Ipilimumab-Based Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events With Ipilimumab Monotherapy and Combination Therapy With Nivolumab

Abstract

MELANOMA OUTCOMES HAVE BEEN DRAMATICALLY ADVANCED by the development of immune checkpoint inhibitors (ICIs), which impede either cytotoxic T lymphocyte-associated antigen 4 (CTLA4) or programmed cell death protein 1 (PD-1) to enhance the patient's immune system recognition and attack on cancer. Ipilimumab (Yervoy ® ) is a CTLA4 inhibitor that improved survival in phase 3 trials in unresectable stage III and stage IV melanoma (advanced melanoma) (Hodi et al., 2010; Robert et al., 2011). In 2011, the U.S. Food and Drug Administration (FDA) approved ipilimumab for advanced melanoma. Subsequently, ipilimumab was shown to prolong recurrence-free and overall survival as an adjuvant therapy in resected stage III melanoma (Eggermont et al., 2016) and received FDA approval for this indication in 2015. In addition, dual checkpoint blockade with ipilimumab, plus the PD-1 inhibitor nivolumab (Opdivo ® ), provides longer progression-free survival versus ipilimumab alone in advanced melanoma (Larkin et al., 2015) and was approved for this use in 2014.Immune checkpoints serve as on-or off-regulators. In particular, CTLA4 and PD-1 act as off, or "brake," mechanisms for the immune system. These pathways are exploited through interruptions to the brake system (i.e., taking the brakes off the immune system through ICIs). Although CTLA4 and PD-1 inhibitors work by sustaining (T-cell) immune responses, anti-CTLA4 tends to act earlier in the process than PD-1 (Boutros et al., 2016). These differences may also account for the divergent efficacy and toxicity profiles of CTLA4 and PD-1 inhibitors when used as monotherapy (Buchbinder & Desai, 2016). In the CheckMate 067 trial by Larkin et al. (2015), the group receiving ipilimumab and nivolumab therapy demonstrated higher response rates as well as increased progression-free survival versus ipilimumab monotherapy. However, the combination of ipilimumab and nivolumab was also associated with a higher proportion of severe toxicity: Fifty-five percent (n = 172) of patients in the combination therapy group experienced a treatment-related grade 3 or 4 adverse event, compared with 27% (n = 85) of those who received ipilimumab and 16% (n = 51) of those who received nivolumab, respectively (Larkin et al., 2015).Members of the Melanoma Nursing Initiative (MNI) noted that the ipilimumab and nivolumab combination and high-dose ipilimumab adjuvant therapy KEYWORDS CTLA4 inhibitor; immune-related adverse events; ipilimumab; nivolumab; melanoma DIGITAL OBJECT IDENTIFIER 10.1188/17.CJON.S4.30-41 BACKGROUND: Ipilimumab (Yervoy ® ) therapy improves outcomes in patients with resected stage III melanoma, and ipilimumab alone or combined with nivolumab (Opdivo ® ) does so in those with unresectable or metastatic melanoma. These immunotherapies are associated with immune-related adverse events (irAEs). With prompt recognition and appropriate management, serious sequelae or unnecessary treatment discontinuation can be prevented.

Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

“…Ipilimumab-related AEs are well characterized and generally tolerated with prompt detection and appropriate management. 21 Importantly, no grade ≥3 V937-related AEs occurred with intratumoral V937 monotherapy in a phase 2 study 5 or in combination with ipilimumab in our study. The rate of grade 3–5 ipilimumab-related AEs was lower with combination therapy in our study (14%) than with ipilimumab monotherapy in phase 3 studies (20%–27%), 19 20 possibly due to differences in trial designs and patient populations.…”