Efficacy and safety of immune checkpoint inhibitor rechallenge in non‐small cell lung cancer: A systematic review and meta‐analysis

Abstract

Background

The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non‐small cell lung cancer (NSCLC).

Methods

Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L‐) and subsequent lines (2L‐) of ICIs were defined as 1L‐ICI and 2L‐ICI, respectively.

Results

A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression‐free survival (mPFS), and median overall survival (mOS) for 2L‐ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L‐ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L‐ICIs were discontinued following clinical decision (the mPFS of 2L‐ICIs was not reach) achieved a more prolonged mPFS of 2L‐ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L‐PFS for more than 2‐years had preferable 2L‐ORR (35.0% vs. 9.8%, p = 0.03), 2L‐DCR (85.0% vs. 49.0%, p = 0.007), and 2L‐mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1‐year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001).

Conclusions

ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long‐term tumor remission for more than 2‐years under 1L‐ICIs.

This meta‐analysis enrolled 17 studies, covering 2,100 patients with non small cell lung cancer who were treated with two lines (the initial line was 1L‐, the subquent line was 2L‐) of immune checkpoint inhibitors (ICIs). It was found that the tumor efficacy of 2L‐ICIs was limited, but for pre‐screened patients in whom the 1L‐ICIs were discontinued following clinical decision and in whom the 1L‐progression free survival (PFS) longer than 2‐years, both showing significantly prolonged median PFS of 2L‐ICIs compared with other subgroups.

INTRODUCTION

Non‐small cell lung cancer (NSCLC) accounts for about 85% of overall lung cancer patients. ¹ There has been a growing number of treatment options for patients with NSCLC, ² including the widely used immune checkpoint inhibitors (ICIs). Owing to the remarkable efficacy, immunotherapy has been the standard care for first‐line treatment in NSCLC without actionable sensitive driver gene variations, irrespective of whether administered as monotherapy or in combination with platinum‐based chemotherapy. ³ Once patients have failed to respond to immunotherapy, the therapeutic options are limited with barely satisfactory efficacy. For example, docetaxel as the standard second‐line chemotherapy treatment only achieved a 7.1% of partial response rate in NSCLC patients. ⁴

For these reasons, ICI therapy is sometimes rechallenged appropriately by clinicians to maximize the benefit of immunotherapy in real‐world application. ⁵ The rechallenge strategy dates back to the 1970s, ⁶ and has achieved success in certain circumstances, such as bevacizumab rechallenge in patients with progressive colorectal cancer, ⁷ and trastuzumab rechallenge after breast cancer progression. ⁸ , ⁹ However, in NSCLC, there are neither clinical guidelines to guide the specific treatment of ICI rechallenge, nor systematic data about the efficacy and safety of ICI rechallenge at present, which further lead to the complexity of the specific clinical environment of ICI rechallenge in real‐world.

Reasons for discontinuation of ICIs usually include disease progression, ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ the occurrence of severe adverse events (AEs), ¹⁵ , ¹⁶ , ¹⁷ and clinician's decision after the completion of a fixed duration course of immunotherapy and the achievement of long‐lasting tumor remission. ¹⁸ ICI rechallenge has been reported in several studies, but the efficacy and survival outcomes vary largely due to a very heterogeneous population. On the basis of clinical experience, patients who discontinued primary ICIs because of AEs or the completion of a fixed treatment course are more likely to benefit from ICI rechallenge. ¹⁹ , ²⁰ Despite this, there is no definite evidence on which subgroups could obtain benefit from ICI rechallenge to date.

Regarding ICI rechallenge during the real‐world NSCLC treatment, some data have been reported, but most studies were single‐arm, with a small sample size, and did not explore factors that might affect the prognosis. ¹⁵ , ²¹ , ²² Therefore, in our present meta‐analysis, we reviewed all the original studies about ICI rechallenge in NSCLC and comprehensively collected the detailed data, to describe the overall efficacy and safety of ICI rechallenge, and more importantly, to explore which subgroups are suitable for ICI rechallenge therapy.

METHODS

Search strategy and inclusion criteria

This study was conducted and reported following the Preferred Reporting Items for Systematic reviews and meta‐analysis (PRISMA) guidelines. ²³ The protocol of this study was registered in PROSPERO (CRD42021284110). A literature search was performed in PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases. The cutoff date for searching was October 15, 2021. Keywords used included “non‐small cell lung cancer”, “immunotherapy”, “immune checkpoint inhibitors”, “programmed cell death protein 1 (PD‐1) inhibitors”, “programmed cell death ligand 1 (PD‐L1) inhibitors”, “cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) inhibitors”, “rechallenge”, “retreatment”, “readministration”, and “restart”. The detailed literature search strategy is exhibited in Table S1.

Two investigators (YF and YXT) independently conducted the initial search to identify potentially eligible articles, and determined the selected literature according to the inclusion criteria. References of the included studies and from previously published systematic reviews were manually assessed to detect any missing study. When consensus was not reached by discussing with the other two investigators (HZC and YZ), the corresponding authors were consulted for the final decision.

The inclusion criteria included: (1) pathologically or cytologically confirmed NSCLC, including but not limited to adenocarcinoma lung cancer, squamous cell lung cancer, and large cell lung cancer; (2) patients who were treated with at least two lines of immunotherapy; (3) the initial ICI discontinuation due to progressive disease (PD), toxicity, completion of a fixed treatment course, or any other reasons; (4) studies which reported any of the clinical endpoints, including objective response rate (ORR), disease response rate (DCR), progression‐free survival (PFS), and overall survival (OS); (5) studies written in English. The exclusion criteria included: (1) pathologically or cytologically confirmed small cell lung cancer (SCLC) or mixed with SCLC; (2) studies that lacked sufficient information for analysis; (3) animal studies; (4) fewer than 10 patients for each study; (5) case reports; (6) reviews and meta‐analyses, editorials and letters to the editors. In the case of duplicate publications, only the most recent or most informative study was included in the analyses.

Rechallenge in our study was defined as patients who received at least two lines of ICIs during their disease course, and the initial line (1L‐) and subsequent line (2L‐) of ICIs were defined as 1L‐ICI and 2L‐ICI, respectively. For studies that received three and above lines of ICIs, data of the first‐ and second‐line of ICIs would be collected. The discontinuation reasons of the 1L‐ICIs included toxicity, disease progression, completion of a fixed course of ICIs, decision of the prescriber, and other reasons that might be involved. The key inclusion criteria of patients in each study (mainly the specific conditions of two lines of ICI treatment) are seen in Table S2.

Data extraction and quality assessment

Two investigators (YF and YXT) independently extracted data and conducted the quality assessment from eligible studies, then cross‐checked all results. For the disagreements, all investigators collaborated in order to reach a consensus. Extracted variables included: (1) general characteristics of included studies (first author, year of publication, study design, study sites, number of patients); (2) clinical characteristics of patients (histology, tumor stage, Eastern Cooperative Oncology Group [ECOG] performance status [PS], and PD‐L1 tumor proportion score [TPS]); (3) treatment information (the 1L‐ and 2L‐ ICI therapy); (4) reasons for 1L‐ICI discontinuation; (5) treatment between the 1L‐ and 2L‐ ICIs; (6) clinical outcomes (ORR, DCR, PFS, OS, and safety), in which, ORR and DCR were separately extracted from the 1L‐ICI and 2L‐ICI therapy, PFS was extracted and calculated from the beginning of the 1L‐ICI and 2L‐ICI therapy separately, OS was extracted and calculated from the beginning of 2L‐ICI therapy.

Additionally, deeper data mining was performed for studies that provided both 1L‐ICI and 2L‐ICI efficacy and survival (PFS) data of each patient, in which, extracted variables were based on a single patient. The mandatory variables included each patient's best tumor response and PFS of 1L‐ and 2L‐ICIs, respectively. The remaining variables of each patient were extracted as much as possible according to the provisions of different studies for further analysis. Since all of the included studies were observational or retrospective cohort studies, the methodological index for nonrandomized studies (MINORS) criteria was performed to evaluate the quality of studies. ²⁴

Statistical analysis

Categorical variables are summarized as total and percentage. Continuous variables were performed as median, mean, range, and 95% confidence interval (CI). ORR was defined as the percentage of complete response (CR) and partial response (PR) obtained as best response, DCR was defined as the percentage of CR, PR, and stable disease (SD). ORR and DCR were collectively called short‐term efficacy, PFS and OS were called long‐term efficacy.

We used ORR, DCR, PFS, and OS with 95% CIs from individual studies to calculate the pooled effect rate and effect time. The differences in ORR and DCR between 1L‐ICIs and 2L‐ICIs were compared through the form of column diagrams. Studies that provided each patient's raw survival time would be filtered further, then pooled together to plot survival curves (Kaplan–Meier method) and conduct subgroup analysis. Cox proportional hazard models were used to evaluate prognostic factors for PFS by univariate and multivariate analysis.

Cochran Q statistical test was used to evaluate between‐study heterogeneity, and a p‐value <0.1 was considered as significant heterogeneity. Higgins I² statistic, in which I² < 25% was regarded as low, 25% ≤ I² < 50% as moderate, I² ≥ 50% as high heterogeneity, was used to calculate the proportion of total variation across studies caused by statistical heterogeneity. ²⁵ A random‐effects model was used to calculate a pooled effect size. ²⁶ Sensitivity analyses were performed to examine statistical heterogeneity by omitting one study at each time and assessing the reliability of the pooled estimates. Publication bias was examined by using Begg's and Egger's test. ²⁷ , ²⁸

Stata software (version 17.0), IBM SPSS software (version 22.0), and GraphPad Prism (version 8.0) were used in statistical analysis. MATLAB (version R2021b) was used to extract the survival data of the swimming maps. A two‐sided p‐value of <0.05 was considered statistically significant, except for the heterogeneity test.

RESULTS

Study selection and characteristics of eligible studies

The literature search identified 615 records, with 179 from PubMed, 167 from Web of Science, 237 from Embase, and 32 from Cochrane. After excluding 248 duplicated records, 367 records were retained. With screening titles and abstracts, 228 records were removed due to irrelevant topics, and 139 studies were selected for full‐text screening. Then, 123 studies were removed due to case reports, reviews, letters, protocols, mini‐symposia, and small sample size (n < 10), and one study from reviews was supplemented. Finally, a total of 17 studies ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁶ , ¹⁷ , ¹⁸ , ²⁰ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ involving 2100 patients with NSCLC were included, with the number of patients ranging from 10 to 1127 in each study (Figure 1 and Table 1).

FIGURE 1.

Flow chart of literature selection.

TABLE 1.

Characteristics of included studies.

Epidemiological data						PD‐L1 TPS (%)		Initial ICI therapy (1L‐ICI)
Study	Country	Study design	No. of patients	ECOG‐PS ≥2 (N)	Stage of IV (N)	1 ~ 49 (N)	≥50 (N)	Prior regimens (median, range)	Treatment	ORR (n/N)	DCR (n/N)	Median PFS (95% CI)	Reasons of discontinuation
Fujita et al. 10	Japan	Retrospective	12	2	6	6	6	2 (1–4)	Mono‐nivolumab	7/12	9/12	6.2 (4.5–7.3)	PD
Fujit et al. 29	Japan	Retrospective	18	7	9	3	9	1 (0–3)	Mono‐nivolumab/mono‐pembrolumab/nivolumab + pembrolumab	7/18	13/18	NR	NR
Fujita et al. 11	Japan	Retrospective	15	2	4	5	0	NR	Mono‐atezolizumab/mono‐durvalumab	0/15	5/15	NR	PD
Furuya et al. 30	Japan	Retrospective	38	NR	NR	NR	NR	NR	Mono‐nivolumab/mono‐pembrolumab/nivolumab + pembrolumab	8/38	24/38	NR	Mixed
a Giaj Levra et al. 31	France	Retrospective	1127	NR	NR	NR	NR	NR	Mono‐nivolumab	NR	NR	NR	NR
			390	NR	NR	NR	NR	NR	Mono‐nivolumab	NR	NR	NR	NR
Gobbini et al. 20	France	Retrospective	144	17	95	22	20	1 (0‐NR)	Mono‐ICI/ICI + chemotherapy	71/144	109/144	13 (10–16.5)	Mixed
Herbst et al. 18	Global	Prospective	14	NR	NR	14	0	NR	Mono‐pembrolizumab	14/14	14/14	27.6 (24.4–30.9)	Clinician's decision
Ito et al. 32	Japan	Retrospective	37	NR	NR	6	14	NR	Mono‐nivolumab mono/mono‐pembrolumab	22/37	31/37	NR	Mixed
Katayama et al. 12	Japan	Retrospective	35	12	19	8	14	2 (0–14)	Mono‐nivolumab/mono‐pembrolumab/mono‐atezolizumab	12/35	24/35	4 (2.8–4.6)	PD
Kitagawa et al. 33	Japan	Retrospective	17	3	12	4	3	1 (0–3)	Mono‐nivolumab/Mono‐pembrolumab/mono‐atezolizumab	6/17	15/17	9.7 (7.4–12)	Mixed
Mouri et al. 16	Japan	Retrospective	21	2	NR	1	1	NR	Mono‐nivolumab	13/21	21/21	14.6 (6.9–19.7)	Toxicity
Niki et al. 13	Japan	Retrospective	11	0	NR	3	0	4 (2–7)	Mono‐nivolumab	5/11	7/11	4.9 (0–12.2)	PD
Santini et al. 17	America	Retrospective	38	NR	NR	NR	NR	NR	Mono‐PD‐1 inhibitor/mono‐PD‐L1 inhibitor/PD‐1 or PD‐L1 inhibitor+CTLA4 inhibitor	13/38	33/38	NR	Toxicity
Spira et al. 35	America	Retrospective	149	25	NR	NR	NR	NR	Mono‐ICI/ICI + chemotherapy/ICI + ICI	NR	NR	NR	NR
Takahama et al. 36	Japan	Retrospective	10	NR	NR	NR	NR	NR	Mono‐nivolumab/mono‐pembrolumab/mono‐atezolizumab	5/10	7/10	NR	NR
Watanabe et al. 14	Japan	Retrospective	14	4	9	1	7	2 (0–4)	Mono‐nivolumab/mono‐pembrolumab/mono‐atezolizumab	3/14	8/14	3.7 (1.3–7.1)	PD
Reck et al. 34	Global	Prospective	10	NR	NR	NR	NR	0 (0–0)	Mono‐pembrolizumab	NR	NR	NR	Clinician's decision

		Subsequent ICI therapy (2L‐ICI)
Time intervals (median, range), months	Treatment between intervals (n/N)	Reasons of rechallenge	Treatment	ORR (n/N)	DCR (n/N)	Median PFS (months, 95%CI)	Discontinuation due to toxicity (n/N, %)	Median OS (months, 95% CI)
NR	8/12	Tumor progression	Mono‐pembrolizumab	1/12	4/12	3.1 (1.4–4.8)	NR	NR
NR	9/18	NR	Mono‐atezolizumab	0/18	7/18	NR	NR	NR
NR	7/15	Tumor progression	Mono‐nivolumab/mono‐pembrolumab	0/15	4/15	NR	NR	NR
NR	NR	NR	Mono‐atezolizumab	1/38	13/38	NR	2/38 (5.3)	NR
2.1 (NR)	0/1127	NR	Mono‐nivolumab/mono‐pembrolumab	NR	NR	NR	NR	14.8 (13.4–16.5)
2.6 (NR)	390/390	NR	Mono‐nivolumab/mono‐pembrolumab	NR	NR	NR	NR	18.1 (14.6–21.6)
8.6 (1.2–31.5)	0/144	Mixed	Mono‐ICI/ICI + chemotherapy/ICI + antiangiogenic drugs	23/144	68/144	4.4 (3–6.5)	18/144 (12.5)	16.0 (12–25.2)
7.5 (2.5–18.9)	0/14	Tumor progression	Mono‐pembrolizumab	6/14	11/14	NA (NA)	NR	NR
NR	0/37	Tumor progression	Mono‐nivolumab/mono‐pembrolumab/mono‐atezolizumab	NR	NR	2.2 (1.5–4.3)	NR	10.7 (4.4–16)
5.2 (NR)	NR	Tumor progression	Mono‐nivolumab/mono‐pembrolumab/Mono‐atezolizumab	1/35	15/35	2.7 (1.4–3.7)	NR	7.5 (3.5–12)
7.0 (0.9–21.7)	11/17	Tumor progression	Mono‐nivolumab/mono‐atezolizumab	1/17	10/17	4.0 (2.1–7.5)	4/17 (23.5)	10.9 (5.9–15.6)
1.9 (0.4–12.1)	0/21	Mixed	Mono‐nivolumab	3/21	18/21	7.4 (3.8–11)	0/21 (0)	20.7 (10.4–30.9)
4.2 (1.0–12.7)	10/11	Tumor progression	Mono‐nivolumab	3/11	5/11	2.7 (0.2–4)	0/11 (0)	NR
1.1 (0.2–5.9)	0/38	Toxicities controlled	Mono‐PD‐1 inhibitor/mono‐PD‐L1 inhibitor/PD‐1 inhibitor or PD‐L1 inhibitor+CTLA4 inhibitor	5/38	33/38	NR	NR	NR
NR	NR	NR	NR	NR	NR	NR	NR	NR
NR	NR	NR	Mono‐nivolumab/mono‐pembrolumab/Mono‐atezolizumab	0/10	3/10	NR	NR	NR
6.5 (2.1–15.1)	14/14	Tumor progression	Mono‐nivolumab/mono‐pembrolumab/mono‐atezolizumab	1/14	3/14	1.6 (0.8–2.6)	NR	6.5 (1.4–19)
NR	0/10	Tumor progression	Mono‐pembrolizumab	7/10	NR	NR	NR	NR

Abbreviations: CTLA‐4, cytotoxic T lymphocyte associated antigen–4; DCR, disease response rate; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; NA, not accessible; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD‐1, programmed cell death 1; PD‐L1, programmed cell death ligand 1; PFS, progression‐free survival; PS, performance status; TPS, tumor proportion score.

^a This study did not provide the whole survival data of all enrolled patients, and is shown as subgroups according to whether there were treatments between two lines of immunotherapy, in which there were 1127 patients with no treatment, and 390 patients with treatment.

A total of 15 studies were retrospective and two were prospective. All studies were published after the year 2018, with 11 conducted in Japan, two in America, two in France, and two worldwide. A total of 12 studies used mono‐ICIs, three used mono or dual ICIs as the initial immunotherapy regimens, and two studies included patients using ICIs plus chemotherapy. For the 2L‐ICIs regimens, 14 studies used mono‐ICIs, one used mono or dual ICIs, one used ICIs plus chemotherapy or antiangiogenic drugs, and the remaining one was not reported.

The characteristics of the included patients are shown in Table 1. A total of 436 patients from 10 studies reported ECOG PS, and 74 (17.0%) patients had a score ≥2. A total of 255 patients from seven studies reported the tumor stage details, and 154 (60.4%) were stage IV. A total of 338 patients from 11 studies reported the results of PD‐L1 TPS, of whom 73 (21.6%) was 1–50%, 74 (21.9%) was ≥50%. Eight studies covering 261 patients reported the lines of prior treatment. All except one study where patients underwent at least one treatment before the 1L‐ICIs, and the highest prior treatment lines were 14.

Quality of studies

The median quality score analyzed with the noncomparative studies' MINORS scale was 14 (range, 10–15), only one study scored as the minimum of 10 (Table S3).

Integrated analysis of short‐term efficacy for 1L‐ and 2L‐ICIs therapy

For 1L‐ICIs, a total of 14 studies with 424 patients were included in the pooled analysis of ORR and DCR, respectively (Figure 2a, b). The pooled ORR of 1L‐ICIs therapy was 43% (95% CI: 30%–56%) with significant heterogeneity (I² = 82.9%, p < 0.01), and pooled DCR was 77% (95% CI: 68%–86%) with significant heterogeneity (I² = 72.5%, p < 0.01). For 2L‐ICIs, a total of 14 studies with 397 patients were included in the pooled analysis of ORR (Figure 2c), and 13 studies with 387 patients were included in the pooled analysis of DCR (Figure 2d). The pooled ORR of 2L‐ICIs therapy was 10% (95% CI: 4%–18%) with significant heterogeneity (I² = 71.1%, p < 0.01), and pooled DCR was 50% (95% CI: 37%–62%) with significant heterogeneity (I² = 79.4%, p < 0.01). Sensitivity analysis was further applied and all the pooled results were not significantly influenced by removing any single study (Figures S1–S4).

FIGURE 2.

Forest plot of the short‐term efficacies of 1L‐ICIs and 2L‐ICIs in patients with NSCLC. (a) The pooled ORR for the 1L‐ICIs of patients with NSCLC. (b) The pooled DCR for the 1L‐ICIs of patients with NSCLC. (c) The pooled ORR for the 2L‐ICIs of patients with NSCLC. (d) The pooled DCR for the 2L‐ICIs of patients with NSCLC. 1L‐ICIs, initial immune checkpoint inhibitors; 2L‐ICIs, subsequent immune checkpoint inhibitors; DCR, disease control rate; NSCLC, non‐small cell lung cancer; ORR, objective response rate.

Next, we further compared the differences in short‐term efficacy between 1L‐ and 2L‐ICIs treatment. A total of 13 studies covering 387 patients reported both 1L‐ and 2L‐ICI efficacy data. The ORR of 1L‐ICIs was higher than that of 2L‐ICIs (Figure 3a). The DCR of 1L‐ICIs was also more favorable than that of 2L‐ICIs except for one study by Santini et al.¹⁷ with the same 1L‐ORR and 2L‐ORR (Figure 3b).

FIGURE 3.

The association of short‐term efficacies between 1L‐ICIs and 2L‐ICIs in patients with NSCLC. (a) The column chart of ORR for NSCLC patients treated with 1L‐ICIs and 2L‐ICIs. (b) The column chart of DCR for NSCLC patients treated with 1L‐ICIs and 2L‐ICIs; 1L‐ICIs, initial immune checkpoint inhibitors; 2L‐ICIs, subsequent immune checkpoint inhibitors; DCR, disease control rate; NSCLC, non‐small cell lung cancer; ORR, objective response rate.

Integrated analysis of survival for 1L‐ and 2L‐ICIs therapy

For the median PFS, there were eight studies ¹⁰ , ¹² , ¹³ , ¹⁴ , ¹⁶ , ¹⁸ , ²⁰ , ³³ involving 274 patients included in the pool‐analysis for 1L‐ICIs treatment, and eight studies ¹⁰ , ¹² , ¹³ , ¹⁴ , ¹⁶ , ²⁰ , ³² , ³³ involving 291 patients included for 2L‐ICIs treatment. The pooled median PFS of 1L‐ICIs and 2L‐ICIs were 10.4 months (95% CI: 5.9–14.9; I² = 96.9%, p < 0.01) and 3.0 months (95% CI: 2.1–3.9; I² = 59.7%, p = 0.02), respectively (Figure S5 and S6). For the median OS, seven studies ¹² , ¹⁴ , ¹⁶ , ²⁰ , ³¹ , ³² , ³³ involving 1785 patients were included in the pool‐analysis for 2L‐ICIs treatment. One study by Giaj Levra et al. ³¹ lacked the whole median OS data of all enrolled patients, so patients in this study were divided into two groups according to whether there were treatments between two lines of immunotherapy, in which 1127 patients with no treatment, and 390 patients with treatments. The pooled median OS of 2L‐ICIs was 13.1 months (95% CI: 10.2–16.1) with high heterogeneity (I² = 69.3%, p < 0.01) (Figure S7). Sensitivity analysis showed that no certain study contributed to the heterogeneity (Figures S8–S10).

Toxicity of 2L‐ICIs therapy

A total of five studies ¹³ , ¹⁶ , ²⁰ , ³⁰ , ³³ covering 231 patients reported the proportion of discontinuation events caused by toxicity during the treatment of 2L‐ICIs, and the rate ranged from 0% to 23.5%. Patients from one study ¹⁶ all discontinued 1L‐ICIs due to toxicity, yet no patient discontinued the 2L‐ICIs due to toxicities. The details are shown in Table 1.

Characteristics of 89 patients with original data extracted from six studies

We further explored the variables that may potentially affect the efficacy of 2L‐ICIs. Among all the included 17 studies, 10 studies did not provide the original data on the best tumor response and PFS of each patient, and one study provided the data on time to treatment failure (TTF) instead of the data on PFS. The specific patient's original efficacy data were extractable in six studies, ¹⁰ , ¹³ , ¹⁴ , ¹⁶ , ¹⁸ , ³³ in which two were presented in the form of swimming plots, and four were presented in the form of tables, in total covering 89 patients with NSCLC. The details are shown in Table S4. Mono ICIs were used as the regimen of 1L‐ and 2L‐ICIs in all patients. Three patients (3.4%) were treated with 1L‐ICIs as first‐line systemic therapy, and one received different immunotherapy (2L‐ICIs) as the second‐line systemic therapy. Among all the 89 NSCLC patients, information on ICI regimens, tumor response, discontinuation reasons of 1L‐ICIs, and PFS of each patient were accessible.

There were 48 (53.9%), 26 (29.2%), and 15 (16.9%) patients who achieved CR/PR, SD, and PD as the best tumor response during the treatment of 1L‐ICIs, respectively. For the PFS of patients treated with 1L‐ICIs, a total of 51 (57.3%) patients achieved PFS less than one year, 18 (20.2%) patients achieved between one and two years, and 20 (22.5%) patients achieved over two years. With regard to the discontinuation reasons for 1L‐ICIs, 47 (52.8%) patients discontinued treatment due to PD, 27 (30.3%) due to toxicity, and 15 (16.9%) due to the decision of their clinician. In addition, other subgroups were defined according to the following indicators: whether there were systematic treatments between two lines of immunotherapy (yes, n = 43, 48.3%; no, n = 46, 51.7%), and whether the 2L‐ICI was the same as 1L‐ICI (yes, n = 36, 40.4%; no, n = 53, 59.6%). The details are shown in Table S5.

Variables affecting the short‐term efficacy of 2L‐ICIs based on 89 patients

We first analyzed the differences in short‐term efficacy according to the above‐mentioned subgroups (Table 2). Patients who discontinued 1L‐ICIs due to their clinician's decision achieved both significantly higher 2L‐ORR (40.0% vs. 10.6%, p = 0.02) and 2L‐DCR (80.0% vs. 40.4%, p = 0.02) compared with patients who discontinued 1L‐ICIs because of PD. No significant short‐term benefits were seen when compared to patients in whom 1L‐ICIs were discontinued because of toxicity. Patients who did not receive other systematic antitumor therapies during the intervals of 1L‐ICIs and 2L‐ICIs tended to achieve a higher 2L‐ORR (23.9% vs. 9.3%, p = 0.09), and obtained a significantly better DCR (76.1% vs. 39.5%, p = 0.001). Patients who achieved more than 2 years 1L‐PFS had both significantly preferable 2L‐ORR (35.0% vs. 9.8%, p = 0.03) and 2L‐DCR (85.0% vs. 49.0%, p = 0.007) than patients with a less than 1 year 1L‐PFS. In addition, patients treated with the same drugs of 1L‐ICIs and 2L‐ICIs achieved a significantly higher 2L‐ORR (24.5% vs. 5.6%, p = 0.02) and 2L‐DCR (69.8% vs. 41.7%, p = 0.01).

TABLE 2.

Subgroup analysis of the short‐ and long‐term efficacy of 2L‐ICIs based on 89 patients.

Subgroup	ORR of 2L‐ICI	p‐value	DCR of 2L‐ICI	p‐value	Median PFS of 2L‐ICI (months)	p‐value	HR (95% CI)
Discontinuation reasons of 1L‐ICI
Toxicity vs. PD	14.8% vs. 10.6%	0.716	77.8% vs. 40.4%	0.003	5.2 vs. 2.1	0.01	0.53 (0.32–0.86)
Clinician's decision vs. PD	40.0% vs. 10.6%	0.018	80.0% vs. 40.4%	0.016	NR vs. 2.1	<0.0001	0.15 (0.06–0.37)
Clinician's decision vs. toxicity	40.0% vs. 14.8%	0.128	80.0% vs. 77.8%	1.000	NR vs. 5.2	0.002	0.22 (0.09–0.58)
Treatment between 1L‐ and 2L‐ICI
No vs. Yes	23.9% vs. 9.3%	0.090	76.1% VS. 39.5%	0.001	7.6 vs. 1.9	<0.0001	0.29 (0.18–0.47)
The best tumor response of 1L‐ICI
CR/PR vs. SD	18.8% vs. 11.5%	0.522	60.4% vs. 61.5%	1.000	5.1 vs. 4.0	0.02	0.54 (0.32–0.91)
CR/PR vs. PD	18.8% vs. 20.0%	1.000	60.4% vs. 46.7%	0.384	5.1 vs. 2.6	0.02	0.50 (0.27–0.91)
SD vs. PD	11.5% vs. 20.0%	0.651	61.5% vs. 46.7%	0.515	4.0 vs. 2.6	0.75	0.90 (0.45–1.77)
Progression‐free survival of 1L‐ICI
1–2 years vs. <1 year	16.7% vs. 9.8%	0.421	55.6% vs. 49.0%	0.785	4.7 vs. 3.0	0.37	0.78 (0.45–1.34)
≥ 2 years vs. <1 year	35.0% vs. 9.8%	0.029	85.0% vs. 49.0%	0.007	12.4 vs. 3.0	<0.0001	0.19 (0.09–0.39)
≥ 2 years vs. ≥1–2 year	35.0% vs. 16.7%	0.278	85.0% vs. 55.6%	0.074	12.4 vs. 4.7	0.001	0.24 (0.11–0.55)
Is 2L‐ICI the same as 1L‐ICI?
Yes vs. No	24.5% vs. 5.6%	0.022	69.8% vs. 41.7%	0.010	5.4 vs. 2.3	0.0004	0.44 (0.28–0.71)

Abbreviations: 1L‐ICI, initial immune checkpoint inhibitor; 2L‐ICI, subsequent immune checkpoint inhibitor; CI, confidence interval; CR, complete response; DCR, disease control rate; HR, hazard ratio; ORR, objective response rate; PD, progressive disease; PFS, progression‐free survival; PR, partial response; SD, stable disease.

Variables affecting the PFS of 2L‐ICIs based on 89 patients

We next analyzed the differences in 2L‐PFS according to the above‐mentioned subgroups through univariate (Table 2 and Figure 4) and multivariate (Table S6) Cox proportional hazard models.

FIGURE 4.

The progression‐free survival (PFS) curves of 2L‐ICIs based on different subgroups of 89 patients with non‐small cell lung cancer (NSCLC). (a) The PFS curves of 2L‐ICIs based on the discontinuation reasons of 1L‐ICIs. (b) The PFS curves of 2L‐ICIs based on whether treatment performed during the intervals of two‐line ICIs. (c) The PFS curves of 2L‐ICIs based on the best tumor response of 1L‐ICIs. (d) The PFS curves of 2L‐ICIs based on the different length of 1L‐PFS time. (e) The PFS curves of 2L‐ICIs based on whether 2L‐ICI same as 1L‐ICIs. 1L‐ICIs, initial ICIs; 1L‐PFS, PFS of 1L‐ICIs; 2L‐ICIs, the subsequent ICIs; CI, confidence interval; CR, complete response; ICIs, immune checkpoint inhibitors; mPFS, median progression‐free survival; PD, progressive disease; PR, partial response; SD, stable disease.

As shown in Figure 4a, patients who discontinued 1L‐ICIs because of their clinician's decision achieved a significantly prolonged median 2L‐PFS than those who discontinued 1L‐ICIs due to toxicity (not reached vs. 5.2 months, p = 0.002; HR: 0.22, 95% CI: 0.09–0.58) and PD (not reached vs. 2.1 months, p < 0.0001; HR: 0.15, 95% CI: 0.06–0.37). In addition, the median 2L‐PFS of patients who discontinued 1L‐ICIs because of toxicity was also significantly longer than those who discontinued 1L‐ICIs due to PD (5.2 vs. 2.1 months, p = 0.01; HR: 0.53, 95% CI: 0.32–0.86). During the interval of two lines of ICIs (Figure 4b), patients who did not accept antitumor treatments achieved a prolonged median PFS compared to patients who did accept treatment (7.6 vs. 1.9 months, p < 0.0001; HR: 0.29, 95% CI: 0.18–0.47). In addition, the efficacy of 1L‐ICIs also affected the treatment outcomes of 2L‐ICIs (Figure 4c, d). The median PFS of patients who achieved CR/PR during the treatment of 1L‐ICIs was significantly longer than those who achieved SD (5.1 vs. 4.0 months, p = 0.02; HR: 0.54, 95% CI: 0.32–0.91) and PD (5.1 vs. 2.6 months, p = 0.02; HR: 0.50, 95% CI: 0.27–0.91). Patients with a 1L‐PFS of more than 2 years were also more likely to benefit from the rechallenge of immunotherapy than patients with a 1L‐PFS of 1–2 years (12.4 vs. 4.7 months, p = 0.001; HR: 0.24, 95% CI: 0.11–0.55) and patients with a 1L‐PFS <1 year (12.4 vs. 3.0 months, p < 0.0001; HR: 0.19, 95% CI: 0.09–0.39). Regarding the drugs applied for 1L‐ICI and 2L‐ICI treatment, patients using the same drugs achieved a significantly prolonged median PFS than the remaining patients (5.4 vs. 2.3 months, p = 0.0004; HR: 0.44, 95% CI: 0.28–0.71) (Figure 4e).

The variables of 1L‐ICI discontinuation reasons, best tumor responses and PFS, treatment between two lines of ICIs, and whether 2L‐ICIs the same as 1L‐ICIs were all included in the multivariate Cox regression analysis (Table S6). The results demonstrated the length of 1L‐PFS (p = 0.006) and whether there were treatments between two lines of ICIs (p = 0.005, HR: 0.473, 95% CI: 0.279–0.802) were independent prognostic factors of 2L‐PFS.

Publication bias

The funnel plot revealed no significant publication bias in all the pooled analysis except the median PFS of 1L‐ICIs for patients with NSCLC (Figures S11–S17). The results of Begg's and Egger's test also indicated there was no evidence of substantial publication bias for all meta‐analyses (Table S7).

DISCUSSION

In the field of NSCLC, there has been no meta‐analysis which has focused on the issue of ICI rechallenge and to the best of the our knowledge this is the first study to do so. Through this meta‐analysis, we first performed the pooled analysis of short‐term and long‐term efficacy of the 1L‐ and 2L‐ICIs individually to assess the feasibility of ICI rechallenge in NSCLC, then conducted a deeper analysis of 89 patients whose original data were extractable to explore what kind of NSCLC patients would get the best profits from ICI rechallenge.

The role of ICI rechallenge therapy has not been completely investigated and established. ⁵ , ³⁷ One previous meta‐analysis ³⁸ has made some efforts to evaluate the feasibility of ICI rechallenge in cancer patients. However, there still exist many questions that need to be addressed, including how the efficacy of 1L‐ICIs influences the outcomes of 2L‐ICIs, whether the different discontinuation reasons of 1L‐ICIs would cause different outcomes of 2L‐ICIs, and so forth.

As shown in the results, patients with NSCLC could benefit from the treatment of ICI rechallenge to a certain degree, with the pooled ORR of 10%, DCR of 50%, median PFS of 3.0 months and OS of 13.1 months. The previous meta‐analysis by Inno et al. ³⁸ investigated ICI rechallenge in multicancer types, demonstrating an overall ORR of 21.8%, median PFS of 4.9 months, and median OS of 15.6 months. The pathological type of our study was limited to NSCLC, which might be one of the important reasons contributing to our inferior results. Additionally, it should be noted that the heterogeneity of our pooled results was high (I² > 50%, p < 0.01), but all the sensitivity analysis results showed there was no single study that significantly influenced the heterogeneity. We found that both the short‐term (ORR, 0% to 43%; DCR, 21% to 87%) ¹¹ , ¹⁸ , ²⁹ , ³⁴ , ³⁶ and the long‐term efficacy (PFS, 1.6 to 7.4 months; OS, 6.5 to 20.7 months) ¹⁴ , ¹⁶ of the included studies varied largely. Since there was no consensus available to guide the clinical decisions of ICI rechallenge, a huge selective bias and different results with high heterogeneity were inevitable. The pooled ORR and DCR of the 1L‐ICIs were 43% and 77%, respectively, also with great heterogeneity. Generally, the ORR and DCR of 2L‐ICIs were worse than that of 1L‐ICIs, which partly reflected the entire status quo of rechallenge strategy in cancer therapy. ³⁹

Previous studies showed that patients enrolled in the precondition of tumor remission during the initial ICIs ¹⁸ , ¹⁹ achieved relatively higher ORR during the treatment of 2L‐ICIs, with that of 40–60%. ¹⁸ , ¹⁹ However, these results are from small sample studies and could not be used as evidence to guide clinical practice. We further integrated these small sample data and conducted thorough research to explore the predictive factors for ICI rechallenge efficacy using the original data of 89 patients with NSCLC from six studies. ¹⁰ , ¹³ , ¹⁴ , ¹⁶ , ¹⁸ , ³³

The findings demonstrated that patients with the tumor response of CR/PR of 1L‐ICIs achieved a 2L‐ORR of 18.8%, 2L‐DCR of 60.4%, and 2L‐PFS of 5.1 months; patients with a 1L‐PFS of more than two years achieved a 2L‐ORR of 35.0%, DCR of 85.0%, and 2L‐PFS of 12.4 months. Actually, the clinical trial of CA180‐002 proved that the ipilimumab retreatment would regain disease control in most melanoma patients (20/31) with initial clinical benefit (any response lasting ≥3 months). ⁴⁰ Despite that, no widely recognized recommendations are available, these results inspired us to consider ICI reinduction in patients that showed an initial response or a lasting disease stabilization when there are few treatment options.

In clinical practice, the discontinuation reasons of ICIs mainly included drug resistance, ⁴¹ severe toxicities, ⁴² completion of a fixed duration of treatment, ¹⁸ , ⁴³ , ⁴⁴ tumor cured, financial reason, or death. In the respect of discontinuation reasons of the initial ICIs, the results demonstrated that patients in whom treatment with ICIs was terminated due to clinical decision achieved the most favorable efficacy of immunotherapy rechallenge compared with the reason of drug resistance (PD) and toxicity, no matter in short‐ or long‐term efficacy.

In conventional clinical practice, once drug resistance occurs, the original drugs are no longer effective. An optional treatment strategy after immunotherapy resistance includes cessation of the original drugs, switching to chemotherapy, the addition of chemotherapy to ICI, or the addition of a novel agent to ICI. ⁴¹ In our study, patients who underwent PD to initial ICIs had dismal outcomes when they switched to other ICIs or continued to use the initial ICIs. Despite this, a small number of patients still obtained objective responses with the application of ICI rechallenge even though they had been resistant to the initial ICIs. The activation of the immune microenvironment caused by the application of other systematic antitumor treatments between the intervals of 1L‐ICIs and 2L‐ICIs might explain this phenomenon. ³¹ , ⁴⁵ Similarly, the better outcomes for patients in whom a clinical decision had been made to discontinue initial ICIs (patients had usually finished a fixed‐duration of treatment or obtained long‐lasting tumor remission) or toxicity may be partly explained by the fact that discontinuation of ICIs occurs before the drug resistance.

Our analysis also suggested improved prognosis for patients with the same drugs of 1L‐ and 2L‐ICIs and for patients with no other systematic antitumor treatments during the ICI treatment intervals. As discussed above, systematic antitumor treatments between the initial and subsequent ICIs might enhance the reactiveness of the tumor microenvironment. ⁴⁵ However, in our study, systematic antitumor treatments during the intervals of two lines of ICIs was not a positive indicator of better outcomes. The possible reason is that the initial ICI was discontinued in the majority of these patients due to drug resistance (PD), and that patients without treatment during the intervals mostly discontinued the initial ICI due to toxicity and clinical decision. The probable reason why patients in whom the same 1L‐ and 2L‐ICI drugs achieved a better prognosis was also attributed to a relatively lower rate of resistance to the initial ICI. However, these conclusions need to be further verified by prospective studies.

Our analysis had several limitations. First, most of the studies included were retrospective and more susceptible to selection bias, therefore, contributing to higher heterogeneities of pooled results. To address this issue, we performed a comprehensive analysis based on the 89 patients with original data, and the positive results consequently pointed out the most important reasons for heterogeneity. Second, very few of the included studies reported the detailed and specific toxicity data of ICI rechallenge, which was the main concern of ICI rechallenge, especially for those that discontinued the 1L‐ICIs due to toxicities. Third, it is well known that EOCG‐PS and PD‐L1 status might affect the efficacy of ICIs, but due to the absence of detailed data in many studies, we finally failed to design a proper method to perform related subgroup analysis. Therefore, there is an urgent need for well‐designed prospective studies to address these issues.

In conclusion, ICI rechallenge therapy appears to be effective as an alternative regimen for NSCLC patients previously treated with ICIs, and especially suitable for those who achieve long‐term tumor remission for more than 2‐years under 1L‐ICIs. Other factors that might affect the efficacy of ICI rechallenge, such as PD‐L1 and ECOG‐PS status, still need further exploration. Considering the great heterogeneity in clinical outcomes and potential severe toxicity of ICI rechallenge, it is important to identify patients who may benefit from ICI rechallenge. More investigations on exploring robust predictive factors to identify these patients are needed.

AUTHOR CONTRIBUTIONS

Yu Feng and Yunxia Tao conceived the idea of this study and conducted the literature search. Yu Feng performed the data analysis. Yu Feng, Yunxia Tao, Haizhu Chen, and Yu Zhou drafted the original manuscript. Le Tang and Chenwei Liu provided partial software technical support. Yuankai Shi and Xingsheng Hu supervised the conduct of this study. All authors reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the final version of the manuscript to be published.

FUNDING INFORMATION

This work was financially supported in part by China National Major Project for New Drug Innovation (2017ZX09304015).

CONFLICT OF INTEREST STATEMENT

All the authors declare no potential competing interests.

Supporting information

Data S1: Supporting Information.

Feng Y, Tao Y, Chen H, Zhou Y, Tang L, Liu C, et al. Efficacy and safety of immune checkpoint inhibitor rechallenge in non‐small cell lung cancer: A systematic review and meta‐analysis. Thorac Cancer. 2023;14(25):2536–2547. 10.1111/1759-7714.15063

DATA AVAILABILITY STATEMENT

The data used to support the findings of this study are available from the corresponding author upon reasonable request.