Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors have become a standard of care option for the treatment of patients with advanced melanoma. Since the approval of the first immune checkpoint (CTLA-4) inhibitor ipilimumab in 2011 and programmed death-1 (PD-1) blocking monoclonal antibodies pembrolizumab and nivolumab thereafter, an increasing proportion of patients with unresectable advanced melanoma achieved long-term overall survival. Little is known about the psychosocial wellbeing, neurocognitive function, and quality of life (QOL) of these survivors. Knowledge about the long term side-effects of these novel treatments is scarce as long-term survivorship is a novel issue in the field of immunotherapy. The purpose of this review is to summarize our current knowledge regarding the survival and safety results of pivotal clinical trials in the field of advanced melanoma and to highlight potential long-term consequences that are likely to impact psychosocial wellbeing, neurocognitive functioning, and QOL. The issues raised substantiate the need for clinical investigation of these issues with the aim of optimizing comprehensive health care for advanced melanoma survivors.

Figure 1

Overlay of Kaplan–Meier curves indicating the probability for overall survival (OS) for patients treated with ipilimumab as first line of immunotherapy, representing (1) the historical probability for OS for patients diagnosed with stage IV melanoma prior to the availability of life-prolonging medical treatment options (dashed black line) [1]; (2) a pooled OS analysis including individual patient survival data from 1,861 patients with metastatic melanoma from 12 clinical investigations of ipilimumab and 2,985 patients with metastatic melanoma from a US ipilimumab EAP (total n = 4,846) (dark blue line) [9]; (3) interim results from EURO-VOYAGE, a multicenter, observational, retrospective study of 1043 patients with advanced melanoma who participated in the EU ipilimumab EAP (purple line) [69]; (4) intention-to-treat population (365+362 patients) of the CA184-367 study comparing ipilimumab at 10 mg/kg (dark green line) to 3 mg/kg dosing level (light green line) [8]; (5) intention-to-treat population (278 patients) on the ipilimumab arm from the Keynote-006 trial (red line) [13]; (6) intention-to-treat population (315 patients) on the ipilimumab arm from the Checkmate-067 trial (pink line) [72].

Figure 2

Overlay of Kaplan–Meier curves indicating the probability for OS (OS) for advanced melanoma patients treated with anti-PD1 as first-line immunotherapy, representing (1) the historical probability for OS for patients diagnosed with stage IV melanoma prior to the availability of life-prolonging medical treatment options (dashed black line) [1]; (2) a pooled OS analysis including individual patient survival data from 1,861 patients with metastatic melanoma from 12 clinical investigations of ipilimumab and 2,985 patients with metastatic melanoma from a US ipilimumab EAP (total n = 4,846) (blue line) [9]; (3) CA209-003 phase I clinical trial with nivolumab for pretreated advanced melanoma patients (dark green line) [11]; (4) treatment naïve patients (n: 151) treated in the Keynote-001 clinical trial with pembrolizumab (light green line) [10]; (5) treatment naïve patients (n, 368) from the Keynote-006 trial (red line) [13]; (6) nivolumab treated patients with BRAF V600 wild-type melanoma (n, 210) from the Checkmate-066 trial (blue line) [73]; (7) nivolumab monotherapy treated patients (n, 314) from the CheckMate-067 trial (pink line) [72]; (8) nivolumab plus ipilimumab treated patients (n, 316) from the CheckMate-067 trial (orange line) [72].