JONT Journal

Introduction

Lung cancer is still the second most frequent cancer and the cancer with the highest mortality worldwide [1] and it has been historically classified as small cell lung cancer (SCLC: 15%) and non-small cell lung cancer (NSCLC: 75%), which is based on morphological features [2]. NSCLC patients have often an advanced, unresectable disease stage not amenable to curative treatment or a metastatic disease stage at their initial diagnosis [3].

Until the advent of immune checkpoint inhibitors (CPIs) in the recent treatment of the aforementioned group of NSCLC patients without oncogenic driver mutations systemic therapy was limited to chemotherapy, which was associated with poor survival times and an unfavorable toxicity profile [4]. The availability of CPIs caused a paradigm shift in the treatment landscape of NSCLC opening new perspectives for a relevant number of patients, particularly of those with comorbidities and a reduced performance status [5].

Results from phase 3 clinical studies comparing second-line treatment with docetaxel versus monoclonal antibodies targeting programmed cell death receptor 1 (PD-1) or programmed cell death receptor-ligand 1 (PD-L1) revealed marked improvements in survival with CPIs compared with standard chemotherapies and led to the approval of nivolumab, pembrolizumab and atezolizumab after platinum-based chemotherapy for the treatment of metastatic NSCLC [6-8].

Due to the success of the CPIs in previously treated NSCLC patients, their effectiveness either as single agent therapy or in combination with chemotherapy in the frontline setting was evaluated. Currently, efficacious first-line treatment options for NSCLC patients without driver alterations include several antibodies directed against CTLA-4, PD-1 and PD-L1 according to phase 3 clinical trials with atezolizumab, cemiplimab, durvalumab, nivolumab, ipilimumab, pembrolimumab and tremelimumab either as single agent therapy or as a combined chemoimmunotherapy [6,7,8]. These agents improved clinical outcomes with patients experiencing prolonged overall survival (OS) and durable responses compared with chemotherapy alone [9]. However, approximately 50% of patients receive subsequent treatment upon progression during or after first-line treatment [10].

The current treatment guidelines for metastatic NSCLC patients who experience disease progression after standard-of care firstline therapy [11,12] recommend single agent chemotherapy or a combination of docetaxel with an antiangiogenic agent such as ramucirumab and nintedanib, or single agent anti-PD-(L)1 antibodies if not previously administered [13,14]. But clinical outcomes with single-agent chemotherapy are modest. In comparison to best supportive care, treatment with docetaxel, resulted in an objective response rate (ORR) of 7.1%, time to progression of 10.6 weeks, and median OS of 7.0 months [15]. Treatment with gemcitabine, nab-paclitaxel or pemetrexed demonstrated a similar median OS of 5.1 months [16], and 8.5 months [17], and 8.3 months respectively [18]. Combination approaches with chemotherapy and antiangiogenic agents in the second-line setting have produced more favorable outcomes compared with chemotherapy alone [9].

Nintedanib is a potent, oral angiokinase inhibitor targeting the pro-angiogenic pathways mediated by vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-3, and platelet-derived growth factor receptors (PDGFR) a and ß [19]. Receptor kinases of RET, FLT3, and the Src family are also inhibited [19]. In phase 1/2 clinical trials, nintedanib showed a manageable safety profile and antitumour activity in patients with solid tumours, including NSCLC [20, 21].

Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody specifically binding to the vascular endothelial growth factor (VEGF) receptor-2 extracellular domain with high affinity, preventing binding of all VEGF ligands and subsequent receptor activation [22].

In the LUME-Lung 1 study, the combination of docetaxel with nintedanib (D+N) [14] resulted in a statistically significant improvement in PFS (3.4 vs. 2.7 months), compared to docetaxel monotherapy as second-line therapy for metastatic NSCLC patients with a previous platinum-based combination chemotherapy. However, a statistically significant improvement in OS was observed only in the subgroup of patients with adenocarcinoma histology (12.6 vs. 10.3 months) but not in the total study population (10.1 vs. 9.1 months) [13, 14]. Hence, the approval of nintedanib by the EMA was restricted to NSCLC patients with adenocarcinoma histology who have undergone firstline chemotherapy.

In the phase 3 REVEL trial, the combination of docetaxel plus ramucirumab (D+R) demonstrated a significant improvement in objective response rates (ORR: 23% vs 14%), median progressionfree survival (PFS: 4.5 vs 3.0 months) and overall survival (OS: 10.5 vs 9.1 months) relative to docetaxel plus placebo in patients with stage IV NSCLC whose disease had progressed during or after first-line platinum-based chemotherapy [13]. Importantly, ramucirumab plus docetaxel had a manageable safety profile and no detrimental impact on quality of life [13, 23].

Additionally, second-line treatment with ramucirumab plus docetaxel resulted in an improvement of median PFS relative to docetaxel in other studies [24, 25].

The currently recommended treatment options for patients with NSCLC whose disease progressed during or after firstline treatment were investigated before the approval of ICIs in immunotherapy-naïve patients.

Therefore, the results from these trials, including LUME-Lung 1 and REVEL, do not optimally reflect the current patient population with disease progression after ICI treatment. Randomized controlled studies investigating the efficacy and safety of docetaxel plus nintedanib or ramucirumab in the post-immunotherapy setting are lacking. Nevertheless, the efficacy and safety of docetaxel plus nintedanib or ramucirumab in patients previously treated with ICIs have been reported in recent years, mostly from retrospective observational studies and electronic health record studies [9] analyzing the efficacy and safety of D+R. Although there are some prospective, non-randomized clinical trials investigating either D+N [26, 27] or D+R [28, 29] after chemoimmunotherapy, no randomized, prospective clinical trial has so far been performed and published, since simultaneous chemoimmunotherapy has become the standard of care for first-line or combined first-/second-line standard of care for a sequential chemoimmunotherapy.

In the clinical routine, the decision whether D+N or D+R should be administered to patients with metastatic pulmonary adenocarcinoma mainly depends on the availability of the antiangiogenic agents, comorbidities of the patients (particularly comorbidities which require anticoagulation and are associated with an increased risk of bleedings) and personal experiences of the treating oncologist. However, no comparison between D+N and D+R in patients with previous chemoimmunotherapy has been performed. Although several pro- and retrospective studies have assessed the value of D+N or D+R after chemoimmunotherapy in metastatic NSCLC patients, the majority of these studies recruited Asian patients and data about dose reductions, and administration of granulocyte colony stimulating factors (GCSF) particularly in Caucasian patients, are lacking. 

Materials and Methods

Study Design and Patients

Data from a total of 173 metastatic NSCLC patients, who started their first cycle of D+N or D+R from May 1, 2018 until April 30, 2024 at the Lung Cancer Center Essen-Mitte, at the MVZ Hematology and Oncology in Bottrop, Essen or Velbert, Germany or at the Medical Practice for Hematology and Oncology Bochum were retrospectively analyzed. All of the patients received the combination of docetaxel with nintedanib (D+N) or ramucirumab (D+R) as second-line or further line therapy after simultaneous or sequential chemoimmunotherapy. The clinical data collected for this analysis were age, gender, the smoking status, TNM or IASLC/Union for International Cancer Control (UICC) stages, dose reduction of chemotherapy and administration of GCSF.

All tumor sample evaluations were conducted by board-certified pathologists. All tissues were stained with hematoxylin and eosin (H&E), rabbit monoclonal immunoglobulin as a negative reagent control, and with the VENTANA PD-L1 (SP263) Assay, which is one of the recommended assays for PD-L1 diagnostics [30]. The H&E staining was performed to determine the adequacy of tumor. A tissue sample was adequate for the assay interpretation if it contained at least 100 viable tumor cells. For each staining run, prequalified human benign tonsil tissue was used as positive and negative tissue control. Tonsil tissue stained with PD-L1 was assessed for staining in lymphocytes and macrophages in germinal centers, and scattered PD-L1 staining cells among PD-L1-negative cells in paracortical regions. Tonsil tissue was also assessed for the presence of diffuse staining observed in the reticulated crypt epithelial cells with the absence of staining of superficial squamous epithelial cells. Patient-matched tissue stained for negative reagent control was evaluated for the presence and acceptability of nonspecific background staining. Once the H&E and the control slides were deemed acceptable, the PD-L1 stained slide was assessed.

The PD-L1 Tumor Proportion Score (TPS) was calculated as the percentage of at least 100 viable tumor cells with complete or partial membrane staining and was separated into the following three groups: <1% (no expression: category 0), 1%–49% (low expression: category 1) and =50% (high expression: category 2).

Immunocyto- and -histochemistry were performed at the Practice for Pathology Essen-Mitte (Zentrum fuer Pathologie Essen-Mitte), Essen, Germany, which is accredited by the German Accreditation Body (Deutsche Akkreditierungsstelle: DAkkS). Furthermore, PD-L1-testing is certified by the Initiative for Quality Assurance in Pathology (Qualitätssicherungsinitiative in der Pathologie: QuIP) of the German Society of Pathology (Deutsche Gesellschaft für Pathologie: DGP).

Treatment and Assessment

Docetaxel (standard dosage of 75 mg/m2, d1, every three weeks or 60 mg/m2, d1, every three weeks in case of primary dose reduction) in combination with nintedanib (200 mg orally bid except on the day of docetaxel infusion) or with ramucirumab (10 mg/kg body weight, d1, every three weeks) was administered according to local standard. Radiological evaluation of response to treatment was carried out using RECIST 1.1 [31]. For progression-free survival (PFS) and overall survival (OS) analysis, patients were followed up until June, the 30th of 2024.

Statistical Analysis

The retrospective study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the institutional review board of the DKG-certified Lung Cancer Center (approval on July 10, 2019 for analysis of docetaxel plus nintedanib resp. April 1, 2020 for analysis of docetaxel plus ramucirumab). Individual consent for this retrospective analysis was waived.

The statistical tests were performed using IBM SPSS Statistics (version 29), the associated figures were created using GraphPad PRISM (version 7). The Chi-square test was used to compare categorical variables (when necessary, Fisher’s exact test). Students t-test was used for age, Mann Whitney U test for „pack years“ and PD-L1 expression (%). Multivariate logistic regression was used to estimate associations (wald test). Models were adjusted for all variables. Kaplan-Meier methodology was used for estimation of medians, survival curves and their comparisons. Cox proportional hazard model was performed to identify prognostic factors in both the univariate analysis and the multivariate analysis (wald test).

Results

Clinicopathological Features

Detailed clinicopathological information is shown in table 1. A total of 173 patients with metastatic NSCLC receiving either D+N or D+R were identified. Due to the approval status by the EMA, docetaxel plus nintedanib was only administered to patients suffering from a non-squamous NSCLC. However, the majority of the patients suffered from an adenocarcinoma (115 patients (66.5%)). In the univariate analysis of the clinicopathological features (table 1), significant differences between patients receiving D+N or D+R regarding age, histology, PD-L1 expression at the time of first diagnosis, number of induction chemotherapy cycles, percentage of patients with dose reductions of docetaxel and the kind of the used PD-1-/PD-L1-antibody were found.

Table 1: Comparison of clinicopathological factors between metastatic non-small cell lung cancer patients receiving docetaxel plus nintedanib or docetaxel plus ramucirumab after chemoimmuntherapy (entire cohort). ADC: Adenocarcinoma, CR: Complete Response, IASLC: International Association for the Study of Lung Cancer, LCNEC: Large Cell Neuroendocrine carcinoma, NOS: Not Otherwise Specified carcinoma, OTH: Others, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SCC: Squamous Cell Carcinoma, SD: Stable Disease, and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

In the subgroup of adenocarcinoma patients, significant differences between patients receiving D+N or D+R regarding age, gender, PD-L1 expression at the time of first diagnosis), number of induction chemotherapy cycles, percentage of patients with reduced docetaxel doses and the chosen PD-1-/PD-L1-antibody were noted.

In the subgroup of patients who only received D+R regardless of histology, significant differences in the percentage of patients with primary metastatic disease at the time of first NSCLC diagnosis (Suppl. table 1), histology, and the type of the used PD-1-/PD-L1-antibody were recognized.

Suppl. Table 1: Comparison of clinicopathological factors between metastatic non-small cell lung cancer patients receiving only docetaxel plus ramucirumab after chemoimmunotherapy (subgroup). ADC: Adenocarcinoma, CR: Complete Response, IASLC: International Association for the Study of Lung Cancer, LCNEC: Large Cell Neuroendocrine carcinoma, NOS: Not Otherwise Specified carcinoma, OTH: Others, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SCC: Squamous Cell Carcinoma, SD: Stable Disease, and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Treatment Effectiveness

ORR was assessable in 141 patients (81.5%), but 7 patients (11.5%) with D+N and 25 patients (22.3%) with D+R discontinued therapy before radiographic assessment of response, but the difference was not statistically significant (p=0.079) Partial response (PR) occurred in 52.5%, stable disease (SD) in 32.6% and progressive disease (PD) in 14.9% of the assessable patients (table 1). There were no differences between the treatment groups (p=0.369, table 1). In the subgroup of adenocarcinoma patients, a trend towards a higher percentage of patients without a radiographic assessment of response in the D+R treated patients (25.5%) compared to the D+N treated patients (11.7%) were observed, but the ORRs between D+N and D+R did not differ (table 2, p=0.673). In the subgroup of patients treated with D+R (Suppl. table 1), ORRs did not differ significantly between non-squamous and squamous cell carcinoma patients (p=0.418).

Table 2: Comparison of clinicopathological factors between metastatic pulmonary adenocarcinoma  patients receiving docetaxel plus nintedanib or docetaxel plus ramucirumab after chemoimmunotherapy (subgroup). CR: Complete Response, IASLC: International Association for the Study of Lung Cancer, NOS: Not Otherwise Specified carcinoma, OTH: Others, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease, and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Median PFS of the entire cohort was 7.2 months and median OS was 7.3 months (figure 1A/B). In contrast, in the subgroup of patients with D+N or D+R as second-line therapy PFS and OS were 6.8 months (95%-CI: 6.1-7.0) and 6.9 months (95%-CI: 3.4-9.7), while they were  8.7 months (95%-CI: 6.2-11.1) and 9.9 months (95%-CI: 4.9-14.8), respectively, in the subgroup of third-line patients.

Figure 1A: Progression-free survival (PFS) of metastatic NSCLC patients receiving either docetaxel plus nintedanib or docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Figure 1B: Overall survival (OS) of metastatic NSCLC patients receiving either docetaxel plus nintedanib or docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Patients with primary dose reduction of docetaxel (p=0.010), with stable disease (p=0.034) or progressive disease (p<0.001) as response and with a previous pembrolizumab therapy (p=0.014) resulted in a worse PFS (table 3) in the multivariate analysis. Median PFS was increased (7.6 months versus 6.3 months, p=0.002) in the D+R cohort compared to the D+N cohort, although there was no significant difference in the univariate analysis (p=0.402). Furthermore, a younger age (<65 years, p<0.001) and a higher number of induction therapy cycles (=3, p=0.047) led to an OS prolongation (table 4) in the multivariate analysis. But stable disease (p=0.002) or progressive disease as response (p<0.001) or an unknown response status resulted in a worse OS (table 4) in the multivariate analysis.

Table 3: Multivariate logistic regression analysis by choosing progression-free survival (PFS) as the terminal point variable. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Table 4: Multivariate logistic regression analysis by choosing overall survival (OS) as the terminal point variable. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

In the subgroup of patients with pulmonary adenocarcinoma, median PFS was 6.9 months and median OS was 7.2 months (figure 2A/B). Results of the multivariate analysis for PFS/OS are shown in tables 5/6. Similarly to the entire cohort, patients with primary dose reduction of docetaxel (p=0.007), with stable disease (p=0.002) or progressive disease (p<0.001) as response resulted in a worse PFS (table 5) in the multivariate analysis. Median PFS was only numerically higher (7.6 months versus 6.3 months, p=0.111) in the D+R cohort compared to the D+N cohort.

Figure 2A: Progression-free survival (PFS) of metastatic pulmonary adenocarcinoma patients receiving either docetaxel plus nintedanib or docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Figure 2B: Overall survival (OS) of metastatic pulmonary adenocarcinoma patients receiving either docetaxel plus nintedanib or docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Table 5: Multivariate logistic regression analysis by choosing progression-free survival (PFS) as the terminal point variable in the subgroup of patients with pulmonary adenocarcinoma. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Furthermore, a higher age (=65 years, p<0.001), an unknown smoking status (p=0.043) and progressive disease as response (p<0.001) or an unknown response (p<0.001) status led to a reduced OS (table 6) in the multivariate analysis.

In the subgroup of patients receiving only D+R, median PFS of NSCLC patients with a pulmonary squamous cell carcinoma was 7.4 months and median OS 7.6 months (Suppl. figure 1A/B), while it was 7.6 months and 6.8 months for non-squamous cell carcinoma patients. However, there were significant differences between the treatment groups (suppl. table 2 and 3) in the multivariate analysis. A higher number of induction cycles were associated with a prolonged PFS (>4, p=0.014), whereas progressive disease during treatment wit D+R worsened PFS (p<0.001). OS was reduced in elderly patients (= 65 years, p=0.001) and in patients with either progressive disease (p<0.001) or an unknown response status (p<0.001), but it was improved in patients with the PD-1-inhibitor nivolumab (p=0.030).

Suppl. Figure 1A: Progression-free survival (PFS) of metastatic NSCLC patients who received only docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Suppl. Figure 1B: Overall survival (OS) of metastatic NSCLC patients who received only docetaxel plus ramucirumab after previous simultaneous or sequential chemoimmunotherapy.

Table 6: Multivariate logistic regression analysis by choosing overall survival (OS) as the terminal point variable in the subgroup of patients with pulmonary adenocarcinoma. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Suppl. Table 2: Multivariate logistic regression analysis by choosing progression-free survival (PFS) as the terminal point variable in the subgroup of patients who received only docetaxel plus ramucirumab. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.

Suppl. Table 3: Multivariate logistic regression analysis by choosing overall survival (OS) as the terminal point variable in the subgroup of patients who received only docetaxel plus ramucirumab. IASLC: International Association for the Study of Lung Cancer, PD: Progressive Disease, PD-L1: Programmed Death receptor Ligand 1, PR: Partial Response, SD: Stable Disease and UICC: Union for International Cancer Control, TPS: Tumor Proportion Score.