging modality for diagnosis and evaluation of musculoskeletal disease. MRI is able to provide excellent high‐resolution morphologic information with multiple contrast mechanisms that has made it the imaging modality of choice in evaluation of many musculoskeletal disorders. PET offers incomparable abilities to provide quantitative information about molecular and physiologic changes that often precede structural and biochemical changes. In combination, hybrid PET‐MRI can enhance imaging of musculoskeletal disorders through early detection of disease as well as improved diagnostic sensitivity and specificity. The purpose of this article is to review emerging applications of PET‐MRI in musculoskeletal disease. Both clinical applications of malignant musculoskeletal disease as well as new opportunities to incorporate the molecular capabilities of nuclear imaging into studies of nononcologic musculoskeletal disease are discussed. Lastly, we discuss some of the technical considerations and challenges of PET‐MRI as they specifically relate to musculoskeletal disease.Level of Evidence5Technical EfficacyStage 3 J. Magn. Reson. Imaging 2018;48:27–47.