Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab–Ipilimumab Therapy in Patients With Advanced Melanoma

TAKE-HOME MESSAGE

• A total of 316 patients with advanced melanoma were included in this cohort study investigating treatment-free survival (TFS) outcomes of various first-line immune checkpoint inhibitor therapies between 2013 and 2020. The results showed that patients treated with nivolumab–ipilimumab combination therapy had longer mean TFS (12.4 months) compared with those receiving pembrolizumab (11.1 months) or nivolumab (8.9 months) monotherapy.
• This study provides real-world data to support the use of nivolumab–ipilimumab combination therapy in patients with advanced melanoma and underscores the significance of incorporating TFS as a measure to potentially capture the impact on the quality of life of patients.

–  Ruth McTighe, MD

Written by



Prof. Dr. Alexander C. J. van Akkooi MD, PhD

This paper by Gupta et al describes a cohort of patients from the Alberta Immunotherapy Database (AID), a multicenter observational database. They report on a somewhat novel surrogate endpoint: treatment-free survival (TFS).

Why is this an interesting surrogate endpoint to look at?

Well, first of all, we know that immunotherapy can have durable responses, even if they are not complete responses. Secondly, combination immunotherapy with ipilimumab and nivolumab (IPI/NIVO) is associated with a higher response rate than single-agent anti–PD-1 (either nivolumab or pembrolizumab). Thirdly, we also know that combination immunotherapy has significantly more toxicity and therefore a higher rate of discontinuation by patients due to toxicity.

The question therefore is: Do patients benefit more from combination immunotherapy — compared with a single-agent anti–PD-1 — if they more often must discontinue therapy prematurely due to toxicity?

Gupta et al report on 316 patients from the AID with stage IV melanoma receiving first-line immunotherapy, either single-agent nivolumab (n = 51) or pembrolizumab (n = 158) or IPI/NIVO (n = 107). They found that TFS was best with the combination immunotherapy and concluded that this is valuable as a patient-centric outcome.

Although I do strongly agree with their conclusions, the study did have a few weaknesses. For example, the retrospective nature of the study, the small sample size, and some imbalances in baseline characteristics among the groups, likely pointing towards a bias regarding why certain patients received combination immunotherapy while others received only single-agent anti–PD-1.

In this case, the added toxicity of combination immunotherapy not only leads to higher response rates and an improved progression-free survival compared with single-agent anti–PD-1, but the duration of treatment is shorter too, leading to an improved TFS. In other words: patients "suffer" the higher rate of toxicity in order to benefit more and be undergoing treatment for a shorter amount of time.

Finally, TFS is an interesting emerging patient-centric outcome measure, which will be used more frequently in future oncology trials.

Abstract

IMPORTANCE

Treatment-free survival (TFS) represents an alternative time-to-event end point, accurately characterizing time spent free of systemic therapy, providing a more patient-centric view of immune checkpoint inhibitor (ICI) therapy regimens. There remains a lack of studies evaluating TFS outcomes among patients with advanced melanoma who are receiving immunotherapy, especially outside of the clinical trial setting.

OBJECTIVE

To evaluate TFS outcomes for patients with advanced melanoma receiving first-line ICI therapy outside of a clinical trial setting.

DESIGN, SETTING, AND PARTICIPANTS

This multicenter cohort study of patients with advanced melanoma receiving first-line ICI therapy between August 1, 2013, and May 31, 2020, was conducted in Alberta, Canada. Data analysis was performed in August 2022.

EXPOSURES

Patients received standard-of-care, first-line ICI therapy treatment regimens including single-agent nivolumab, single-agent pembrolizumab, or ipilimumab-nivolumab.

MAIN OUTCOMES AND MEASURES

Treatment-free survival was defined as the difference in the 36-month restricted mean survival time between 2 conventional survival end points: (1) time from treatment initiation to ICI cessation, death, or censoring at last follow-up and (2) time from treatment initiation to subsequent systemic anticancer therapy, death, or censoring at last follow-up.

RESULTS

A total of 316 patients with advanced melanoma receiving first-line nivolumab (n = 51; median age, 66 years [IQR, 56-78 years]; 31 men [60.8%]), pembrolizumab (n = 158; median age, 69 years [IQR, 60-78 years]; 112 men [70.9%]), or combination nivolumab-ipilimumab (n = 107; median age, 53 years [IQR, 42-60 years]; 72 men [67.3%]) were included. Treatment groups were similar with regard to sex, primary tumor location, and presence of metastasis, although patients receiving combination nivolumab-ipilimumab had a lower Eastern Cooperative Oncology Group status, were younger, and were more likely to be BRAF V600E positive than those receiving anti-programmed cell death protein 1 (anti-PD-1) monotherapy. The restricted mean TFS was longer for nivolumab-ipilimumab (12.4 months [95% CI, 8.8-16.0 months]) compared with nivolumab (8.9 months [95% CI, 4.4-13.5 months]) and pembrolizumab (11.1 months [95% CI, 8.5-13.8 months]). During the 36-month follow-up interval, patients treated with nivolumab-ipilimumab spent 34.4% of their time (12.4 of 36 months) not receiving systemic anticancer treatments compared with 30.8% (11.1 of 36 months) and 24.7% (8.9 of 36 months) of the time for the pembrolizumab and nivolumab treatment groups, respectively.

CONCLUSIONS AND RELEVANCE

This cohort study of patients with advanced melanoma receiving first-line ICI therapy suggests that TFS represents a patient-centric, informative end point. Patients treated with combination nivolumab-ipilimumab spent more time alive and free from systemic anticancer therapy than those treated with anti-PD-1 monotherapy alone.

JAMA Network Open

Treatment-Free Survival After Nivolumab vs Pembrolizumab vs Nivolumab-Ipilimumab for Advanced Melanoma

JAMA Netw Open 2023 Jun 01;6(6)e2319607, M Gupta, I Stukalin, D Meyers, S Goutam, DYC Heng, T Cheng, J Monzon, V Navani