Left Ventricular Ejection Fraction in Patients With Ovarian Cancer Treated With Avelumab, Pegylated Liposomal Doxorubicin, or Both

Abstract In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors. ClinicalTrials.gov Identifier NCT02580058.


Background
Immune checkpoint inhibitors (ICIs) have revolutionized anticancer treatment and are increasingly being combined with chemotherapies or targeted therapies to enhance antitumor activity.ICIs are associated with immune-related cardiovascular adverse events (AEs), including myocarditis. 1 In addition, reports of noninflammatory cardiomyopathy, albeit from retrospective studies, suggest that ICI-induced toxicities may lead to cardiac dysfunction potentially through direct mechanisms. 2 Few studies of ICIs have prospectively and systematically collected left ventricular ejection fraction (LVEF) data using echocardiography or multigated acquisition (MUGA) scans.Avelumab, an anti-programmed death ligand 1 ICI, is an approved treatment for several tumors. 3,4In the phase III JAVELIN Ovarian 200 trial, patients with platinum-resistant or platinum-refractory ovarian cancer were randomized to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. 5The trial failed to meet its primary endpoints of improved progression-free survival and overall survival with avelumab alone or combined with PLD vs. PLD alone. 5No new safety signals were observed.Because PLD is an anthracycline associated with cardiotoxicity, 6 LVEF was assessed in each patient using systemic and sequential cardiac monitoring.Here, we report LVEF data from the trial.

Methods
The design of the multicenter, open-label, phase III JAVELIN Ovarian 200 trial (NCT02580058) has been described previously. 5Briefly, eligible women had advanced platinum-resistant or platinum-refractory epithelial ovarian, fallopian tube, or peritoneal cancer and had received 1-3 prior treatment lines for platinum-sensitive disease and none for platinum-resistant disease.Exclusion criteria included baseline LVEF <50% (by echocardiography or MUGA scans) and prior anthracycline-related cardiotoxicity or anthracycline exposure approaching the lifetime limit (450-550 mg/m 2 ).Full eligibility e978 The Oncologist, 2023, Vol. 28, No.  B) had an LVEF decrease of 11% that was <LLN at time of assessment; however, their maximum LVEF decrease of 13% (included in the figure) was not <LLN.*Decrease from 63% to 46%; patient subsequently recovered.† Decrease from 54% to 43%; no subsequent assessments.‡ Decrease from 68% to 36%; patient subsequently recovered.§ Decrease from 64% to 49%; patient subsequently recovered.‖ Decrease from 68% to 51%; patient subsequently recovered.Abbreviations: LLN: lower limit of normal; LVEF: left ventricular ejection fraction; PLD: pegylated liposomal doxorubicin.

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The Oncologist, 2023, Vol. 28, No. 10 criteria have been reported previously. 5Patients were randomized 1:1:1 to receive avelumab 10 mg/kg intravenously every 2 weeks, PLD 40 mg/m 2 intravenously every 4 weeks, or avelumab plus PLD.Cardiac monitoring was performed throughout the trial, and comprised electrocardiogram at baseline and every 4 weeks and LVEF assessment by MUGA scans or echocardiography at baseline and every 8 weeks until discontinuation or end of treatment.Electrocardiogram and LVEF results were read locally.Decrease in LVEF to below institutional lower limit of normal (LLN) or by ≥15% from baseline required treatment interruption, and LVEF was reassessed within 45 days and every 3 months.Upon recovery (LVEF increase to within 5% of baseline within 45 days from nadir), treatment could be resumed at investigator's discretion, and an additional LVEF evaluation was performed within 2 weeks.AEs were investigator reported, analyzed descriptively, and graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
At baseline, 1 patient (avelumab plus PLD arm) had an LVEF <LLN. Figure 1 shows maximum LVEF change from baseline during treatment in patients with baseline and postbaseline on-treatment LVEF assessments (n = 415 [avelumab, n = 129; avelumab plus PLD, n = 154; PLD, n = 132]).During follow-up, LVEF decreases of ≥10% to <LLN at any time during the on-treatment period were rare and were only observed in 1 patient (0.8%) in the avelumab alone arm, 3 patients (1.9%) in the avelumab plus PLD arm, and 2 patients (1.5%) in the PLD alone arm.Of these 6 patients, 2 did not have subsequent assessments (treatment was discontinued due to disease progression; both in the avelumab plus PLD arm).For the remaining 4 patients with subsequent assessments, LVEF decreases were transient, and recovery occurred without therapeutic intervention.One patient in the avelumab plus PLD arm had an LVEF decrease from 68% to 36% and subsequently recovered to >LLN (50%) within 1 month.None of these 6 patients had a cardiovascular AE (ie, symptomatic heart failure) related to LVEF decrease.

Discussion
JAVELIN Ovarian 200 was an open-label, phase III trial that was designed to include cardiac monitoring for LVEF in all patients across all 3 arms due to the administration of PLD. 5 To our knowledge, this is the first and largest analysis of LVEF in patients receiving ICIs and the largest analysis in patients with ovarian cancer receiving PLD.In patients with preserved LVEF at baseline, significant LVEF decreases were rare with avelumab or PLD treatment alone or in combination.Observed changes in LVEF were transitory and were not associated with cardiovascular AEs.These findings align with the absence of increased cardiomyopathy or heart failure seen in other avelumab studies 7,8 and the relatively low rate of cardiotoxicity PLD treatment in ovarian cancer. 6

Figure 1 .
Figure 1.Maximum change in LVEF from baseline during treatment in the (A) avelumab alone, (B) avelumab plus PLD, and (C) PLD alone arms.One patient in the avelumab plus PLD arm (panel B) had an LVEF decrease of 11% that was <LLN at time of assessment; however, their maximum LVEF decrease of 13% (included in the figure) was not <LLN.*Decrease from 63% to 46%; patient subsequently recovered.† Decrease from 54% to 43%; no subsequent assessments.‡ Decrease from 68% to 36%; patient subsequently recovered.§ Decrease from 64% to 49%; patient subsequently recovered.‖ Decrease from 68% to 51%; patient subsequently recovered.Abbreviations: LLN: lower limit of normal; LVEF: left ventricular ejection fraction; PLD: pegylated liposomal doxorubicin.