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Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study

Open AccessPublished:January 07, 2022DOI:https://doi.org/10.1016/j.clon.2021.12.010

      Highlights

      • Limited clinical data are available to guide treatment decisions after ICI failure in patients with NSCLC.
      • VARGADO cohort B included patients with adenocarcinoma NSCLC after failure of chemotherapy and ICI.
      • Nintedanib plus docetaxel showed real-world efficacy after failure of prior ICIs.
      • Median PFS and overall survival were 6.4 and 12.1 months; 1-year overall survival rate was 52% and DCR was 86%.
      • 74% of patients reported treatment-related adverse events, with diarrhoea being the most common.

      Abstract

      Aims

      To evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy.

      Materials and methods

      VARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy.

      Results

      The median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%).

      Conclusions

      Nintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.

      Key words

      Introduction

      The treatment landscape in advanced non-small cell lung cancer (NSCLC) has undergone significant changes during the last decade, including the approval of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for first-line treatment of metastatic non-‍squamous NSCLC lacking an actionable driver mutation [
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      ]. However, limited clinical data are available to help guide treatment decisions after immunotherapy failure, as the currently available options were originally approved in the post-chemotherapy setting, before the widespread inclusion of ICIs in treatment algorithms [
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      ].
      Understanding the underlying tumour biology is important for the selection of subsequent therapies. Based on the results of published immunotherapy clinical trials, patients are often categorised as responders, or those with either innate or acquired resistance [
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      Anti-angiogenic agents in the age of resistance to immune checkpoint inhibitors: do they have a role in non-oncogene-addicted non-small cell lung cancer?.
      ]. However, the clinical reality is more complicated, with response (or resistance) occurring with a range of spatiotemporal dynamics (in different lesions, at different times and with varying speeds) [
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      Anti-angiogenic agents in the age of resistance to immune checkpoint inhibitors: do they have a role in non-oncogene-addicted non-small cell lung cancer?.
      ]. The particular immune response profile displayed in the tumour microenvironment (TME) may have implications for subsequent treatment. An increasing body of evidence connects angiogenesis with the development of an immunosuppressive TME, which can promote resistance to ICI treatment [
      • Popat S.
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      Anti-angiogenic agents in the age of resistance to immune checkpoint inhibitors: do they have a role in non-oncogene-addicted non-small cell lung cancer?.
      ]. Therefore, an anti-angiogenic treatment strategy involving inhibition of vascular endothelial growth factor (VEGF) (as well as platelet-derived growth factor [PDGF] and fibroblast growth factor [FGF]) could be effective in patients with acquired resistance to ICIs, by supporting vessel normalisation and improving access of immune cells into the tumour, tipping the balance towards an immunosupportive TME in a so-called angio-immunogenic switch [
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      Anti-angiogenic agents in the age of resistance to immune checkpoint inhibitors: do they have a role in non-oncogene-addicted non-small cell lung cancer?.
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      Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma.
      ].
      Nintedanib is an oral, triple angiokinase inhibitor targeting VEGF receptors 1–3, PDGF receptors α/β and FGF receptors 1–3, as well as RET oncogene (RET) [
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      ]. Nintedanib is approved in the EU and other countries in combination with docetaxel for the treatment of patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology after first-line chemotherapy. In the pivotal phase III LUME-Lung 1 trial in patients with NSCLC who had progressed on first-line chemotherapy, nintedanib plus docetaxel significantly prolonged overall survival in patients with adenocarcinoma histology versus the docetaxel plus placebo group (median overall survival, 12.6 months [95% confidence interval 10.6, 15.1] versus 10.3 months [95% confidence interval 8.6, 12.2]; hazard ratio 0.83 [95% confidence interval 0.70, 0.99]; P = 0.0359) [
      • Reck M.
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      • et al.
      Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.
      ]. Moreover, patients who progressed within 9 months after the start of first-line chemotherapy achieved a significant and clinically meaningful overall survival improvement with nintedanib plus docetaxel (10.9 months versus 7.9 months; hazard ratio 0.75 [95% confidence interval 0.60, 0.92]; P = 0.0073) [
      • Reck M.
      • Kaiser R.
      • Mellemgaard A.
      • Douillard J.Y.
      • Orlov S.
      • Krzakowski M.
      • et al.
      Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.
      ].
      The VARGADO study was conceived as a prospective, non-interventional study of nintedanib plus docetaxel in a real-world setting [
      • Grohé C.
      • Gleiber W.
      • Haas S.
      • Losem C.
      • Mueller-Huesmann H.
      • Schulze M.
      • et al.
      Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma.
      ]. In accordance with the approved nintedanib label, all patients had previously received first-line chemotherapy. To accurately reflect recent changes in the treatment landscape and generate clinical data to inform clinical decision-making in the era of ICI therapy, the study includes patients who had progressed on sequential chemotherapy and ICI therapy (cohort B) and those who had progressed on chemotherapy in combination with ICI therapy (cohort C) [
      • Grohé C.
      • Gleiber W.
      • Haas S.
      • Losem C.
      • Mueller-Huesmann H.
      • Schulze M.
      • et al.
      Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma.
      ]. Here, we present an interim efficacy and safety analysis of cohort B.

      Materials and Methods

       Patients and Study Design

      VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC [
      • Grohé C.
      • Gleiber W.
      • Haas S.
      • Losem C.
      • Mueller-Huesmann H.
      • Schulze M.
      • et al.
      Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma.
      ]. The study is ongoing in about 100 centres across Germany. Three patient cohorts in VARGADO are being evaluated (Figure 1). The present study focuses on cohort B, which is assessing third-line nintedanib plus docetaxel following first-line chemotherapy and second-line ICI therapy.
      Fig 1
      Fig 1Patient cohorts in VARGADO. FPI, first patient in; ICI, immune checkpoint inhibitor.
      Eligible patients were aged ≥18 years with locally advanced, metastatic or locally recurrent NSCLC (adenocarcinoma histology). Patients must have received treatment with first-‍line chemotherapy and second-line therapy with ICIs. Patients with contraindications for either nintedanib or docetaxel, or who had received more than one previous chemotherapy for NSCLC (previous adjuvant or neoadjuvant therapies were permitted) were ineligible. Participation in other non-interventional trials was permitted. Patients participating simultaneously in other types of clinical trial were not eligible.
      The decision to treat was taken by the treating investigators before participation in VARGADO was considered. Each patient had consented to be observed within the non-interventional study. An average of four patients is scheduled per practice. Nintedanib and docetaxel were administered according to the approved label. Patients received docetaxel (75 mg/m2) by intravenous infusion on day 1, plus oral nintedanib (200 mg twice daily) on days 2–21 of each 21-day cycle. Any dose adjustments required were made in accordance with the approved label.
      Patients were followed up for safety and efficacy for up to 24 months after the start of treatment. Data on patient and disease characteristics, prior and concomitant medications, and efficacy and safety were collected during routine clinic visits via electronic case report forms (eCRFs).
      The VARGADO observational plan was approved by the ethics committee of the Charité Berlin before study initiation. All patients provided written informed consent prior to participation in the study.

       Assessments

      The primary end point was overall survival rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary end points included progression-free survival (PFS), overall survival, objective response rate (ORR), disease control rate (DCR) and safety. The clinical response to treatment was evaluated based on routine staging investigations and assessed in accordance with Response Evaluation Criteria in Solid Tumors (RECIST).
      The incidence and severity of adverse events were reported according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. The relationship between adverse events and study drug was determined by the treating investigator.

       Statistical Analyses

      All statistical analyses are descriptive. PFS and overall survival were analysed using the Kaplan–‍Meier method. PFS was calculated from the start of nintedanib plus docetaxel treatment to the date of disease progression or death, whichever occurred first. Overall survival was calculated from initial diagnosis, the start of first-line therapy, the start of second-line therapy or the start of third-line therapy until the date of death.

      Results

       Patient Demographics and Clinical Characteristics

      Between 15 March 2015 and 2 August 2021, 547 patients were enrolled in the VARGADO study in centres across Germany. Of the approximately 100 centres participating in VARGADO, 35 sites recruited patients in cohort B (median patients per site: 1, range 1–2). Baseline characteristics for the 80 patients included in this analysis are shown in Table 1. Fifty-eight patients (73%) had Eastern Cooperative Oncology Group performance status 0–1, 63 (79%) were current or former smokers and 16 (20%) had brain metastases at baseline. In addition, 63 patients (79%) had an initial biopsy for tumour mutational analysis and 55 (87%) underwent further biomarker analysis. Of these, 60/63 patients (95%) did not exhibit EGFR mutations and for two patients the EGFR mutation status was not reported. One patient had an EGFR mutation; the reasons for not treating the patient with a tyrosine kinase inhibitor were not reported by the treating investigator. In patients who underwent further biomarker analysis, 39/55 (71%) did not have EML4-ALK translocations and in 16/55 (29%) the EML4-ALK status was not reported in the eCRFs at the time of analysis. Forty-three patients (53%) had received prior second-line treatment with nivolumab, 22 (27%) with pembrolizumab and 15 (19%) with atezolizumab. In terms of best overall response to second-line ICI therapy, 11/52 (21%) had a partial response, 8/52 (15%) had stable disease and 32/52 (62%) had progressive disease.
      Table 1Demographic and clinical characteristics at baseline (n = 80)
      Median age, years (range)63 (41–80)
      Gender, n (%)
       Male44 (55)
       Female36 (45)
      ECOG PS, n (%)
       018 (23)
       140 (50)
       26 (8)
       31 (1)
       Not reported15 (19)
      Clinical stage at diagnosis, n (%)
       ≤III32 (40)
       IV46 (58)
       Not reported2 (3)
      Smoking status, n (%)
       Current or former smokers63 (79)
       Non-smokers5 (6)
       Not reported12 (15)
      Presence of brain metastases, n (%)
       Present16 (20)
       Absent64 (80)
      Previous first-line therapy, n (%)
      Previous first- and second-line therapy includes combination regimens.
       Carboplatin52 (65)
       Pemetrexed51 (64)
       Cisplatin32 (40)
       Bevacizumab17 (21)
       Paclitaxel15 (19)
       Vinorelbine13 (16)
       Other4 (5)
      Time since start of first-line therapy until start of second-line therapy, n (%)
       <9 months44 (55)
       3 months8 (10)
       ≥3 months to <6 months14 (18)
       ≥6 months to <9 months22 (28)
       ≥9 months33 (41)
       Missing3 (4)
      Time since start of second-line therapy until start of third-line therapy, n (%)
       <2 months8 (10)
       ≥2 months to <4 months23 (29)
       ≥4 months to <6 months15 (19)
       ≥6 months33 (41)
       Unknown1 (1)
      Previous second-line therapy, n (%)
      Previous first- and second-line therapy includes combination regimens.
       Nivolumab43 (53)
       Pembrolizumab22 (27)
       Atezolizumab15 (19)
       Other1 (1)
      Best response to second-line ICI therapy, n (%)
      Percentages based on patients with a documented response at the time of analysis.
       Complete response0/52 (0)
       Partial response11/52 (21)
       Stable disease8/52 (15)
       Progressive disease32/52 (62)
       Other1/52 (2)
       Not determined28
      ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitor.
      Previous first- and second-line therapy includes combination regimens.
      Percentages based on patients with a documented response at the time of analysis.

       Efficacy

      At the time of this analysis (data cut-off: 1 December 2020), best overall response data were available for 64 patients who received third-line nintedanib plus docetaxel after failure of second-line ICI therapy (Table 2). One patient (2%) had a complete response, 31 (48%) had a partial response and 23 (36%) had stable disease, resulting in an ORR of 32/64 (50%) and a DCR of 55/64 (86%). Treatment duration and best response to nintedanib plus docetaxel for each patient with a documented response are shown in Figure 2. Although there was no apparent relationship between the duration of prior therapy and the response to nintedanib plus docetaxel, the duration of nintedanib plus docetaxel treatment frequently exceeded that of prior lines.
      Table 2Best response to treatment with third-line nintedanib plus docetaxel after failure of immune checkpoint inhibitor therapy
      Responsen (%)
      Complete response1 (2)
      Partial response31 (48)
      Stable disease23 (36)
      Progressive disease9 (14)
      Objective response rate
      Sum of complete and partial response rates.
      32 (50)
      Disease control rate
      Sum of complete response, partial response and stable disease rates.
      55 (86)
      Data are shown for 64 patients in the treated set who had a documented response at the data cut-off (1 December 2020).
      Sum of complete and partial response rates.
      Sum of complete response, partial response and stable disease rates.
      Fig 2
      Fig 2Swimmer plot showing treatment duration for each patient with a documented response to third-line nintedanib plus docetaxel (n = 64). ICI, immune checkpoint inhibitor. ∗Time on second-line treatment not yet documented. Time on first-line treatment not yet documented; five chemotherapy cycles documented. Time on first-line treatment not yet documented.
      The median duration of follow-up was 12.4 months for patients treated with nintedanib plus docetaxel. The median PFS from the start of third-line nintedanib plus docetaxel after failure of second-line ICI therapy was 6.4 months (95% confidence interval 4.8, 7.3; n = 80) (Figure 3a). In total, 54 PFS events had occurred (10 patients had disease progression and 44 patients had died) and 26 patients were censored.
      Fig 3
      Fig 3Progression-free survival (a) and overall survival (b) from the start of third-line treatment with nintedanib plus docetaxel after failure of immune checkpoint inhibitor therapy (n = 80).
      In patients with time since the start of first-line therapy until the start of second-line therapy <9 months (n = 44), the median PFS from the start of third-line nintedanib plus docetaxel was 5.5 months (95% confidence interval 2.8, 7.1) (Figure 4). In patients with time since the start of first-line therapy ≥9 months (n = 33), the median PFS from the start of third-line nintedanib plus docetaxel was 7.3 months (95% confidence interval 6.0, 10.8).
      Fig 4
      Fig 4Progression-free survival from the start of third-line treatment with nintedanib plus docetaxel by time since start of first-line therapy until start of second-line therapy (<9 months [n = 44] and ≥9 months [n = 33]).
      The median overall survival from the start of third-line nintedanib plus docetaxel was 12.1 months (95% confidence interval 9.4, 13.5; n = 80) (Figure 3b), based on 44 patients who had died and 36 patients who were censored. The 1-year overall survival rate after the start of nintedanib plus docetaxel was 52% (95% confidence interval 38.0%, 64.4%). Of note, the median overall survival from the start of second-line therapy was 18.6 months (95% confidence interval 14.6, 23.5; n = 77); meanwhile, the median overall survival from the start of first-line therapy was 27.2 months (95% confidence interval 22.7, 35.7; n = 78) and was 35.9 months (95% confidence interval 24.7, 44.7; n = 80) from initial diagnosis.

       Safety

      Safety was evaluated in all 80 patients treated with nintedanib plus docetaxel. Seventy-three patients (91%) had adverse events, with 59 (74%) experiencing treatment-related adverse events, as assessed by the investigators. The most common treatment-related adverse events reported in ≥10% of patients are shown in Table 3. Grade ≥3 treatment-emergent adverse events occurred in 46 patients (58%); serious treatment-emergent adverse events occurred in 43 patients (54%). Twenty-five patients (31%) had at least one nintedanib dose reduction and 17 patients (21%) had at least one docetaxel dose reduction. Treatment-emergent adverse events led to discontinuation of study treatment in 32 patients (40%); 14 (18%) were considered to be related to study treatment. There were 13 deaths attributed to serious treatment-emergent adverse events; one (due to sepsis) was considered to be related to study treatment by investigators.
      Table 3Treatment-related adverse events reported in ≥10% of patients (n = 80)
      Adverse eventNintedanib-relatedDocetaxel-related
      All grades

      n (%)
      Grade ≥3

      n (%)
      All grades

      n (%)
      Grade ≥3

      n (%)
      Diarrhoea27 (34)2 (3)19 (24)0
      Nausea10 (13)2 (3)13 (16)3 (4)
      Stomatitis10 (13)4 (5)8 (10)4 (5)
      Decreased white blood cell count9 (11)8 (10)15 (19)13 (16)
      Fatigue3 (4)010 (13)1 (1)
      Safety data are presented for all treated patients.

       Discussion

      In this analysis of the prospective, non-interventional VARGADO study, third-line nintedanib plus docetaxel showed clinical efficacy in patients with adenocarcinoma NSCLC previously treated with sequential chemotherapy and ICI therapy. The ORR of 50% and DCR of 86%, alongside the median PFS of 6.4 months and median overall survival of 12.1 months, were encouraging, given that patients received nintedanib plus docetaxel in the third-line setting. Also of note were the median overall survival from the start of second-line therapy, first-line therapy and initial diagnosis of 18.6 months, 27.2 months and 35.9 months, respectively. Treatment was generally tolerable, with no new safety signals or unexpected toxicities in the third-line setting.
      The investigator-assessed ORR reported here was 50% for patients receiving nintedanib plus docetaxel in the third line who had previously failed on one line of chemotherapy and one line of ICI treatment. This is higher than the ORR of about 12% (for second-line pemetrexed or docetaxel chemotherapy) or 20% (for second-line ICI monotherapies after failure of first-line chemotherapy) [
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      ]. The current results from VARGADO cohort B are consistent with the effectiveness of nintedanib plus docetaxel observed in a similar patient population in the ICI-pretreated subgroup analysis of the prospective, non-interventional LUME-BioNIS study [
      • Reck M.
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      • et al.
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      ]. In this post hoc analysis, 14.9%/85.1% of patients received nintedanib plus docetaxel in the second line/third line or later; median PFS was 4.6 months, median overall survival was 8.8 months and the DCR was 78.2% [
      • Reck M.
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      Non-interventional LUME-BioNIS study of nintedanib plus docetaxel after chemotherapy in adenocarcinoma non-small cell lung cancer: a subgroup analysis in patients with prior immunotherapy.
      ]. Furthermore, the DCR in VARGADO cohort B was also consistent with that reported in other real-world analyses of third-line nintedanib plus docetaxel in advanced lung adenocarcinoma after failure on first-line chemotherapy and second-line ICI therapy (82–83%) [
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      ].
      A clear biological rationale for the use of anti-angiogenic agents (such as nintedanib) after ICI therapy is provided by the growing appreciation that angiogenesis and antitumour immunity are interlinked processes [
      • Popat S.
      • Grohe C.
      • Corral J.
      • Reck M.
      • Novello S.
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      ,
      • Fukumura D.
      • Kloepper J.
      • Amoozgar Z.
      • Duda D.G.
      • Jain R.K.
      Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
      ,
      • Yi M.
      • Jiao D.
      • Qin S.
      • Chu Q.
      • Wu K.
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      ,
      • Manegold C.
      • Dingemans A.C.
      • Gray J.E.
      • Nakagawa K.
      • Nicolson M.
      • Peters S.
      • et al.
      The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC.
      ]. In addition to its role in stimulating neovascularisation, high levels of VEGF can promote immunosuppression within the TME by modulating immune cell function and impeding migration of immune cells into the tumour – simultaneously promoting tumour growth and ICI resistance [
      • Fukumura D.
      • Kloepper J.
      • Amoozgar Z.
      • Duda D.G.
      • Jain R.K.
      Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
      ,
      • van der Woude L.L.
      • Gorris M.A.J.
      • Halilovic A.
      • Figdor C.G.
      • de Vries I.J.M.
      Migrating into the tumor: a roadmap for T cells.
      ]. VEGF also exerts direct immunosuppressive effects on numerous cell types; for example, by inhibiting dendritic cell maturation and promoting the expansion of regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages [
      • Fukumura D.
      • Kloepper J.
      • Amoozgar Z.
      • Duda D.G.
      • Jain R.K.
      Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
      ,
      • Manegold C.
      • Dingemans A.C.
      • Gray J.E.
      • Nakagawa K.
      • Nicolson M.
      • Peters S.
      • et al.
      The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC.
      ]. The ‘angio-immunogenic switch’ hypothesis proposes that anti-angiogenic treatment could reverse the immunosuppressive TME that contributed initially to the failure of ICI therapy [
      • Popat S.
      • Grohe C.
      • Corral J.
      • Reck M.
      • Novello S.
      • Gottfried M.
      • et al.
      Anti-angiogenic agents in the age of resistance to immune checkpoint inhibitors: do they have a role in non-oncogene-addicted non-small cell lung cancer?.
      ,
      • Fukumura D.
      • Kloepper J.
      • Amoozgar Z.
      • Duda D.G.
      • Jain R.K.
      Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
      ,
      • Grohé C.
      • Gleiber W.
      • Haas S.
      • Losem C.
      • Mueller-Huesmann H.
      • Schulze M.
      • et al.
      Nintedanib plus docetaxel after progression on immune checkpoint inhibitor therapy: insights from VARGADO, a prospective study in patients with lung adenocarcinoma.
      ], and this is supported by preclinical data [
      • Yi M.
      • Jiao D.
      • Qin S.
      • Chu Q.
      • Wu K.
      • Li A.
      Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment.
      ,
      • Kato R.
      • Haratani K.
      • Hayashi H.
      • Sakai K.
      • Sakai H.
      • Kawakami H.
      • et al.
      Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.
      ], the efficacy results observed in this latest analysis of VARGADO cohort B and in patients treated with nintedanib plus docetaxel in the second line, following first-line chemotherapy plus ICIs in VARGADO cohort C [
      • Grohé C.
      • Wehler T.
      • Dechow T.
      • Henschke S.
      • Schuette W.
      • Dittrich I.
      • et al.
      Second-line nintedanib plus docetaxel for patients with lung adenocarcinoma after failure on first-line immune checkpoint inhibitor combination therapy: initial efficacy and safety results from VARGADO Cohort C.
      ,
      • Grohé C.
      • Gleiber W.
      • Haas S.
      • Krüger S.
      • Schulze M.
      • Atz J.
      • et al.
      Efficacy and safety of nintedanib + docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): updated results of the ongoing non-interventional study (NIS) VARGADO (NCT02392455).
      ].
      Available data indicate that anti-angiogenics may be used effectively following ICIs in prior lines. For example, a US analysis of electronic health records, in which 160 patients with squamous or non-squamous NSCLC, treated sequentially with ICI therapy followed by the anti-VEGFR2 agent ramucirumab in any line, achieved a median overall survival from diagnosis of 26.5 months [
      • Molife C.
      • Hess L.M.
      • Cui Z.L.
      • Li X.I.
      • Beyrer J.
      • Mahoui M.
      • et al.
      Sequential therapy with ramucirumab and/or checkpoint inhibitors for non-small-cell lung cancer in routine practice.
      ]. Additionally, in a small, retrospective chart review of 20 patients (16/20 of adenocarcinoma histology) who received ramucirumab plus docetaxel after failure on nivolumab, ORR was 60%, DCR was 90%, median PFS was 5.6 months and median overall survival was 11.3 months [
      • Shiono A.
      • Kaira K.
      • Mouri A.
      • Yamaguchi O.
      • Hashimoto K.
      • Uchida T.
      • et al.
      Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non-small cell lung cancer patients.
      ]. A more recent retrospective analysis investigated the efficacy of third-line ramucirumab plus docetaxel after failure of first-line chemotherapy and second-line ICI therapy (n = 67); ORR was 36%, DCR was 69%, median PFS was 6.8 months and median overall survival was 11.0 months after the start of third-line treatment [
      • Brueckl W.M.
      • Reck M.
      • Rittmeyer A.
      • Kollmeier J.
      • Wesseler C.
      • Wiest G.H.
      • et al.
      Efficacy of docetaxel plus ramucirumab as palliative third-line therapy following second-line immune-checkpoint-inhibitor treatment in patients with non-small-cell lung cancer stage IV.
      ]. Preclinical data indicate potential synergies stemming from the combination of ICIs with anti-angiogenic agents [
      • Kato R.
      • Haratani K.
      • Hayashi H.
      • Sakai K.
      • Sakai H.
      • Kawakami H.
      • et al.
      Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.
      ]. Many clinical trials are underway investigating such combinations in NSCLC, and early data are encouraging [
      • Ren S.
      • Xiong X.
      • You H.
      • Shen J.
      • Zhou P.
      The combination of immune checkpoint blockade and angiogenesis inhibitors in the treatment of advanced non-small cell lung cancer.
      ].
      The strengths of the VARGADO study include the comprehensive, prospective electronic data collection and evaluation of a real-world cohort that reflects contemporary patient treatment patterns. A further strength is that outcomes of patients with ‘aggressive’ NSCLC who relapse within <6–9 months of chemotherapy are often overlooked in clinical trials [
      • Reck M.
      • Kerr K.M.
      • Grohe C.
      • Manegold C.
      • Pavlakis N.
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      • et al.
      Defining aggressive or early progressing nononcogene-addicted non-small-cell lung cancer: a separate disease entity?.
      ]; our data therefore help to inform clinical decision-making for these patients. The limitations of the study include the non-interventional, non-comparative design and the reliance on retrospectively collected medical data on baseline characteristics and previous lines of treatment, resulting in incomplete data for some patients. Furthermore, owing to the non-interventional nature of this study, no examinations (such as scans to determine disease status per RECIST) were undertaken in addition to those that would usually have been carried out at local sites, as directed by the treating physicians. This probably contributed to the lack of recorded data on the response to previous lines of treatment.
      In terms of future studies, the combination and sequencing of anti-angiogenic agents and ICI therapy remains a major focus of investigation. The aim is to identify the most effective regimens, rationally targeted towards the biological changes in the TME that arise as a result of previous therapies. For example, the phase I/II NintNivo study (NCT04046614) is evaluating nintedanib in combination with nivolumab in previously treated patients with advanced adenocarcinoma NSCLC. The PEMBIB trial (NCT02856425) will investigate nintedanib plus pembrolizumab in solid tumours including NSCLC. In addition, patient recruitment and analyses are ongoing for VARGADO cohort C, in patients treated with second-line nintedanib plus docetaxel after first-line combination chemotherapy and ICI treatment [
      • Grohé C.
      • Wehler T.
      • Dechow T.
      • Henschke S.
      • Schuette W.
      • Dittrich I.
      • et al.
      Second-line nintedanib plus docetaxel for patients with lung adenocarcinoma after failure on first-line immune checkpoint inhibitor combination therapy: initial efficacy and safety results from VARGADO Cohort C.
      ]. Ramucirumab is also under investigation in previously treated advanced NSCLC in combination with atezolizumab, (NCT03689855), nivolumab (NCT03527108) and platinum-based chemotherapy (NCT03904108). In other avenues of investigation, emerging KRASG12C inhibitors may provide a treatment option for patients carrying the KRASG12C mutation [
      • Skoulidis F.
      • Li B.T.
      • Dy G.K.
      • Price T.J.
      • Falchook G.S.
      • Wolf J.
      • et al.
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      ] and the cancer vaccine OSE2101 is under investigation in patients with NSCLC who are HLA-A2 positive (NCT02654587). Additionally, recent findings indicate that combination therapy with docetaxel plus plinabulin offers improved efficacy versus docetaxel alone in patients with NSCLC progressing on prior platinum-based chemotherapy [
      • Han B.
      • Shi Y.
      • Feinstein T.
      • Feng D.
      • Mitchell D.
      • Lelorier Y.
      • et al.
      LBA48 - DUBLIN-3 (BPI-2358-103): a global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen.
      ].

      Conclusions

      In this latest analysis of the prospective, non-interventional VARGADO study, nintedanib plus docetaxel showed encouraging real-world efficacy and a manageable safety profile in patients with adenocarcinoma NSCLC who failed on first-line chemotherapy and subsequent second-line ICI treatment. Third-line nintedanib plus docetaxel was associated with a high response rate and a prolonged overall survival after failure of a prior ICI. The study results help inform clinical decision-making and treatment sequencing in the changing therapeutic landscape for NSCLC. Future analyses from VARGADO will further expand on our knowledge of outcomes in the post-ICI setting, with results in patients who received first-line combination chemotherapy and ICI treatment followed by second-line nintedanib plus docetaxel.

       Data sharing statement

      To ensure independent interpretation of clinical study results, Boehringer Ingelheim grants all external authors access to relevant material, including participant-level clinical study data, as needed by them to fulfil their role and obligations as authors under the ICMJE criteria. Clinical study documents and participant clinical study data are available to be shared on request after publication of the primary manuscript in a peer-reviewed journal, and if regulatory activities are complete and other criteria met as per the BI Policy on Transparency and Publication of Clinical Study Data (see https://www.mystudywindow.com/msw/datasharing). Bona fide, qualified scientific and medical researchers are eligible to request access to the clinical study data with corresponding documentation describing the structure and content of the datasets. Upon approval, and governed by a Legal Agreement, data are shared in a secured data-access system for a limited period of 1 year, which may be extended upon request. Prior to providing access, clinical study documents and data will be examined, and, if necessary, redacted and de-identified, to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

      Conflicts of interest

      The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: C. Grohé has received consulting fees from AstraZeneca , Boehringer Ingelheim , Merck Sharp & Dohme ; speaker honoraria from AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novartis , Roche and Takeda ; and support for attending meetings from Boehringer Ingelheim, Bristol Myers Squibb and Roche. S. Krüger has received research funds, honoraria and support for attending meetings from Boehringer Ingelheim. H. Müller-Huesmann has participated on a Data Safety Monitoring Board or Advisory Board for, and received honoraria and personal/institutional financial grants or contracts from, Roche , Bristol Myers Squibb , Boehringer Ingelheim, AstraZeneca, Merck Sharp & Dohme, Merck , Eisai and Janssen . H. Müller-Huesmann has also received support for travel or attending meetings from Janssen and AstraZeneca. S. Haas has received presentation fees from Roche and support for attending meetings from Ipsen , Roche and Novartis. S. Hammerschmidt has received consulting fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme and Roche. T. Wehler has received consulting fees from, and participated in Advisory Boards for, AbbVie , AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag , Merck Serono , Merck Sharp & Dohme, Pfizer and Roche/Genentech . T. Wehler has received grants or contracts from AstraZeneca, Boehringer Ingelheim and Roche/Genentech; honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme and Roche/Genentech; payment for expert testimony from Boehringer Ingelheim and Roche/Genentech; support for attending meetings from AstraZeneca, Boehringer Ingelheim, Celgene , Pfizer and Roche/Genentech; and medical writing services funded by Boehringer Ingelheim, Merck Sharpe & Dohme and Roche/Genentech. J. Atz and R. Kaiser are employees of Boehringer Ingelheim. RK reports employment with Boehringer Ingelheim and patent (EP 2994125) planned, issued or pending. M. Schulze, W. Blau and W. Gleiber report no conflicts of interest.

      Funding

      This study was sponsored by Boehringer Ingelheim. Boehringer Ingelheim was involved in the study design, collection, analyses and interpretation of the data in collaboration with the authors.

      Acknowledgements

      During the preparation of this manuscript, medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Michael Fisher (Syneos Health, London, UK), and Sherridan Henness PhD and Jim Sinclair PhD of Ashfield MedComms, an Ashfield Health Company. Participating investigators were financially compensated by Boehringer Ingelheim for the time taken for eCRF documentation, monitoring and study initiation, within the range set out in the official German Physicians' Fee Schedule (GOÄ). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of the manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

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