
==== Front
Neoplasia
Neoplasia
Neoplasia (New York, N.Y.)
1522-8002
1476-5586
Neoplasia Press

S1476-5586(24)00085-X
10.1016/j.neo.2024.101043
101043
Original article
Treatment options for tumor progression after initial immunotherapy in advanced non-small cell lung cancer: A real-world study
Li Ying a1
Zhao Junfeng b1
Li Ruyue c
Yao Xiujing c
Dong Xue a
Zhang Ruidan b
Li Yintao yintaoli@fudan.edu.cn
a⁎
a Department of Respiratory Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China
b Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China
c Department of Respiratory Oncology, Shandong Cancer Hospital and Institute, Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shan Dong, 261000, China
⁎ Corresponding author. yintaoli@fudan.edu.cn
1 Ying Li and Junfeng Zhao contributed equally to this work.

02 9 2024
11 2024
02 9 2024
57 1010439 6 2024
14 8 2024
22 8 2024
© 2024 The Authors. Published by Elsevier Inc.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• NSCLC patients may benefit from immunotherapy rechallenge.

• The optimal treatment is immunotherapy combined with antiangiogenic therapy.

• This is a real-world immunotherapy rechallenge study.

Objective

Whether to continue administering immunotherapy to patients with advanced non-small cell lung cancer (NSCLC) who have experienced tumor progression remains controversial after immunotherapy. The aims were to explore survival outcomes after further immunotherapy post-progression and to determine the optimal combination therapy in such cases.

Methods

Overall, 507 patients with NSCLC who underwent immunotherapy and experienced tumor progression were retrospectively divided into Immuno-combination and No-immuno groups according to whether additional combination therapy involving immunotherapy was administered post-progression. Progression-free survival (PFS) and overall survival (OS) were evaluated. Subgroup analyses were performed according to the different treatment regimens for patients in the Immuno-combination group.

Results

After propensity score matching, there were 150 patients in the No-immuno group and 300 patients in the Immuno combination group. Superior PFS was observed in the Immuno-combination group compared with those in the No-immuno group (6-month PFS: 25.3 % vs. 60.6 %; 12-month PFS: 6.7 % vs. 24.4 %; P < 0.001). Similar intergroup differences were observed for OS (12-month OS: 22.3 % vs. 69.4 %; 18-month OS: 6.4 % vs. 40.4 %; P < 0.001). Superior PFS outcomes were observed in the Immuno+Antiangiogenic group compared with the Immuno+Chemo group (6-month PFS: 51.3 % vs. 71.5 %; 12-month PFS: 23.1 % vs. 25.7 %; P = 0.017). Similar differences in OS were observed between those same subgroups (12-month OS: 62.1 % vs. 77.9 %; 18-month OS: 33.3 % vs. 48.7 %; P = 0.006).

Conclusion

Patients with NSCLC experiencing tumor progression post-immunotherapy can still benefit from further treatment, with immunotherapy combined with antiangiogenic therapy the most efficacious option.

Keywords

Non-small cell lung cancer
Immunotherapy
Antiangiogenic therapy
Chemotherapy
Immune checkpoint inhibitor
Abbreviations

ALK anaplastic lymphoma kinase

DCs dendritic cells

EGFR epidermal growth factor receptor

ICI immune checkpoint inhibitor

Immuno+Antiangiogenic immunotherapy combined with antiangiogenic therapy

Immuno+Chemo immunotherapy combined with chemotherapy

Immuno-combination immunotherapy combined with other treatment modalities

iRECIST immune Response Evaluation Criteria in Solid Tumors

MDSCs myeloid-derived suppressor cells

NSCLC non-small cell lung cancer

OS overall survival

PC pemetrexed plus platinum agents

PD progressive disease

PD-1 programmed cell death protein 1

PD-L1 programmed death-ligand 1

PFS progression-free survival

RECIST Response Evaluation Criteria in Solid Tumors

TP Taxol/paclitaxel/albumin paclitaxel and platinum agents

TAMs tumor-associated macrophages

TME tumor microenvironment

Tregs regulatory T cells

VEGF vascular endothelial growth factor

VEGFR-2 vascular endothelial growth factor receptor 2
==== Body
pmcIntroduction

Immunotherapy has ushered in a new era of cancer treatment, and the implementation of immune checkpoint inhibitors (ICIs) has had a remarkable effect on the survival of those with advanced lung cancer [[1], [2], [3]]. However, most patients inevitably experience disease progression after the initiation of treatment with ICIs; in such cases, it may sometimes be assumed that the immunotherapy was ineffective or that failure resulted from the development of drug resistance [[4], [5], [6]]. Whether it is appropriate to continue administering immunotherapy in patients who have experienced tumor progression after their initial treatment remains controversial.

A 19-month follow-up report from the OAK study demonstrated that patients whose tumors had progressed following the initiation of immunotherapy had a higher median survival time and 18-month survival rate when immunotherapy continued uninterrupted compared to the outcomes of other treatment modalities [7]. The 5-year follow-up results of the phase III KEYNOTE-024 trial showed that the 12 patients who experienced progressive disease (PD) after receiving a first course of pembrolizumab had an objective response rate of 33.3 % and a disease control rate of 83.3 % when they went on to receive the second course of pembrolizumab [8]. In the KEYNOTE-010 study, the 14 patients who were re-treated with pembrolizumab after experiencing tumor progression exhibited an objective response rate of 42.9 % and a disease control rate of 78.6 % [9] In addition, the results of a study conducted by Topp et al. showed a clinical benefit in a subset of patients who continued to be treated with pembrolizumab after tumor progression, with at least 30 % of lesions shrinking post-progression in 8.9 % to 24.4 % of patients, and no further lesion progression was observed in 64.8 % to 75.9 % of cases [10]. Furthermore, the results of a clinical study conducted by Escudier et al. revealed that efficacy of treatment was maintained after continuing drug administration in patients with advanced renal cancer who were resistant to or failed to respond to immunotherapy, with a prolongation of survival [11].

A Wang et al. study revealed that, in comparison to those who had been given anti-programmed cell death-1 (PD-1) monotherapy, patients with Hodgkin's lymphoma treated with decitabine (Dacogen) in conjunction with the PD-1 inhibitor camrelizumab experienced a marked increase in median progression-free survival (PFS) time [12]. In addition, the phase Ib/II KEYNOTE-146 study, which evaluated the efficacy of lenvatinib in combination with pembrolizumab in patients with metastatic renal cell carcinoma who had failed to respond to immunotherapy, showed that the combination therapy induced better anti-tumor activity and could be a viable treatment option for metastatic renal cell carcinoma in cases involving resistance to ICIs [13]. Because those two studies did not include patients with advanced non-small cell lung cancer (NSCLC), the effects of immunotherapy combined with other treatments such as chemotherapy or antivascular therapy are currently unknown in patients with NSCLC whose tumors have progressed since the initiation of immunotherapy. Such combination treatments involving immunotherapy could represent new treatment options in this patient population.

However, a study by Akamatsu et al. showed that even in patients who were effective on an initial ICI, treatment with nivolumab had limited efficacy once resistance developed [14]. Currently, there is no definitive treatment for tumor progression after immunotherapy in advanced NSCLC. Although previous studies have shown that patients experiencing tumor progression after immunotherapy can still benefit from immunotherapy alone [7,8], in the real world, clinicians often do not use an immunotherapeutic agent alone when tumor progression after immunotherapy occurs, but may combine chemotherapy, antivascular, and other agents at the same time to improve the effectiveness of antitumor therapy. Therefore, the purpose of this study was to explore the outcomes associated with continued administration of immunotherapy after PD and the optimal post-progression treatment regimen.

Material and methods

Patient selection

This retrospective study included 507 patients with stage III–IV NSCLC who had experienced disease progression after receiving immunotherapy between January 2019 and December 2022 at the Affiliated Cancer Hospital of Shandong First Medical University. The inclusion criteria were as follows: (1) pathologically confirmed NSCLC (either squamous cell carcinoma or adenocarcinoma); (2) clinical stage III–IV; and (3) the continued administration of systemic antitumor therapy after the detection of tumor progression following the initial immunotherapeutic regimen. The following were the exclusion criteria: (1) the presence of sensitive gene mutations such as those involving epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK); (2) death from non-cancer-related causes; and (3) incomplete information or loss to follow-up (Fig. 1). The Union for International Cancer Control/American Joint Committee on Cancer 8th edition Tumor, Node, Metastasis (TNM) staging system was used in this study.Fig. 1 Flow chart of the study design.

Abbreviations: No-immuno, patients whose immunotherapy was discontinued and was no longer a component of their systemic antitumor regimen after experiencing tumor progression; Immuno-combination, patients who continued to receive immunotherapy combined with other treatments as part of the systemic antitumor regimen after experiencing tumor progression; PSM, propensity score matching; Immuno+Chemo, immunotherapy combined with chemotherapy; Immuno+Antiangiogenic, immunotherapy combined with antiangiogenic therapy.

Fig. 1

Treatment

All patients underwent consultation with a multidisciplinary team to assess their condition and select an appropriate treatment plan. The patients were categorized into an Immuno-combination or a No-immuno group according to whether combination therapy involving immunotherapy and other treatment types was administered or not, respectively, as part of the systemic antitumor regimen after the occurrence of disease progression following the initial immunotherapeutic regimen. Systemic antitumor regimens in the No-immuno group included chemotherapy, antiangiogenic therapy, and chemotherapy combined with antiangiogenic therapy. The chemotherapeutic regimens comprised intravenous Taxol/paclitaxel/albumin-bound paclitaxel and platinum agents (TP regimen) or pemetrexed plus platinum agents (PC regimen). More specifically, the TP regimen consisted of platinum agents (nedaplatin 75 mg/m2 or carboplatin with an area under the curve of 5, or cisplatin 25 mg/m2 administered on days 1–3), as well as paclitaxel 135–175 mg/m2 or albumin-bound paclitaxel 260 mg/m2. The PC regimen consisted of pemetrexed 500 mg/m2. The antiangiogenic regimens included the use of anlotinib (orally administered, 12 mg once daily for 2 weeks, followed by a 1-week withdrawal period) and bevacizumab (intravenously administered, 15 mg kg-1 every 3 weeks). The systemic antitumor regimen in the Immuno-combination group included immunotherapy in combination with chemotherapy and/or antiangiogenic therapy. The immunotherapy regimen consisted of a PD-1 inhibitor (tislelizumab at a dose of 200 mg, pembrolizumab at a dose of 200 mg, camrelizumab at a dose of 200 mg, toripalimab at a dose of 240 mg, or sintilimab at a dose of 200 mg) administered every three weeks and a programmed cell death-ligand 1 (PD-L1) inhibitor (durvalumab at a dose of 1,500 mg, atezolizumab at a dose of 1,200 mg) administered every three weeks. The chemotherapeutic and antiangiogenic regimens in the Immuno-combination group were the same as those used in the No-immuno group.

Follow-up and study endpoints

All enrolled patients received regular outpatient assessments and telephone follow-ups after admission to the hospital. For patients whose last case record had been recorded >1 month before the cut-off time of this study, a telephone-based follow-up was conducted to complete the collection of clinical data and establish a database for the statistical analysis. By December 31, 2023, the follow-up had concluded and the median length of follow-up for all patients was 13 (range, 1–33) months. The primary and secondary endpoints of this study were PFS and overall survival (OS), respectively. PFS was defined as the interval between the time of initiation of systemic antitumor therapy after the occurrence of tumor progression following the initial immunotherapeutic regimen and the time of recurrence, death due to cancer-related causes, or the last follow-up visit. OS was defined as the interval between the time of initiation of systemic antitumor therapy after the occurrence of tumor progression following the initial immunotherapeutic regimen and the time of death due to cancer-related causes or the last follow-up visit.

Statistical analysis

Propensity score matching (PSM) was used to form a well-balanced cohort using the full range of available explanatory factors. To achieve this, we used R software (version 4.3.2; R Foundation for Statistical Computing, Vienna, Austria) to perform a 1:2 matching analysis between the No immuno and Immuno combination groups to adjust for existing explanatory factors that could affect the results. The independent samples t-test or rank sum test were utilized to compare continuous variables, while the chi-square test or Fisher's exact test was employed to compare categorical variables. The Kaplan-Meier method was employed to evaluate the PFS and OS of the patients, and a log-rank test was then utilized to contrast them. Using Cox proportional risk models, univariate and multivariate analyses were conducted to find independent prognostic variables for PFS and OS. Significance was determined by P < 0.1, and all tests were conducted in two-sided form. All data analyses and graphing were performed using R software version 4.3.2.

Results

Patients’ baseline characteristics

From January 2019 to December 2022, 507 patients with stage III–IV NSCLC had received immunotherapy and subsequently experienced disease progression, 153 of whom comprised the No-immuno group and 354 of whom comprised the Immuno-combination group. After PSM, there were a total of 150 patients in the No immune group and 300 patients in the Immuno combination group. The baseline characteristics and respective intergroup comparisons are listed in Table 1. There were 361 (80.2 %) males and 89 (19.8 %) females across the two groups, with 245 (54.4 %) and 205 (45.6 %) patients < 60 and ≥ 60 years old, respectively. Squamous cell carcinoma was diagnosed in 147 (32.7 %) patients, whereas 303 (67.3 %) patients were diagnosed with adenocarcinoma.Table 1 Baseline characteristics of enrolled patients.

Table 1Characteristics	Before PSM	After PSM	
	No-immuno (n=153)	Immuno-combination (n=354)	P value	No-immuno (n=150)	Immuno-combination (n=300)	P value	
Sex (%)							
 Female	30 (19.6)	72 (20.3)	0.851	29 (19.3)	60 (20.0)	0.904	
 Male	123 (80.4)	282 (79.7)		121 (80.7)	240 (80.0)		
Age (%)							
 < 60 years	81 (52.9)	171 (57.6)	0.339	80 (53.3)	165 (55.5)	0.864	
 ≥ 60 years	72 (47.1)	183 (42.4)		70 (46.7)	135 (44.5)		
Smoking (%)							
 YES	73 (27.2)	141 (39.8)	0.099	61 (40.7)	136 (45.3)	0.697	
 NO	80 (72.8)	213 (60.2)		89 (59.3)	164 (54.7)		
Drinking (%)							
 YES	31 (20.3)	88 (24.9)	0.499	30 (20.0)	68 (22.7)	0.956	
 NO	122 (79.7)	266 (75.1)		120 (50.0)	232 (77.3)		
Family history (%)							
 YES	34 (22.3)	83 (23.4)	0.892	33 (22.0)	66 (22.0)	1.000	
 NO	119 (77.7)	271 (76.6)		117 (78.0)	234 (78.0)		
Pathology (%)							
 Squamous cell carcinoma	49 (32.0)	131 (37.0)	0.283	49 (32.7)	98 (32.7)	1.000	
 Adenocarcinoma	104 (68.0)	223 (63.0)		101 (67.3)	202 (67.3)		
Progression (%)							
 LRR	47 (30.7)	96 (27.1)	0.703	77 (70.0)	43 (78.2)	0.354	
 DM	106 (69.3)	258 (72.9)		33 (30.0)	12 (21.8)		
Comorbidity (%)							
 YES	42 (27.4)	110 (31.1)	0.604	42 (28.0)	84 (28.0)	1.000	
 NO	111 (72.6)	244 (68.9)		109 (72.0)	216 (72.0)		
Clinical T stage							
 T1	13 (8.5)	42 (11.9)	0.124	13 (8.7)	27 (9.0)	0.563	
 T2	50 (32.7)	132 (37.3)		50 (33.3)	105 (35.0)		
 T3	42 (27.4)	90 (25.4)		41 (27.3)	85 (28.3)		
 T4	48 (31.4)	90 (25.4)		46 (30.7)	83 (27.7)		
Clinical N stage							
 N0	12 (7.9)	12 (3.4)	0.070	9 (6.0)	12 (4.0)	0.725	
 N1	9 (5.9)	33 (9.3)		9 (6.0)	19 (6.3)		
 N2	66 (43.1)	138 (39.0)		66 (44.0)	128 (42.7)		
 N3	66 (43.1)	171 (48.3)		66 (44.0)	141 (47.0)		
Stage (%)							
 III	18 (11.7)	33 (9.3)	0.401	15 (10.0)	33 (11.0)	0.853	
 IV	135 (88.3)	321 (90.7)		135 (90.0)	267 (89.0)		
ECOG PS (%)							
 0–1	144 (94.1)	325 (91.8)	0.666	141 (94.0)	282 (94.0)	1.000	
 ≥ 2	9 (5.9)	29 (8.2)		9 (6.0)	18 (6.0)		
PD-L1 expression (%)							
 Tumor cell <1 %	49 (32.0)	122 (34.5)	0.621	49 (32.7)	100 (33.3)	0.921	
 Tumor cell 1–49 %	61 (39.9)	141 (39.7)		61 (40.7)	119 (39.7)		
 Tumor cell ≥50 %	43 (28.1)	91 (25.8)		40 (26.7)	81 (27.0)		
No. of metastatic sites							
 ≤ 2	42 (27.5)	92 (25.9)	0.939	40 (26.7)	80 (26.7)	1.000	
 > 2	111 (72.5)	262 (74.1)		110 (73.3)	220 (73.3)		
Radiotherapy (%)							
 YES	100 (65.4)	216 (61.0)	0.482	97 (64.7)	186 (62.0)	0.633	
 NO	53 (34.6)	138 (39.0)		53 (35.3)	114 (38.0)		
PSM, propensity score matching; No-immuno, Patients whose immunotherapy was discontinued and was no longer a component of their systemic antitumor regimen after experiencing progression; Immuno-combination, Patients who continued to receive immunotherapy combined with other treatments as part of their systemic antitumor regimen after experiencing progression; Progression, Progress after initial immunotherapy; LRR, local regional recurrence; DM, distant metastasis; Comorbidity included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and coronary atherosclerotic heart disease; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PD-L1, programmed cell death-ligand 1; Radiotherapy, Received radiotherapy after experiencing progression following the initiation of immunotherapy.

Tumor progression and survival outcomes

After PSM, the median PFS times were 4 and 7 months in the No-immuno and Immuno-combination groups, respectively. As shown in Fig. 2, compared with the PFS rates in the No-immuno group, the Immuno-combination group exhibited significantly better outcomes at the 3-, 6-, and 12-month time points (3-month PFS: 51.3 % vs. 83.3 %, 6-month PFS: 25.3 % vs. 60.6 %, and 12-month PFS: 6.7 % vs. 24.4 %; P < 0.001). The median OS times were 8 and 16 months in the No-immuno and Immuno-combination groups, respectively. Compared with the OS rates in the No-immuno group, the Immuno-combination group experienced significantly better outcomes at the 6-, 12-, and 18-month time points (6-month OS: 72.5 % vs. 97.7 %, 12-month OS: 22.3 % vs. 69.4 %, and 18-month OS: 6.4 % vs. 40.4 %; P < 0.001). The results obtained before PSM mirrored those obtained after PSM, as shown in Supplementary Fig. 1.Fig. 2 Kaplan-Meier survival analysis of PFS (A) and OS (B) after PSM between the No-immuno and Immuno-combination groups.

Abbreviations: PFS, progression-free survival; OS, overall survival; PSM, propensity score matching; No-immuno, patients whose immunotherapy was discontinued and was no longer a component of their systemic antitumor regimen after experiencing progression; Immuno-combination, patients who continued to receive immunotherapy combined with other treatments as part of the systemic antitumor regimen after experiencing progression.

Fig. 2

The Cox regression analyses demonstrated that clinical TNM stage (P = 0.095), pathological type (P = 0.041), PD-L1 expression (P < 0.001) and treatment regimen administered post-progression (P < 0.001) were significantly associated with PFS; however, only PD-L1 expression and treatment regimen administered post-progression were independent prognostic factors for PFS (both Ps < 0.001; Table 2). The Cox regression analyses also revealed that PD-L1 expression (P < 0.001) and treatment regimen administered post-progression (P < 0.001) were significantly associated with OS, and both the PD-L1 expression and the treatment regimen administered post-progression were independent prognostic factor for for OS (P < 0.001, P < 0.001).Table 2 Cox regression analysis of the PFS and OS in the overall population.

Table 2Variables	PFS Univariate analysis	PFS Multivariate analysis	OS Univariate analysis	OS Multivariate analysis	
	HR (95 %CI)	P	HR (95 %CI)	P	HR (95 %CI)	P	HR (95 %CI)	P	
Age									
 < 60 years	Reference				Reference				
 ≥ 60 years	1.005 (0.919, 1.100)	0.907			1.126 (0.930, 1.363)	0.226			
Sex									
 Female	0.961 (0.768, 1.203)	0.729			0.949 (0.746, 1.208)	0.670			
 Male	Reference				Reference				
Smoking									
 YES	Reference				Reference				
 NO	0.977 (0.814, 1.172)	0.800			0.987 (0.815, 1.195)	0.894			
Drinking									
YES	Reference				Reference				
NO	0.912 (0.822, 1.216)	0.791			0.944 (0.810, 1.346)	0.811			
No. of metastatic sites									
 ≤ 2	Reference				Reference				
 >2	1.314 (0.719, 2.399)	0.374			1.170 (0.734, 1.864)	0.510			
Comorbidity									
 YES	Reference				Reference				
 NO	0.908 (0.510, 1.617)	0.744			1.042 (0.674, 1.610)	0.854			
ECOG PS									
 0–1	0.776 (0.431, 1.395)	0.396			0.942 (0.603, 1.472)	0.794			
 ≥ 2	Reference				Reference				
Family history									
 YES	1.191 (0.606, 2.341)	0.611			1.026 (0.593, 1.774)	0.928			
 NO	Reference				Reference				
Progression									
 LRR	Reference				Reference				
 DM	1.222 (0.731, 2.109)	0.521			1.276 (0.522, 1.907)	0.894			
Clinical T stage									
 T1–T2	Reference				Reference				
 T3–T4	1.205 (0.699, 1.821)	0.506			1.443 (0.672, 1.762)	0.712			
Clinical N stage									
 N0	Reference				Reference				
 N+	1.349 (0.566, 2.254)	0.322			1.401 (0.792, 1.892)	0.801			
Clinical TNM stage									
 ⅡI	Reference		Reference		Reference				
 IV	1.288 (0.957,1.733)	0.095	1.066 (0.911, 2.126)	0.257	1.029 (0.748,1.416)	0.860			
Pathology									
 Adenocarcinoma	Reference		Reference		Reference				
 Squamous cell carcinoma	0.820 (0.678, 0.992)	0.041	0.905 (0.746, 1.097)	0.308	0.932 (0.764, 1.136)	0.485			
PD-L1 expression									
 Tumor cell <1 %	2.019 (1.544, 2.491)	<0.001	2.762 (1.831, 2.934)	<0.001	3.541 (2.765, 4.923)	<0.001	3.622 (2.686, 4.359)	<0.001	
 Tumor cell ≥1 %	Reference		Reference		Reference		Reference		
Post-PD treatment									
 No-immuno1	2.220 (1.819, 2.709)	<0.001	2.182 (1.783, 2.669)	<0.001	3.322 (2.686, 4.109)	<0.001	3.101 (2.481, 3.959)	<0.001	
 Immuno-combination2	Reference		Reference		Reference		Reference		
PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; Comorbidity included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and coronary atherosclerotic heart disease; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Progression, Progress after initial immunotherapy; LRR, local regional recurrence; DM, distant metastasis; TNM, tumor, node, metastasis; PD-L1, programmed cell death-ligand 1; PD, disease progression based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines; No-immuno, Patients whose immunotherapy was discontinued and was no longer a component of their systemic antitumor regimen after experiencing progression; Immuno-combination, Patients who continued to receive immunotherapy combined with other treatments as part of their systemic antitumor regimen after experiencing progression.

Subgroup analyses in patients who received immuno-combination therapy

After PSM, the patients in the Immuno-combination group were classified into an immunotherapy combined with chemotherapy (Immuno+Chemo; n = 163 [54.3 %]) group and an immunotherapy combined with antiangiogenic therapy (Immuno+Antiangiogenic; n = 137 [45.7 %]) group according to the immunotherapy combination regimen administered. The median PFS times in the Immuno+Chemo and Immuno+Antiangiogenic groups were 7 and 8 months, respectively. As shown in Fig. 3, compared with the PFS rates in the Immuno+Chemo group, the Immuno+Antiangiogenic exhibited significantly better outcomes at the 3-, 6-, and 12-month time points (3-month PFS: 76.7 % vs. 91.2 %, 6-month PFS: 51.3 % vs. 71.5 %, and 12-month PFS: 23.1 % vs. 25.7 %; P = 0.017). The median OS times in the Immuno+Chemo and Immuno+Antiangiogenic groups were 16 and 18 months, respectively. Compared with the OS rates in the Immuno+Chemo group, the Immuno+Antiangiogenic group exhibited significantly improved outcomes at the 6-, 12-, and 18-month time points (6-month OS: 97.5 % vs. 97.8 %, 12-month OS: 62.1 % vs. 77.9 %, and 18-month OS: 33.3 % vs. 48.7 %; P = 0.006). The results obtained before PSM mirrored those obtained after PSM, as shown in Supplementary Fig. 2.Fig. 3 Kaplan-Meier survival analysis of PFS (A) and OS (B) after PSM between the Immuno+Chemo and Immuno+Antiangiogenic groups, and PFS (C) and OS (D) after PSM between the Duration > 6 months and Duration ≤ 6 months groups.

Abbreviations: PFS, progression-free survival; OS, overall survival; PSM, propensity score matching; Immuno+Chemo, immunotherapy combined with chemotherapy; Immuno+Antiangiogenic, immunotherapy combined with antiangiogenic therapy; Duration, the time interval between the initiation of immunotherapy and disease progression.

Fig. 3

The Cox regression analyses showed that clinical N stage (P = 0.093), clinical TNM stage (P = 0.032), pathological type (P = 0.018), PD-L1 expression (P < 0.001), immunotherapy combination regimen administered post-progression (P = 0.009), and time interval from the initiation of the first immunotherapy treatment to tumor progression (Duration; P < 0.001) were significantly associated with PFS; however, only pathological type (P = 0.001), PD-L1 expression (P < 0.001), immunotherapy combination regimen administered post-progression (P < 0.001), and Duration (P < 0.001) were independent prognostic factors for PFS (Table 3). The Cox regression analyses also showed that PD-L1 expression (P < 0.001), immunotherapy combination regimen (P = 0.005), type of ICI administered (P = 0.044), and Duration (P < 0.001) were significantly associated with OS and were independent prognostic factors for it (P < 0.001, P = 0.010, P = 0.035, and P < 0.001, respectively).Table 3 Cox regression analysis of PFS and OS in the Immuno-combination subgroups.

Table 3Variables	PFS univariate analysis	PFS multivariate analysis	OS univariate analysis	OS multivariate analysis	
	HR (95 %CI)	P	HR (95 %CI)	P	HR (95 %CI)	P	HR (95 %CI)	P	
Age									
 < 60 years	Reference				Reference				
 ≥ 60 years	1.037 (0.833, 1.290)	0.745			1.253 (0.989, 1.588)	0.161			
Sex									
 Female	0.891 (0.679, 1.168)	0.402			0.995 (0.741, 1.336)	0.973			
 Male	Reference				Reference				
Smoking									
 YES	Reference				Reference				
 NO	0.942 (0.755, 1.176)	0.600			0.951 (0.750, 1.205)	0.678			
Drinking									
 YES	Reference				Reference				
 NO	0.936 (0.776, 1.342)	0.533			0.922 (0.652, 2.093)	0.498			
No. of metastatic sites									
 ≤ 2	Reference				Reference				
 > 2	1.443 (0.766, 2.363)	0.254			1.213 (0.546, 1.847)	0.402			
Comorbidity									
 YES	Reference				Reference				
 NO	0.822 (0.422, 1.517)	0.654			1.125 (0.613, 1.404)	0.843			
ECOG PS									
 0–1	0.876 (0.613, 1.553)	0.562			0.925(0.593, 1.452)	0.804			
 ≥ 2	Reference				Reference				
Family history									
 YES	1.211 (0.561, 2.213)	0.591			1.161(0.633, 1.834)	0.911			
 NO	Reference				Reference				
Progression									
 LRR	Reference				Reference				
 DM	1.043 (0.566, 1.745)	0.873			1.126 (0.648, 1.475)	0.901			
Clinical T stage									
 T1–T2	Reference				Reference				
 T3–T4	1.283 (0.602, 1.740)	0.693			1.173 (0.421, 1.962)	0.801			
Clinical N stage									
 N0	Reference		Reference		Reference				
 N+	1.683 (1.301, 2.098)	0.093	1.483 (0.851, 1.868)	0.284	1.501 (0.793, 1.492)	0.305			
Clinical TNM stage									
 ⅡI	Reference		Reference		Reference				
 IV	1.502 (1.035, 2.179)	0.032	1.421 (0.974, 2.073)	0.068	1.016 (0.687,1.503)	0.938			
Pathology									
 Adenocarcinoma	Reference		Reference		Reference				
 Squamous cell carcinoma	0.757 (0.601, 0.953)	0.018	0.643 (0.500, 0.827)	0.001	0.993 (0.779, 1.267)	0.957			
PD-L1 expression									
 Tumor cell <1 %	1.719 (1.267, 2.512)	<0.001	1.624 (1.331, 2.584)	<0.001	2.141 (1.567, 2.823)	<0.001	2.223 (2.011, 2.509)	<0.001	
 Tumor cell ≥1 %	Reference		Reference		Reference		Reference		
Post-PD treatment									
 Immuno+Chemo	1.338 (1.075, 1.666)	0.009	1.561 (1.230, 1.980)	<0.001	1.411 (1.112, 1.791)	0.005	1.369 (1.079, 1.737)	0.010	
 Immuno+Antiangiogenic	Reference		Reference		Reference		Reference		
ICI									
 PD-1	1.351 (0.912, 2.002)	0.133			1.571 (1.012, 2.439)	0.044	1.619 (1.035, 2.533)	0.035	
 PD-L1	Reference				Reference		Reference		
Duration									
 > 6 months	0.483 (0.387, 0.604)	<0.001	0.489 (0.389, 0.613)	<0.001	0.474 (0.371, 0.606)	<0.001	0.470 (0.368, 0.601)	<0.001	
 ≤ 6 months	Reference		Reference		Reference		Reference		
PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; Comorbidities included hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and coronary atherosclerotic heart disease; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Progression, Progress after initial immunotherapy; LRR, local regional recurrence; DM, distant metastasis; TNM, tumor, node, metastasis; PD-L1, programmed cell death-ligand 1; PD, disease progression based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines; No-immuno, Patients whose immunotherapy was discontinued and was no longer a component of their systemic antitumor regimen after experiencing progression; Immuno-combination, Patients who continued to receive immunotherapy combined with other treatments as part of their systemic antitumor regimen after experiencing progression.

After PSM, the patients in the Immuno-combination group were also categorized into two subgroups, depending on the aforementioned Duration variable (> 6 months and ≤ 6 months). The median PFS times in the Duration > 6 months and Duration ≤ 6 months groups were 10 months and 7 months, respectively. As shown in Fig. 3, compared with the PFS rate in the Duration ≤ 6 months group, the Duration > 6 months group exhibited significantly better outcomes at the 3-, 6-, and 12-month time points (3-month PFS: 71.9 % vs. 96.4 %, 6-month PFS: 51.2 % vs. 71.4 %, and 12-month PFS: 11.7 % vs. 38.7 %; P < 0.001). The median OS times for the Duration > 6 months and Duration ≤ 6 months groups were 21 and 14 months, respectively. Compared with the OS rates in the Duration ≤ 6 months group, the Duration > 6 months group experienced significantly advantageous outcomes at the 6-, 12-, and 18-month time points (6-month OS: 98.1 % vs. 97.1 %, 12-month OS: 61.2 % vs. 79.2 %, and 18-month OS: 28.1 % vs. 55.5 %; P < 0.001). The results obtained before PSM mirrored those obtained after PSM, as shown in Supplementary Fig. 2.

Discussion

Immunotherapy has been widely utilized and has helped achieved milestones in the treatment of patients with advanced NSCLC; however, a large proportion of patients inevitably develop immune resistance. In the OAK study, for example, approximately 78 % of 425 patients with NSCLC who received immunotherapy eventually experienced tumor progression [7]. Whether it is appropriate and efficacious to continue to administer immunotherapy once disease progression has developed remains controversial, and despite the urgent need for better options, the optimal implementation of treatment regimens that combine immunotherapy and other modalities post-progression remains underexplored. The present study is the first to analyze and compare the clinical benefits of several treatment modalities for tumor progression after immunotherapy in real-world cases of advanced NSCLC. These findings may help inform future treatment choices in this patient population. The results of the current study demonstrated the superior efficacy and survival outcomes in the patients with NSCLC who continued to receive immunotherapy after tumor progression compared with the outcomes in those who did not. Furthermore, the subgroup analyses demonstrated that the administration of immunotherapy in combination with antiangiogenic therapy was the most efficacious combination therapy evaluated, with the efficacy improving with longer initial immunotherapy treatment durations.

Immunotherapy is often discontinued in patients whose tumors have progressed following the initial treatment; however, a growing number of studies have reported that re-treatment with ICIs is a viable option [[7], [8], [9],15,16]. Compared with the mechanisms of action of traditional antitumor agents, ICIs exert their effects through the reactivation of antitumor immune responses by modulating the immune system [17]. The anti-tumor effects of immunotherapy are not simply dependent on the pharmacodynamic activity of the administered drugs, optimizing the outcomes requires coordinated functionality between tumor cells and the host immune system. The processes modulated by immunotherapy are diverse and time-dependent, ranging from tumor-specific T-cell induction, to activation and proliferation, the infiltration of tumor tissue, and the generation of an immune response throughout the body, a process that may take weeks or even months [18]. Therefore, tumor progression after ICI treatment does not necessarily result from the development of drug resistance; any perceived lack of effect could be a result of the immune system having not yet developed an anti-tumor response [19,20]. Some tumors increase in size upon initiation of ICI treatment; this is followed by a decrease in dimensions, a condition known as "pseudoprogression" that is mainly driven by the infiltration of immune cells within the tumor, increasing the extent of detection on imaging evaluations [21,22].

Due to the unique mechanisms of action of various immunotherapeutic agents, atypical response patterns can be observed during treatment, and accurate identification of these responses is critical for selecting subsequent treatment regimens for each patient. In addition, differences in the criteria used to evaluate the efficacy of antitumor therapies may lead to variability in the observed outcomes. At present, the most widely used criteria for the assessment of antitumor efficacy are the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines [23], which were initially used to assess antitumor responses to cytotoxic drugs [10]. The RECIST v1.1 guidelines recommend discontinuing current therapy upon the detection of PD [24]. The mode of action of cytotoxic drugs usually induces meaningful and quantifiable effects within a few weeks of the initial administration, such as tumor shrinkage in baseline lesions [25]. Because immunotherapy paradigms differ from those of cytotoxic drugs, measurable antitumor effects do not appear within the first few weeks following the initiation of immunotherapy, and discontinuation of ICI therapy is not appropriate during this timeframe. The traditional criteria that have historically been used to assess the antitumor efficacy of various pharmacotherapies, including the RECIST v1.1 guidelines, cannot adequately assess the efficacy of immunotherapy [10,25]. Thus, in order to accurately assess atypical tumor responses, researchers have proposed certain criteria for assessing immunotherapeutic response assessment criteria such as the immune RECIST (iRECIST) guidelines; these new frameworks have facilitated the identification of responses not observed in traditional systemic therapies and allow for better documentation of related outcomes [26,27]. However, further validation of the iRECIST criteria is required to ensure the integrity of the content and its intended functionality in order to provide a more scientific and rational efficacy evaluation system for use in clinical immunotherapy. The results of the OAK, KEYNOTE-010, and KEYNOTE-024 clinical trials have confirmed that patients experiencing tumor progression after immunotherapy still benefit from the continuation of ICI treatment [[7], [8], [9]], and a study conducted by Sun et al. similarly showed that even in cases in which tumor progression occurred after the cessation of ICI treatment, clinical benefits could still be derived from a rechallenge with ICI [15]. A study by Topp et al. reported that some patients with a variety of solid tumors, including NSCLC, could still benefit from the continued use of pembrolizumab after the detection of tumor progression [10]. However, most of the results of the clinical trials conducted to date have been based on the administration of immunotherapies as a monotherapy, and different outcomes might be expected in real-world clinical settings.

This study presents several key findings that may be useful for guiding the selection of appropriate treatments for patients whose tumors have progressed after the initial immunotherapy. First, this study evaluated survival outcomes, including PFS and OS, in patients who experienced tumor progression after immunotherapy and compared the results between those who did or did not continue to receive immunotherapy combined with other treatments; those that did experienced significantly better outcomes. This suggests that one can still benefit from immunotherapy post-progression after having received immunotherapy, which is consistent with the results of the OAK study. In contrast, the patients who continued to receive immunotherapy did so in combination with another treatment regimen, whereas the patients who did not continue to receive immunotherapy were treated not only with chemotherapy but also with other therapeutic modalities, such as antivascular drugs; such patients experienced similar outcomes, meaning that the initial treatment with immunotherapy likely inferred a survival benefit even after tumor progression. The findings suggest that immunotherapy can play a stable and powerful role throughout the course of antitumor therapy.

Second, the patients in the Immuno-combination group were stratified into subgroups depending on the combination therapy they received, including the Immuno+Chemo and Immuno+Antiangiogenic groups, with the subgroup analyses revealing a significant survival advantage in the Immuno+Antiangiogenic group. It has been demonstrated that the combined administration of immune modulating and antivascular drugs results in a coordinated synergistic effect and a strong combination effect [13,[28], [29], [30], [31]]. There is a complex relationship between the processes involved in tumor angiogenesis and immunity. Hypoxia in the tumor microenvironment (TME) induces tumor and stromal cells to secrete a variety of pro-angiogenic factors, leading to pathological angiogenesis [32]. This pathologically abnormal vasculature, which is flexural and highly permeable, forms within the tumor, potentially leading to the development of a hypoxic and acidic TME that hinders immune effector cell infiltration and promotes myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), ultimately creating an immunosuppressive microenvironment [33,34]. Antiangiogenic drugs can inhibit this pathological process and increase T-cell infiltration, reversing this immunosuppressive state and enhancing the immune response [32]. Zhao et al. demonstrated that the administration of low doses of apatinib in a mouse model of lung cancer resulted in increased T-cell infiltration and hindered the recruitment of relevant suppressor immune cells to the site of tumors [35]. Other studies have found that vascular endothelial growth factor (VEGF) binds to VEGF receptor 2 (VEGFR-2) in dendritic cells (DCs), increasing PD-1 expression in DCs and inhibiting their development, while drastically reducing their antigen-presenting capacity [36]. Antiangiogenic drugs attenuate the inhibitory effect of VEGF on DCs, thereby enhancing their presentation of tumor antigens. The TME is enriched with suppressive immune cells, and antiangiogenic drugs can transform the TME from an immunosuppressive to an immunosupportive state by inhibiting the proliferation of Tregs [37], suppressing MDSCs [38], and facilitating the conversion of tumor-associated macrophages (TAMs) to the M1-like antitumor phenotype that inhibits tumor angiogenesis [39]. Immunotherapy also enables activated immune cells to secrete anti-tumor cytokines, which regulate the immune microenvironment and help maintain normal angiogenic and vascular processes [40,41]. Therefore, combination therapies involving antiangiogenic agents and immunotherapy can exert synergistic anti-tumor effects, and published clinical trial results also suggest that this combination is a promising therapeutic option for the treatment of advanced NSCLC [[42], [43], [44]].

Third, in the Immuno-combination group in this study, a more pronounced prognostic advantage was observed in patients whose time interval between the initiation of immunotherapy and tumor progression exceeded 6 months, an effect that may have been related to the efficacy of the initial treatment. This is consistent with previous findings that have shown that in patients who responded to the first immunotherapy treatment, an immunotherapy rechallenge was able to elicit further responses, even in cases in which the tumors had progressed [7,8,15]. The Society for Immunotherapy of Cancer distinguishes between three different resistance scenarios for immunotherapy resistance, which include primary resistance, secondary resistance, and progression after the discontinuation of therapy for any reason [45]. Primary resistance has been defined as evidence of disease progression in the period ranging from 6 weeks (two cycles) to 6 months after the initiation of ICI therapy. Secondary resistance has been defined as the occurrence of disease progression after having achieved a clinical benefit (i.e., objective remission or disease stabilization lasting 6 months or longer) [45]. The TME [46], signaling pathways [47], and gene deletions [48] have been shown to be associated with primary drug resistance. The mechanisms driving secondary resistance are associated with the upregulation of other immune checkpoints, genetic defects, or genetic mutations [47,49,50]. The mechanisms of immunotherapy resistance have not been well-studied to date, and it is often accompanied by various confounding factors and special circumstances in clinical practice. Further research is required to clarify the mechanisms through which immunotherapeutic resistance develops and to explore predictive markers of therapeutic benefit for patients.

It is important to note that this study has some limitations. First, not all sources of bias could be controlled for due to the retrospective nature of the study. Second, the sample size was small, and prospective multi-center studies as well as randomized controlled clinical trials are necessary to further validate the optimal treatment regimen for patients who have experienced tumor progression following initial immunotherapy. Third, due to the nature of this real-world study, it was not possible to know the specific reasons why immunotherapy was continued after disease progression was confirmed.

Conclusions

In real-world settings, patients with advanced NSCLC who have experienced tumor progression after the initiation of immunotherapy can still derive some benefits from continuing to receive it, with immunotherapy administered in combination with antiangiogenic therapy being the most efficacious option.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Cancer Hospital Affiliated to Shandong First Medical University, which waived the need for informed consent because of the retrospective nature of the study. We declare that the patients’ information will be kept confidential and that we have adhered to the principles of the Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed in this study are available from the corresponding author upon request.

Funding

This work was supported by the 10.13039/501100001809 National Natural Science Foundation of China [grant number 82373044 ] and the 10.13039/501100007129 Natural Science Foundation of Shandong Province [grant numbers ZR2022LSW001 , ZR2023LSW023 ].

CRediT authorship contribution statement

Ying Li: Writing – original draft, Visualization, Validation, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Junfeng Zhao: Visualization, Software, Methodology, Investigation, Formal analysis, Conceptualization. Ruyue Li: Software, Data curation. Xiujing Yao: Data curation. Xue Dong: Software. Ruidan Zhang: Data curation. Yintao Li: Writing – review & editing, Visualization, Supervision, Resources, Project administration, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix Supplementary materials

Image, application 1

Image, application 2

Acknowledgments

We thank each patient for permitting the use of their clinicopathological data for this study.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.neo.2024.101043.
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