The prognostic factors of clinical outcomes in non-small cell lung cancer patients receiving subsequent treatments after progression on initial immunotherapy

Introduction

With a series of in-depth research on tumor immunity, the evolving immunotherapy has become a landmark in the history of tumor medicine. Over the past few years, immune checkpoint inhibitors (ICIs) based therapy has shown an excellent efficacy for patients diagnosed as advanced or metastatic non-small cell lung cancer (NSCLC) patients without targetable driver gene (1-4), and ICI monotherapy or combined with chemotherapy with or without anti-angiogenic agents has mainly constituted the treatment for NSCLC in daily clinical practice (5). However, disease progression which is usually inevitable would occur in the vast majority of patients (6). Since there is no universally accepted subsequent treatment after progression (STAP) (defined as the next treatment after progression from the initial immunotherapy), traditional platinum-based chemotherapy dominates treatment options for patients suffering initial ICI treatment failure, with median overall survival (OS) ranging from 4.4 to 6.8 months, median progression-free survival (PFS) ranging from 2.4 to 4.1 months and objective response rate (ORR) ranging from 20.0% to 22.8% (7,8). As the limited efficacy of salvage chemotherapy, novel treatments are worth being explored.

ICI retreatment has emerged in recent years, gradually becoming another option available after disease progression on initial immunotherapy treatment. Several clinical trials have demonstrated the potential validity of treatment beyond progression with ICI in other carcinoma (9,10). Regarding NSCLC, ICI retreatment has also been proven to be feasible (11,12). A phase 2 trial showed that patients receiving pembrolizumab plus next-line chemotherapy gained better PFS compared with others receiving single-agent chemotherapy alone, when progression of the disease was observed on initial immunotherapy (13). In addition, some retrospective research has proved that patients receiving ICI retreatment achieve better clinical outcomes than those not receiving any anticancer therapy, in real-world situations (14-16). For ICI retreatment, most studies have focused on the effectiveness of the same ICI as the initial option (12,17). OAK study, a randomized phase III study, showed that patients can still derive survival benefit again without extra increased safety risk for receiving atezolizumab beyond progression on initial atezolizumab therapy (12). Although the data of retreatment with another ICI are limited, they show an inspiring result (18). A retrospective study showed that patients who had progressed on nivolumab can still benefit from new ICI—pembrolizumab with the median PFS of 3.1 months, but notably, those responding to pembrolizumab had very high (≥80%) expression of programmed cell death ligand 1 (PD-L1) (18).

PD-L1 expression in tumors is regarded as a productive predictive biomarker for efficacy of ICI therapy (19) which is widely applied in clinical practice, while standard predictors to predict the efficacy of STAP remain to be explored.

Therefore, we performed the retrospective study aiming to explore influencing factors of efficacy of STAP for NSCLC patients who had received initial ICI-based treatment and experienced disease progression, and to discover an appropriate regimen for them. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-57/rc).

Methods

Study design and patients

In this retrospective cohort study, advanced or metastatic NSCLC patients receiving subsequent treatment with or without ICI after progression on initial immunotherapy at Beijing Chest Hospital, Capital Medical University, between March 2016 and May 2023 were included for analysis. The follow-up data were obtained by phone calls, clinic medical records and hospital discharge records. The data were censored if the patient had not experienced progression at the last follow-up. All the patients were followed up until 31 May 2023. Patients older than 18 years, diagnosed with primary NSCLC and at least one target lesion, receiving STAP because of progression of initial ICI-based treatment were eligible. Patients whose initial ICI-based treatment was interrupted by immune-related adverse events and those receiving targeted therapy as STAP were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Beijing Chest Hospital, Capital Medical University [(2020) - Scientific Research - Provisional Review No. (09)] and individual consent for this retrospective analysis was waived.

Study assessment

Demographic and baseline characteristics and survival outcomes were retrieved from the medical information system, including age, gender, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), histological subtype, tumor clinical stage, driver gene mutation status, PD-L1 expression status, treatment line, regimens of initial immunotherapy and STAP, etc. PD-L1 expression [tumor proportion score (TPS)] was evaluated by the Dako PD-L1 IHC 22C3 pharmDx assay (PD-L1 positive expression: TPS ≥1%; PD-L1 negative expression: TPS <1%). Disease progression and the response evaluation was confirmed according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) by two senior tumor physicians.

The primary efficacy endpoint was PFS2, defined as the time from the initiation of next treatment after initial immunotherapy failure to disease progression or death from any cause. Secondary endpoints were ORR2 (ORR of STAP), and disease control rate 2 (DCR2) (DCR of STAP). ORR was defined as the proportion of patients with complete response (CR) and partial response (PR). DCR was defined as the proportion of patients with CR, PR and stable disease (SD).

Statistical analysis

The continuous and categorical variables were presented as medians [interquartile range (IQR)] and numbers (percentages), individually. PFS and 95% confidence intervals (CIs) were calculated by the Kaplan-Meier method, and differences were compared by log-rank test.

Subgroup analyses for efficacy predictors were performed based on age (<65 vs. ≥65 years), gender (female vs. male), smoking status (current/previous vs. never), ECOG PS (≥2 vs. 0–1), histological subtypes at initial ICI-based treatment (squamous cell carcinoma vs. adenocarcinoma), PD-L1 expression at initial ICI-based treatment (TPS; negative <1% vs. positive ≥1%), treatment lines (2nd vs. ≥3rd), best overall response [BOR; PR vs. SD/progressive disease (PD)], PFS1 defined as PFS of initial ICI-based treatment (PFS1 <3 vs. PFS1 ≥3 months; PFS1 <6 vs. PFS1 ≥6 months), and regimens of STAP hazard ratios (HRs) and 95% CI were evaluated with Cox proportional-hazards model in multivariable analyses. P value <0.05 was considered statistically significant, and all statistical tests were two-sided. All statistical analyses were performed using SPSS 26.0 and GraphPad Prism 8.0.

Results

Demographic information

There were 176 patients who received follow-up treatments after acquiring resistance residence between March 2016 and April 2023 included, and the process of patient inclusion and exclusion is shown in Figure 1. Among them, 140 (79.5%) patients were male, and 123 (69.9%) had been smokers. The median age of patients was 64 years (IQR, 58–68 years). Most patients (157/176, 89.2%) had ECOG PS of 1. The predominant histological subtype was adenocarcinoma. Moreover, in view of the complex conditions in the real world, two (1.1%) adenosquamous carcinoma and two (1.1%) NSCLC which were unable to define the exact subtype in pathology were also included. Before receiving initial immunotherapy, driver genes were tested in 143 patients, of which 63 (35.8%) were positive, including 25 (14.2%) patients who were EGFR-mutated, and 133 (75.6%) patients who were confirmed to be at stage IV. PD-L1 expression data were available for all patients, which were measured when they prepared to receive initial immunotherapy, of whom 95 (54%) patients were PD-L1 positive. Treatment lines of STAP were second in 98 (55.7%) patients, and third or beyond in 78 (44.3%) patients, respectively. Detailed demographic information of patients included is presented in Table 1.

Figure 1 Flowchart of patient inclusion and exclusion. NSCLC, non-small cell lung cancer; ICI immune checkpoint inhibitor; irAE, immune-related adverse event.

Characteristics of initial ICI-based treatment

In reference to the initial ICI-based treatment, most patients (110 /176, 62.5%) had received ICI combined with chemotherapy. Median PFS1 was 4.9 months; 57 (32.4%), 79 (44.9%), and 40 (22.7%) patients had achieved PR, SD, and PD, respectively, with an ORR1 (ORR of initial ICI-based treatment) of 32.4% and a DCR1 (DCR of initial ICI-based treatment) of 77.3% (Table 2).

Risk factors associated with PFS2

The last follow-up was on May 31, 2023. The median follow-up was 26.0 months (IQR, 17.2–35.4 months). During follow-up, 156 (88.6%) cases of progression occurred and median PFS2 was 3.6 months (95% CI: 2.8–4.4). While most patients (82/176, 46.6%) achieved SD, PR was observed in 16 cases (9.1%). ORR2 was 9.1% and DCR2 was 55.7% (Table 3). For univariate analysis, tendencies for longer PFS2 were related to patients with longer PFS1 [PFS1 ≥3 months (P=0.0013), PFS1 ≥6 months (P<0.0001)], BOR1 (BOR of initial ICI-based treatment) of PR (P=0.024), or whose PD-L1 expression were positive (P=0.0036). However, age, gender, smoking status, histological, and treatment lines did not affect PFS (Figure 2). Multivariate analysis was used to adjust for the confounders of these factors, which indicated that patients with PD-L1 positive expression (positive vs. negative, HR =0.672, 95% CI: 0.477–0.947; P=0.023) or PFS1 ≥6 months (PFS1 ≥6 vs. <6 months, HR =0.543, 95% CI: 0.358–0.824; P=0.004) were associated with longer PFS2 (Figure 3).

Figure 2 Kaplan-Meier curves of PFS2 in patients with different baseline characteristics. (A) gender; (B) age [patients were divided into ≥65 years group (n=81) and <65 years group (n=95)]; (C) smoking status; (D) PD-L1 TPS (negative means PD-L1 expression <1%, positive means PD-L1 expression ≥1%), PD-L1 positive expression predicts a better PFS2 (P=0.0036); (E) treatment line; (F) histologic subtype (we only analysis the patients whose histologic subtype is adenocarcinoma or squamous cell carcinoma); (G) patients achieved PR of initial BOR have a longer PFS2 (P=0.024); (H) PFS1 <6 months predicts a worse PFS2 (P<0.0001); (I) PFS1 <3 months predicts a worse PFS2 (P=0.0013). PD-L1, programmed cell death ligand 1; TPS, tumor proportion score; ICI, immune checkpoint inhibitor; PFS1, progression-free survival of initial immunotherapy; m, months; BOR, best overall response; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 3 Univariate and multivariate analysis of progression-free survival 2. CI, confidence interval; PD-L1, programmed cell death ligand 1; PR, partial response; SD, stable disease; PD, progressive disease; PFS1, progression-free survival of initial immunotherapy; m, months.

Different options of STAP

After progression to the first immunotherapy, depending on a distinct condition of individual, some patients (84/176, 47.7%) switched to receive other treatments including chemotherapy, radiotherapy or anti-angiogenesis therapy, while others [92 (52.3%)] received ICI-based treatments again, and 20 (11.4%) of them switched to new ICI. Half of the 72 (40.9%) patients who used the original ICI received the same treatment regimen as the initial immunotherapy regimen, which was the most common regimen for patients still using ICI, and most of the remaining patients underwent ICI combined chemotherapy with or without anti-angiogenic agents (Table 4). For patients without ICI treatment in subsequent therapy, they separately received local radiotherapy, chemotherapy, anti-angiogenic therapy or a combination of those regimens (Table 4).

Subgroup analysis of PFS2 according to subsequent regimens

To explore the optimal regimen for patients after progression, we conducted a subgroup analysis of the subsequent regimens in relation to their PFS2 (Figure 4). Because of the differences between local radiotherapy and other systemic therapies, we excluded patients whose next treatment after initial immunotherapy progression included radiotherapy. After excluding the interference of radiotherapy, 81 (46.0%) patients received immunotherapy or its combination therapy, and 55 (31.3%) patients received non-immunotherapy. According to our results, immunotherapy had no effect on the PFS2 (P=0.60) (Figure 4A).

Figure 4 Kaplan-Meier curves of progression-free survival 2 in patients with different systemic regimens after initial immunotherapy progression. (A) Survival curves for patients with and without ICI-based treatment; (B) survival curves for patients with and without ICI-based treatment, excluding patients receiving initial regimen; (C) survival curves for patients with initial regimen and non-immunotherapy; (D) survival curves for patients with initial regimen and patients receiving new regimen but still using original ICI; (E) survival curves for patients with new ICI and patients receiving new regimen but still using original ICI; (F) survival curves for patients with initial regimen and new ICI-based treatment; (G) survival curves for patients with new ICI-based treatment and initial regimen; (H) survival curves for patients receiving ICI with chemotherapy and patients receiving ICI with chemotherapy plus anti-angiogenic therapy. ICI, immune checkpoint inhibitor; chemo, chemotherapy; A, anti-angiogenic therapy.

In this study, a subset of patients (36/176, 20.5%) continued receiving the original regimen after progressing on initial immunotherapy. No statistically significant difference was observed in PFS2 between patients (45/176, 25.6%) receiving immunotherapy after exclusion patients treated with original regimen, and those (55/176, 31.3%) receiving non-immunotherapy, according to our results (P=0.10) (Figure 4B), probably because of the small sample size. After excluding the interference of initial regimens, of the patients who continued to receive immunotherapy, 26 (14.8%) still used the initial ICI, while others (19/176, 10.8%) switched to new ICI. We analyzed the PFS2 of both, and found that changing ICI is not a risk factor for PFS2 (P=0.39) (Figure 4E).

By contrast, PFS2 was significantly shorter in patients (36/176, 20.5%) who did not change their regimens than in patients (19/179, 10.8%) who were treated with a new ICI (P=0.019) (Figure 4G). Besides, there was no significant difference in PFS2 (P=0.23) (Figure 4C) between patients (36/176, 20.5%) receiving the original regimens compared to those (53/176, 30.1%) receiving non-immunotherapy, and there was a significantly shorter PFS2 (P=0.0082) (Figure 4F) when they (36/176, 20.5%) compared to patients (45/176, 25.6%) receiving ICI and changing regimens.

In addition, according to our results, there was a tendency for a longer PFS2 in patients (26/176, 14.8%) who received the same ICI but new regimens compared to patients (36/176, 20.5%) who used original regimens, although the tendency is not statistically significant (P=0.055) (Figure 4D).

Finally, considering that anti-angiogenic therapy is a common therapy as a combination with immunotherapy and chemotherapy in practice, we analyzed the PFS2 difference between patients (19/176, 10.8%) who received immunotherapy with chemotherapy and those (17/176, 9.7%) who received immunology with chemotherapy and anti-angiogenic agent, and found anti-angiogenic agent did not affect PFS2 (P=0.06) (Figure 4H).

Discussion

With the growing knowledge of immune checkpoints, especially the discovery of programmed cell death protein 1 (PD-1)/PD-L1 (20-23), a new era of immunotherapy for tumor treatment has begun. The application of immunotherapy represented by anti-PD-L1 and PD-1 antibodies, either alone or in combination, has dramatically improved the survival of NSCLC patients without druggable genomic alteration (1-4), innovating the regimens of NSCLC therapy. However, progression will occur inevitably in a majority of patients, even if they have achieved good outcomes from initial ICI-based treatment. There is no standard regimen for patients to choose after progression of initial ICI-based treatment, in real-world settings, some patients undergo ICI retreatment, while others return to other treatments, such as chemotherapy, radiotherapy, anti-angiogenic drugs or combination of them. Rebiopsy after progression is also an option to find potential druggable molecular alterations, as the heterogeneity of NSCLC, however, most patients would miss this chance because of its invasive nature. A phase 2 clinical trial reported patients derived more survival benefits when they received ICI combined with chemotherapy after failure in previous immunotherapy, compared with receiving chemotherapy alone (13). In this study, 92 (52.5%) of 176 patients received ICI retreatment while the rest received non-immunotherapy as STAP of initial ICI-based treatment. We analyzed the difference in PFS2 between them, however, we did not find a survival advantage of ICI retreatment in patients (Figure 4A, P=0.60; Figure 4B, P=0.10). The explanation for our result may be due to the fact that most of the patients who received non-immunotherapy were treated with combinations of drugs, such as chemotherapy plus anti-angiogenic agents, and the synergistic effect (24-26) among the antitumor drugs, allowed them to have a decent efficacy as well. Jain reported that intra-tumoral vascular disruption and “leakage” can be resulted from elevated levels of vascular endothelial growth factor; such effects increase interstitial pressure, which decreases the delivery of chemotherapy to the tumor (27). Besides, a clinical trial conducted by Willett and colleagues demonstrated that bevacizumab may enhance the delivery of medications and increase endothelial sensitivity to chemotherapy (28).

Some patients may be re-exposed to ICI despite the initial progression, however, the need to change the original ICI is inconclusive. Several retrospective studies have demonstrated STAP with the same regimen as initial immunotherapy can provide longer survival for NSCLC patients, compared with non-STAP (12,14,15). However, we have not found to find the advantage of original regimen compared with new ICI-based treatment (Figure 4F, P=0.0082). Meanwhile, we found new ICI excluding radiotherapy led to longer PFS than original regimen (Figure 4G, P=0.019). After excluding radiotherapy and original regimen, there was no difference of PFS2 between new ICI and prior ICI (Figure 4E, P=0.39), which is consistent with a previous study (29).

A considerable number of patients receiving STAP will also unavoidably re-progress, which emphasizes the need to screen a beneficial candidate group for STAP. A retrospective study showed that advanced NSCLC patients who achieved CR/PR with initial immunotherapy had a longer PFS of ICI retreatment than those with SD/PD (30). Another retrospective study reported that patients with ECOG PS ≥2 or body mass index <20 had poorer PFS of ICI rechallenge after progression of initial immunotherapy (31). In this study, we found PFS1 ≥6 months, positive PD-L1 expression was associated with better PFS2. According to our results, the length of PFS of initial ICI-based treatment is cue to the PFS of STAP; patients with PFS1 ≥6 months obtained a better survival benefit in STAP of initial ICI-based treatment. Other researchers also observed this phenomenon (32) which may be perhaps explained by the effect of immune memory cells patients produced in prior immunotherapy. PD-L1 expression measured before receiving initial ICI-based treatment plays a key role in prediction of clinical benefits of initial immunotherapy (19). PD-L1 status (positive vs. negative, HR =0.672, 95% CI: 0.477–0.947; P=0.023) showed a significant relation of PFS in STAP with prior immunotherapy in this study, and patients with PD-L1 positive expression would have a longer PFS2. Our results further stress the essential role of evaluating PD-L1 expression in immunotherapy. All above-mentioned results provide new insights into the risk factors associated with PFS of STAP after initial immunotherapy of NSCLC, but more prospective research is needed.

There are several limitations in this study. Firstly, the small size of the sample and the nature of retrospective study precluded additional analysis. Secondly, various STAPs of initial immunotherapy were mainly determined by the patient’s supervising physician, which led to selection bias.

Conclusions

The present study showed that NSCLC patients with PD-L1 positive expression, or PFS1 ≥6 months tend to have a longer PFS2. For NSCLC patients continuing ICI-based treatment after progression of initial immunotherapy, new ICI would provide a longer PFS2 compared with initial regimen. More related research is needed to further demonstrate our findings.

Acknowledgments

The authors appreciate all the people who helped us during the research and writing stage for their lots of useful advice.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-57/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-57/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-57/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-57/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Beijing Chest Hospital, Capital Medical University [(2020) - Scientific Research - Provisional Review No. (09)] and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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