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- W4224991245 abstract "In this issue of Clinical Oncology, the VARGADO investigators present the results of a cohort of 80 patients with non-small cell lung cancer (NSCLC) from an ongoing prospective real-world non-interventional study [[1]Grohé C. Blau W. Gleiber W. Haas S. Hammerschmidt S. Krüger S. et al.Real-world efficacy of nintedanib plus docetaxel after progression on immune checkpoint inhibitors: results from the ongoing, non-interventional VARGADO study.Clin Oncol. 2022; 34: 459-468Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. This study has been recruiting since 2015 in about 100 centres across Germany, assessing the efficacy of nintedanib and docetaxel in patients who have progressed on immune checkpoint inhibitors (ICI). The presented cohort received third-line nintedanib plus docetaxel following first-line chemotherapy and second-line ICI [[1]Grohé C. Blau W. Gleiber W. Haas S. Hammerschmidt S. Krüger S. et al.Real-world efficacy of nintedanib plus docetaxel after progression on immune checkpoint inhibitors: results from the ongoing, non-interventional VARGADO study.Clin Oncol. 2022; 34: 459-468Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. Traditionally, clinicians have wanted data from randomised controlled trials to guide treatment decisions, to give information as to efficacy and toxicity that can be used to consent patients appropriately and enable discussions with funders as to the cost-effectiveness of therapies. However, problems can arise with this approach, including if the agent is being evaluated in a very rare population where a clinical trial is not feasible or in situations where treatment algorithms have changed rapidly and agents may no longer be used in the same context or line of therapy as previously. This latter situation is the case for patients with non-oncogene driven NSCLC, where treatment algorithms have dramatically changed over the last 8 years, with the introduction of ICI. The LUME-Lung 1 clinical study was published in January 2014 and showed the potential benefits of adding nintedanib to docetaxel, leading to its license for use ‘after first-line chemotherapy’ [[2]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.Lancet Oncol. 2014; 15: 143-155https://doi.org/10.1016/S1470-2045(13)70586-2Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar]. Nintedanib is an oral inhibitor with activity against vascular endothelial growth factor receptors 1–3 (VEGFR1–3), platelet-derived growth factor receptors α/β and fibroblast growth factor receptors 1–3; signalling that is important in both neo-angiogenesis and maintenance of the tumour microenvironment [[2]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.Lancet Oncol. 2014; 15: 143-155https://doi.org/10.1016/S1470-2045(13)70586-2Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar]. Together with the REVEL study (published in August 2014), which looked at the addition of ramucirumab (a monoclonal antibody against VEGFR2) to docetaxel, these studies suggested a small but significant survival benefit of adding anti-angiogenics to docetaxel in patients who had progressed on first-line platinum-based doublet chemotherapy (PDC) [[3]Garon E.B. Ciuleanu T.E. Arrieta O. Prabhash K. Syrigos K.N. Goksel T. et al.Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.Lancet. 2014; 384: 665-673https://doi.org/10.1016/S0140-6736(14)60845-XAbstract Full Text Full Text PDF PubMed Scopus (881) Google Scholar]. However, both studies were quickly supplanted in terms of the treatment algorithms for patients who had progressed on PDC in the second-line setting by the publication of positive phase III studies of second-line ICI including nivolumab, pembrolizumab and atezolizumab (published September 2015, December 2015 and December 2016, respectively) [[4]Ellis P.M. Vella E.T. Ung Y.C. Immune checkpoint inhibitors for patients with advanced non-small-cell lung cancer: a systematic review.Clin Lung Cancer. 2017; 18: 444-459.e1https://doi.org/10.1016/j.cllc.2017.02.001Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. This pushed docetaxel-based therapies into the third-line setting for most patients. So, can we just assume that the data generated in LUME-Lung 1 remain valid now this regimen is being used outside of license in the third-line setting? And what about when it is used in patients who have received combined chemotherapy and ICI in the frontline setting, which is now the most common treatment strategy. The VARGADO study helps to answer some of these questions; although scans were carried out according to standard care, they were formally reported according to Response Evaluation Criteria in Solid Tumours and toxicity was collected prospectively using Common Toxicity Criteria for Adverse Events as would be carried out in an interventional study. Progression-free survival in VARGADO (6.4 months) seems to be at least as good as that reported in LUME-Lung-1 (4.0 months) and higher response rates were seen. The reported 50% response rate in the 80% of patients with evaluable response in VARGADO (95% confidence interval 38–62%) is very different from the 4.7% (95% confidence interval 2.8–7.5%) reported with central review in LUME-Lung-1 [[1]Grohé C. Blau W. Gleiber W. Haas S. Hammerschmidt S. Krüger S. et al.Real-world efficacy of nintedanib plus docetaxel after progression on immune checkpoint inhibitors: results from the ongoing, non-interventional VARGADO study.Clin Oncol. 2022; 34: 459-468Abstract Full Text Full Text PDF Scopus (3) Google Scholar,[2]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.Lancet Oncol. 2014; 15: 143-155https://doi.org/10.1016/S1470-2045(13)70586-2Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar]. Response is an important end point in lung cancer, where quality of life is often driven by lung cancer-related symptoms [[5]Choi S. Ryu E. Effects of symptom clusters and depression on the quality of life in patients with advanced lung cancer.Eur J Cancer Care. 2018; 27e12508https://doi.org/10.1111/ecc.12508Crossref Scopus (44) Google Scholar]. The use of hard clinical end points, such as overall survival, can allow comparison with interventional studies and other real-world cohorts (with similar survival seen in VARGADO to LUME-Lung-1; 12.1 versus 12.6 months) [[1]Grohé C. Blau W. Gleiber W. Haas S. Hammerschmidt S. Krüger S. et al.Real-world efficacy of nintedanib plus docetaxel after progression on immune checkpoint inhibitors: results from the ongoing, non-interventional VARGADO study.Clin Oncol. 2022; 34: 459-468Abstract Full Text Full Text PDF Scopus (3) Google Scholar,[2]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.Lancet Oncol. 2014; 15: 143-155https://doi.org/10.1016/S1470-2045(13)70586-2Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar]. However, real-world cohorts can suffer from uncertainty as to the exact length of the progression-free survival; even when performed prospectively, scans are carried out within standard clinical care and not necessarily at prescribed intervals. The response rate can be difficult to determine, given the number of patients who are non-evaluable and the unblinded investigator-led nature of the review. A comparison of survival needs to take into account the inclusion in non-interventional studies of patients who would have been ineligible for the registration studies, such as the 9% of patients with performance status ≥2 in VARGADO, and where worse survival may be anticipated. The VARGADO data do match with other small cohorts suggesting higher response rates to anti-angiogenics and docetaxel combinations in patients who have previously progressed on ICI. This has been seen in lung cancer with nintedanib (n = 55; response rate 18%) and ramucirumab (n = 20; response rate 60%) and in other tumour types, such as gastric cancer [6Reck M. Syrigos K. Miliauskas S. Zochbauer-Muller S. Fischer J.R. Buchner H. et al.Non interventional LUME-BioNIS study of nintedanib plus docetaxel after chemotherapy inadenocarcinoma non-small cell lung cancer: a subgroup analysis in patients with prior immunotherapy.Lung Cancer. 2020; 148: 159-165https://doi.org/10.1016/j.lungcan.2020.08.004Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 7Shiono 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.Thorac Cancer. 2019; 10: 775-781https://doi.org/10.1111/1759-7714.12998Crossref PubMed Scopus (46) Google Scholar, 8Sasaki A. Kawazoe A. Eto T. Okunaka M. Mishima S. Sawada K. et al.Improved efficacy of taxanes and ramucirumab combination chemotherapy after exposure to anti-PD-1 therapy in advanced gastric cancer.ESMO Open. 2020; 4e000775https://doi.org/10.1136/esmoopen-2020-000775Crossref PubMed Scopus (13) Google Scholar]. There is extensive pre-clinical evidence linking VEGF with immune suppression [[9]Popat S. Grohé 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?.Lung Cancer. 2020; 144: 76-84https://doi.org/10.1016/j.lungcan.2020.04.009Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This occurs directly through impacts on dendritic cell maturation, antigen presentation and decreased trafficking of immune cells into the tumour. Indirect effects also occur as the hypoxia, low pH and high stromal pressure from the abnormal tumour vasculature lead to induction of other proinflammatory cytokines and metabolites, such as transforming growth factor-β, interleukin-10 and adenosine, and the infiltration of cancer associated fibroblasts, myeloid-derived suppressor cells and TRegs, which all suppress the local immune response [[9]Popat S. Grohé 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?.Lung Cancer. 2020; 144: 76-84https://doi.org/10.1016/j.lungcan.2020.04.009Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. Whether this angiogenic switch that develops in immunotherapy resistance accounts for the clinical observation of an increased response rate is not yet clear; nor is the exact contribution of the nintedanib over the chemotherapy. In mouse models, both nintedanib and the original taxane paclitaxel result in a positive impact on the tumour microenvironment, potentially enhancing ICI effects [[10]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.Br J Cancer. 2021; 124: 914-924https://doi.org/10.1038/s41416-020-01201-zCrossref PubMed Scopus (17) Google Scholar,[11]Sevko A. Michels T. Vrohlings M. Umansky L. Beckhove P. Kato M. et al.Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model.J Immunol. 2013; 190: 2464-2471https://doi.org/10.4049/jimmunol.1202781Crossref PubMed Scopus (159) Google Scholar]. A small retrospective series from MD Anderson suggested a similarly high response rate to single-agent docetaxel (50%) in patients with NSCLC who had previously received ICI [[12]Schvartsman G. Peng S.A. Bis G. Lee J.J. Benveniste M.F.K. Zhang J. et al.Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer.Lung Cancer. 2017; 112: 90-95https://doi.org/10.1016/j.lungcan.2017.07.034Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar]. Overall, VARGADO and the other studies cited above mandate further evaluation of anti-angiogenic combinations on progression of ICI both in NSCLC and other tumour types. This could be carried out in interventional studies, with up to date biopsies before treatment to allow investigation of the biological mechanisms of resistance. An example of such a study is the Morpheus platform evaluating novel immunotherapy combinations (ClinicalTrials.gov Identifier: NCT03337698). The VARGADO study also addressed the question as to whether there is any additional toxicity from treatment with nintedanib and docetaxel when administered following treatment with ICI. There have been instances where the use of kinase inhibitors immediately following ICIs has led to increased toxicity; particularly when there may be overlapping toxicity profiles. A recent well-described example is the increased incidence of pneumonitis when osimertinib is used immediately following ICI [[13]Schoenfeld A.J. Arbour K.C. Rizvi H. Iqbal A.N. Gadgeel S.M. Girshman J. et al.Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.Ann Oncol. 2019; 30: 839-844https://doi.org/10.1093/annonc/mdz077Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar]. Although all three agents of nintedanib, docetaxel and ICI cause diarrhoea, there does not seem to be any increase in toxicity in this situation (grade 3 diarrhoea at 3% in VARGADO versus 6.6% in LUME-Lung-1 [[1]Grohé C. Blau W. Gleiber W. Haas S. Hammerschmidt S. Krüger S. et al.Real-world efficacy of nintedanib plus docetaxel after progression on immune checkpoint inhibitors: results from the ongoing, non-interventional VARGADO study.Clin Oncol. 2022; 34: 459-468Abstract Full Text Full Text PDF Scopus (3) Google Scholar,[2]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.Lancet Oncol. 2014; 15: 143-155https://doi.org/10.1016/S1470-2045(13)70586-2Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar]). However, there are unanswered questions that we hope that similar non-interventional studies may be able to answer in the future. The biology of resistance to immunotherapy may vary in patients where the cancer has innate resistance to ICI, compared with those who develop early resistance, late resistance or progression following cessation of treatment [[9]Popat S. Grohé 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?.Lung Cancer. 2020; 144: 76-84https://doi.org/10.1016/j.lungcan.2020.04.009Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This may affect the response to subsequent lines of treatment, particularly when using a therapy such as an anti-angiogenic. Unfortunately, given the timescales of the study, the molecular data presented is relatively sparse, with epidermal growth factor receptor status available in 79%; Anaplastic Lymphoma Kinase (ALK) status in 48% and no reported analysis of K-RAS, B-RAF, MET, RET and ROS-1 or PDL1 status or other important genomic markers that may be associated with both chemotherapy and immunotherapy resistance, such as KEAP1 [[14]Hellyer J.A. Padda S.K. Diehn M. Wakelee H.A. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC.J Thorac Oncol. 2021; 16: 395-403https://doi.org/10.1016/j.jtho.2020.11.015Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Non-interventional studies will have the most value if they can also be linked with tumour molecular profiling data collected in large national networks such as carried out in France or the Netherlands [[15]Barlesi F. Mazieres J. Merlio J.P. Debieuvre D. Mosser J. Lena H. et al.Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).Lancet. 2016; 387: 1415-1426https://doi.org/10.1016/S0140-6736(16)00004-0Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar,[16]Bins S. Cirkel G.A. Gadellaa-Van Hooijdonk C.G. Weeber F. Numan I.J. Bruggink A.H. et al.Implementation of a multicenter biobanking collaboration for next-generation sequencing-based biomarker discovery based on fresh frozen pretreatment tumor tissue biopsies.Oncologist. 2017; 22: 33-40https://doi.org/10.1634/theoncologist.2016-0085Crossref PubMed Scopus (24) Google Scholar]. Given the increasing amount of tumour profiling with large panels that is becoming standard in patients with NSCLC, hopefully these data can be accumulated in the future. Although the individual cohorts may be small and will not be statistically powered for analysis, clinical observations of this nature can give insights into biology that can be investigated in ‘reverse-translation’ or confirmed in alternative cohorts. Given the increasing number of options available to patients with lung cancer and the resulting complex treatment decisions, non-interventional studies such as VARGADO provide an important role in guiding clinicians and patients as to the potential benefits and side-effects of treatment regimens outside their original design. Although a further change in treatment patterns means the number of patients that this applies to is rapidly reducing, the authors are to be congratulated, and we look forward to the full publication of the next cohort of patients in VARGADO who received second-line nintedanib and docetaxel following combination PDC and ICI in the first-line setting. In particular, it will be of interest to assess the response rate in patients who have received a taxane and the anti-angiogenic antibody bevacizumab as part of their frontline treatment (in the atezolizumab, bevacizumab, carboplatin and paclitaxel combination). It is now vital that both regulators and funders show that they accept the value of these studies in terms of license and funding extension, accepting the lower level of evidence given the context. The US Food and Drugs Administration has set out a framework for the use of real-world evidence; although traditionally most utility has been shown in assessing safety, it states that it ‘will evaluate the potential role of observational studies in contributing to evidence of drug product effectiveness’ [[17]Food and Drugs Administrationhttps://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidenceDate accessed: March 14, 2022Google Scholar]. Similarly, the National Institute for Health and Care Excellence has set out a framework for using real-world evidence in funding decisions in the UK [[18]National Institute for Health and Care Excellencehttps://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/chte-methods-and-processes-consultationDate accessed: March 14, 2022Google Scholar]. Prospective observational studies as carried out in VARGADO may have higher value in determining radiological response rates and safety signals, but require patient consent and may be more expensive. Retrospective analysis of large numbers of patients linked to systemic administration records can help to provide surrogate measures of efficacy, such as time on therapy and survival, and of toxicity, such as dose reductions. In either scenario, if the maximum value is going to be acquired from these studies, and the efforts of patients and investigators recognised, they need to be appropriately funded. This could be from payers in national healthcare systems or interested pharmaceutical partners. A. Greystoke has received consultancy and speaker fees from Boehringer Ingelheim and Eli-Lilly." @default.
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- W4224991245 title "Re-evaluating Subsequent Treatment Options in Non-small Cell Lung Cancer in the Era of Immune Checkpoint Inhibitors" @default.
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