Corrine Zarwan

Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy. Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane. Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure. The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.

Background We assessed the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with previously treated metastatic adrenocortical carcinoma (mACC). Methods In this phase 1b expansion cohort, patients with mACC and prior platinum-based therapy received avelumab at 10 mg/kg intravenously every 2 weeks. Continuation of mitotane was permitted; however, mitotane levels during the study were not recorded. Tumor response was assessed by Response Evaluation Criteria In Solid Tumors v1.1. Results Fifty patients received avelumab and were followed for a median of 16.5 months. Prior treatment included ≥2 lines in 74.0%; mitotane was continued in 50.0%. The objective response rate (ORR) was 6.0% (95% CI, 1.3% to 16.5%; partial response in 3 patients). Twenty-one patients (42.0%) had stable disease as best response (disease control rate, 48.0%). Median progression-free survival was 2.6 months (95% CI, 1.4 to 4.0), median overall survival (OS) was 10.6 months (95% CI, 7.4 to 15.0), and the 1-year OS rate was 43.4% (95% CI, 27.9% to 57.9%). In evaluable patients with PD-L1+ (n = 12) or PD-L1− (n = 30) tumors (≥5% tumor cell cutoff), ORR was 16.7% vs 3.3% (P = .192). Treatment-related adverse events (TRAEs) occurred in 82.0%; the most common were nausea (20.0%), fatigue (18.0%), hypothyroidism (14.0%), and pyrexia (14.0%). Grade 3 TRAEs occurred in 16.0%; no grade 4 to 5 TRAEs occurred. Twelve patients (24.0%) had an immune-related TRAE of any grade, which were grade 3 in 2 patients (4.0%): adrenal insufficiency (n = 1), and pneumonitis (n = 1). Conclusions Avelumab showed clinical activity and a manageable safety profile in patients with platinum-treated mACC. Trial registration Clinicaltrials.gov NCT01772004; registered January 21, 2013.

4516 Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of single-agent avelumab in patients (pts) with metastatic adrenocortical carcinoma (mACC), a rare malignancy for which there are limited therapeutic options (NCT01772004). Methods: Pts with mACC who had progressed after platinum-based therapy and were unselected for PD-L1 expression were treated with avelumab at 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Prior and ongoing treatment with mitotane was permitted. Tumors were assessed every 6 wks (RECIST 1.1). Objective response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Oct 23, 2015, 37 pts were treated with avelumab (median 8 wks [range 2-48]) and followed for a median of 13 wks (range 0-58). Median age was 50 y (range 23-71), ECOG PS was 0 (37.8%) or 1 (62.2%), and median number of prior treatments for metastatic disease was 1 (range 0-5). Treatment-related (TR) AEs occurred in 23 pts (62.2%); the most common (> 10%) were nausea (6 [16.2%]), fatigue (5 [13.5%]), pyrexia (5 [13.5%]), and infusion-related reaction (5 [13.5%]), all of grade 1/2. Grade ≥3 TRAEs occurred in 5 pts (13.5%; each 1 event): hyperkalemia, increased ALT, GGT, or transaminase, sepsis, spinal cord infection, and pneumonitis. Potential immune-related TRAEs occurred in 4 pts (10.8%): 3 pts with grade 1/2 events and 1 pt with grade 3 pneumonitis that resolved. There were no treatment-related deaths. Among 19 pts with ≥13 wks f/u, unconfirmed ORR was 10.5% (2 partial responses; 95% CI: 1.3, 33.1). Stable disease was observed in 5 pts (26.3%); disease control rate was 36.8% (7/19). Median PFS was 7.6 wks (95% CI: 5.9, 23.9), and PFS rate at 12 wks was 30.3% (95% CI: 12.3, 50.7). Conclusions: Avelumabshowed an acceptable safety profile and clinical activity in pts with mACC, a dataset representing the first study to date of an anti-PD-(L)1 agent in this rare tumor type. Analyses of activity, including response correlated with PD-L1 expression, are ongoing. *Proposed INN. Clinical trial information: NCT01772004.