“It is possible that patients who discontinue combination therapy because of [adverse events] may still benefit from additional treatment with anti–PD-1 monotherapy….”

— Dirk Schadendorf, MD

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IN A RETROSPECTIVE pooled analysis of the CheckMate 069 and 067 studies reported in the Journal of Clinical Oncology, Dirk Schadendorf, MD, of the University Hospital Essen and the German Cancer Consortium, and colleagues found little difference in the efficacy of combined nivolumab (Opdivo) and ipilimumab (Yervoy) among patients with advanced melanoma who discontinued or did not discontinue treatment due to adverse events during the induction therapy phase.¹ 

Study Details 

IN THE RANDOMIZED phase II CheckMate 069 and phase III CheckMate 067 trials, 407 evaluable patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at 3 mg/kg every 2 weeks. Overall, 176 patients (43%) discontinued treatment due to adverse events. The remaining 231 patients did not discontinue treatment due to adverse events but may have discontinued treatment for other reasons, including disease progression (97 patients [42%]). 

Efficacy was analyzed among the 96 patients (24%) who discontinued treatment due to adverse events during the induction phase vs 233 patients who did not discontinue treatment due to adverse events. Safety was assessed in patients who discontinued treatment due to adverse events at any time (n = 176) vs those who did not discontinue treatment due to adverse events. 

Baseline characteristics were similar among patients who discontinued treatment due to adverse events during induction and those who did not. M1c disease and elevated lactate dehydrogenase levels were less common among patients discontinuing treatment due to adverse events at any time vs those who did not discontinue treatment due to adverse events. 

Subsequent Systemic Treatment 

PATIENTS DISCONTINUING treatment during induction received a median of three doses of both nivolumab and ipilimumab. Those who did not discontinue treatment due to adverse events received a median of 14 doses of nivolumab and 4 doses of ipilimumab. The median durations of treatment were 1.5, 1.4, and 9.4 months among patients discontinuing treatment due to adverse events at any time, those discontinuing treatment during induction, and those who did not discontinue treatment due to adverse events. 

Subsequent systemic treatment was given to 61 patients (35%) who discontinued treatment due to adverse events at any time, 37 (39%) who discontinued treatment during the induction phase, and 55 patients (24%) who did not discontinue treatment due to adverse events. The median time to subsequent treatment was not reached in patients who discontinued treatment due to adverse events at any time or in those not discontinuing treatment due to adverse events and was 25.3 months in those discontinuing treatment during induction; 65%, 76%, and 61% were free of systemic treatments at 12 months. 

Efficacy Outcomes 

MINIMUM FOLLOW-UP was 18 months. Objective response rates were 58.3% among patients discontinuing treatment during induction vs 50.2% among those not discontinuing treatment due to adverse events (P = .180). The median duration of response was not reached in either group. The median time to response was 2.7 vs 2.8 months. The median progression-free survival was 8.4 months (95% confidence interval [CI] = 5.8–16.7 months) vs 10.8 months (95% CI = 5.9–23.0 months; hazard ratio [HR] = 0.99, P = .966). Progression-free survival at 18 months was 38% vs 49%. The median overall survival was not reached in either group (HR = 0.79, P = .234), with 18-month overall survival of 67% vs 62%. 

Immune-Related Adverse Events 

OVERALL, 156 PATIENTS (38%) discontinued treatment due to any grade treatment-related adverse events, with 124 discontinuing treatment due to grade 3 or 4 adverse events (31% of all patients, 79% of those discontinuing treatment). The most common cause of treatment discontinuation among treatment-related events was colitis, which led to discontinuation of treatment in 40 patients (10%), followed by elevated alanine transaminase (5%) and elevated aspartate transaminase (4%). The most common grade 3 or 4 potentially immune-related treatment-related adverse events among patients discontinuing treatment at any time were gastrointestinal events, including colitis in 20% and diarrhea in 20%. The most common adverse events among patients who did not discontinue treatment due to adverse events were hepatic events (10%). 

In both groups, most grade 3 or 4 potentially immune-related adverse events appeared to occur during induction; skin effects were observed earliest (2–3 weeks), followed by gastrointestinal (6–11 weeks), hepatic (8–10 weeks), and endocrine effects (11–12 weeks). The majority of these adverse events resolved with the use of established safety algorithms, with resolution usually occurring within 3 to 5 weeks, except for endocrine adverse events. 

The investigators concluded: “Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of [adverse events] during the induction phase and those who did not discontinue because of [adverse events]. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.” 

They noted: “New, prospective trials are required to better address the role of antiprogrammed cell death protein 1 (anti– PD-1) maintenance therapy after induction with nivolumab plus ipilimumab. It is possible that patients who discontinue combination therapy because of [adverse events] may still benefit from additional treatment with anti–PD-1 monotherapy, provided there is complete resolution of their [adverse events]…. More evidence is needed to determine whether patients should discontinue therapy after they have demonstrated a clinical response and to determine the optimal duration of treatment required to reach a maximum response. In addition, there is interest in understanding the predictive capacity of onset of [adverse events] on efficacy outcomes.” ■

DISCLOSURE: The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. For full disclosures of the study authors, visit www.jco. ascopubs.org. 

REFERENCE 

1. Schadendorf D, Wolchok JD, Hodi FS, et al: Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase II and III trials. J Clin Oncol. August 25, 2017 (early release online).