Outcomes of patients with advanced solid tumors who discontinued immune-checkpoint inhibitors: a systematic review and meta-analysis

Abstract

Background: The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis of all studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD.

Methods: We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan-Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure's method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level.

Findings: Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8-30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1-77.3), 51.0% (95% CI, 43.4-59.8) and 34.0% (95% CI, 27.0-42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value < 0.001), and in NSCLC when the reason of treatment discontinuation was elective as compared with toxicity onset (19.6 versus 4.8 months; p-value = 0.003). The multivariable analysis confirmed these differences.

Interpretation: The long-term outcome of patients who stopped ICIs for reasons other than PD was substantially affected by clinicopathological features: PFS after treatment discontinuation was longer in patients with melanoma, and/or treated with anti-PD-(L)1 + anti-CTLA-4, and shorter in patients with RCC or in those patients with NSCLC who stopped treatment for toxicity onset.

Funding: The Italian Ministry of University and Research (PRIN 2022Y7HHNW).

Keywords: Discontinuation; Immune-checkpoint inhibitors; Meta-analysis melanoma; NSCLC.

Fig. 1

PRISMA flow chart. Figure shows the process of studies’ selection.

Fig. 2

Progression-free survival (PFS) in the whole patients’ population. Figure shows the Kaplan–Meier PFS curves in all patients included in the analysis. The solid red line showed the pooled PFS and dotted red lines the 95% confidence interval (CI), while gray lines showed PFS reported in each single study.

Fig. 3

Progression-free survival (PFS) according to tumor histotype. Figure shows the Kaplan–Meier PFS curves according to tumor histotype. Thick lines showed the pooled PFS while thin lines showed PFS reported in each single study. Colors indicate tumor histotype: red for melanoma, blue for non-small cell lung cancer (NSCLC), and green for renal cell carcinoma (RCC).

Fig. 4

Progression-free survival (PFS) according to treatment type. Figure shows the Kaplan–Meier PFS curves according to treatment type. Thick lines showed the pooled PFS while thin lines showed PFS reported in each single study. Colors indicate treatment type: red for anti-PD-(L)1 as monotherapy, blue for anti-PD-(L)1 + anti-CTLA-4, and green for anti-PD-(L)1 + other drugs.

Fig. 5

Progression-free survival (PFS) according to reason of treatment discontinuation and tumor histotype. Figure shows the Kaplan–Meier PFS curves according to reasons of treatment discontinuation and tumor histotype. Thick lines showed the pooled PFS while thin lines showed PFS reported in each single study. Line type indicates reasons for treatment discontinuation: solid lines indicate elective reasons and dotted lines indicates toxicity reasons; colors indicate tumor histotype: red for melanoma, blue non-small cell lung cancer (NSCLC), and green for renal cell carcinoma (RCC).