Identifying Nivolumab-Related Adverse Effects Early in Advanced HCC

As nivolumab (Opdivo) has demonstrated durable tumor responses and promising survival benefit for patients with advanced hepatocellular carcinoma (HCC), it is key for nurses to be able to identify and manage treatment-related adverse effects (AEs) early, according to a study presented at the Oncology Nursing Society Annual Congress.

“Early identification and management of treatment-related AEs in patients receiving immune checkpoint inhibitors can prevent treatment delays and improve outcomes,” said Aralee Galway, MSN, ANP-BC, AOCNP, from Massachusetts General Hospital.

In the phase I/II, open-label Checkmate-040 trial, patients treated with nivolumab, a programmed death-1 (PD-1) inhibitor, demonstrated long-term survival and a manageable safety profile. Since, the Food and Drug Administration (FDA) approved the agent for patients with HCC who have been previously treated with sorafenib (Nexavar).

The researchers who presented at the annual congress aimed to assist practitioners in managing AEs that occur with nivolumab. For their study, they looked retrospectively at data about patients who participated in Checkmate-040, and the management in that trial of select categories of treatment-related AEs—including dermatologic, endocrine, gastrointestinal, hepatic, pulmonary, and renal. Within Checkmate-040, management was carried out according to algorithms developed to address treatment-related AEs with potential immunologic etiology requiring more frequent monitoring.

In her presentation at the congress¾held May 17-20 in Washington, D.C.¾Galway provided an overview of the safety profile of nivolumab in the dose-escalation and -expansion phases of the CheckMate-040 study, an overview the treatment of those events with immune-modulating agents, and a look at AE status after those interventions.

In the trial, patients received nivolumab monotherapy intravenously every 2 weeks in the dose-escalation (0.1—10 mg/kg) and dose-expansion (3 mg/kg) arms. The primary endpoints included safety and tolerability in the dose-escalation phase and objective response rate in the dose-expansion phase.

If a select treatment-related AE occurred, it was managed using protocol-specified algorithms, which could include corticosteroid treatment.

In total, 262 treated patients were assessed in Checkmate-040, including 214 in the dose-expansion phase and 48 in the dose-escalation phase, with a median age of 63 years and Eastern Cooperative Oncology Group (ECOG) performance status of 0—1. Median duration of nivolumab treatment was 4.9 months.

Any grade AE occurred in 68% of patients, while 19% of patients experienced grade 3/4 AEs. One treatment-related grade 5 event occurred (pneumonitis).

The most frequently occurring select treatment-related AEs included skin (35.5%), gastrointestinal (14.5%), and hepatic (14.1%), which were mostly grade 1/2. Incidences of grade 3/4 select treatment-related AEs in 1% or more of patients were increased aspartate aminotransferase (AST; 5.3%), increased alanine aminotransferase (ALT; 3.4%), and diarrhea (1.1%).

“The PD-1 inhibitor nivolumab demonstrated a manageable safety profile in patients with advanced HCC, consistent with that of nivolumab in other tumor types,” Galway noted.

Median time to onset for select treatment-related AEs ranged from 3.6 weeks to 47.6 weeks. However, 68% of these events resolved¾including 63 of 93 skin, 29 of 37 gastrointestinal, 26 of 37 hepatic, 13 of 25 endocrine, 2 of 3 pulmonary, and 1 of 2 renal AEs¾with median time to response ranging from 3.7 weeks to 28.4 weeks.

The select treatment-related AEs that were managed with immune-modulating medications included pulmonary (66.7%), skin (44.1%), hepatic (18.9%), gastrointestinal (15.8%), and endocrine (12%). Of those treated with immune-modulating medications, the majority were treated with corticosteroids. All hepatic events were resolved with treatment, while the rates of resolution were 83.3% for gastrointestinal, 71.1% for skin, 66.7% for endocrine and 50% for pulmonary.

In the presentation, select treatment-related AEs were managed using protocol-specified algorithms. For example, in the management of hepatic events algorithm, if baseline AST or ALT was within normal limits, nurses would then delay dosing for drug-related grade ≥2 toxicity, and then increase frequency of monitoring to every 3 days.

“Overall, select treatment-related AEs were effectively managed with the use of specific treatment algorithms, and approximately two-thirds of these resolved,” said Galway. “Among those patients who resumed treatment after dose delay and had recurrence of select treatment-related AEs, most events were low grade.”

The most common select treatment-related AEs of any grade that led to dose delays included hepatic (37.8%), renal (50%), and pulmonary (33.3%) events. Of note, grade 3/4 events appeared to be uncommon except for hepatic events (24.3%). Five patients (1.9%) discontinued nivolumab treatment due to hepatic select treatment-related AEs.

Among patients with dose delays due to select treatment-related AEs, 22 of 30 resumed treatment. Of those, 13 patients (59.1%) experienced a recurrent AE, although most (84.6%) were grade 1/2 events.

“All hepatic AEs resolved with treatment, and among those with dose delay, most were able to resume nivolumab treatment,” Galway said. “Nivolumab has demonstrated durable tumor responses and promising survival benefit with a manageable safety profile in patients with advanced HCC.”

Galway A, DiFebo H, Brutcher E, Julien K. Safety Profile and Management of Select Treatment-Related Adverse Events in Patients With Advanced Hepatocellular Carcinoma (aHCC) Treated With Nivolumab in the CheckMate-040 Study. Presented at: ONS 43rd Annual Congress; May 17-20, 2018; Washington, DC. Poster IS-10. https://ons.confex.com/ons/2018/meetingapp.cgi/Paper/2348