Abstract
Purpose
Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting.
Methods
Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models.
Results
Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337–0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305–0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298–0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group.
Conclusion
Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Borghaei H, Paz-Ares L, Horn L et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New Engl J Med 373(17):1627–1639
Christian M, Dingemans Anne-Marie C, Gray Jhanelle E et al (2017) The Potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC. J Thorac Oncol 12:194–207
Dai F, Jonas K, Zohreh A et al (2018) Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15:325–340
Du Four S, Maenhout SK, Niclou SP et al (2016) Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs. Am J Cancer Res 6(11):2514
Gandhi L, Rodriguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092
Gettinger SN, Horn L, Jackman DM et al (2018) Five-Year follow-up of nivolumab in previously treated advanced non–small-cell lung cancer: results from the CA209-003 Study. J Clin Oncol 36(17):1675–1684
Herbst RS, Arkenau HT, Rafael SD et al (2019) Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol 20:1109–1123
Herbst RS, Baas P, Kim DW et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550
Hodi FS, Lawrence DP, Lezcano C et al (2014) Bevacizumab plus Ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2(7):632–642
Horn L, Spigel DR, Vokes EE et al (2017) Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, Phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35(35):3924–3933
Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W (2018) Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 18(3):195–203. https://doi.org/10.1038/nri.2017.145
Jianming Xu, Yun Z, Jia Ru et al (2019) Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res 25:515–523
Martin R, Mok Tony SK, Makoto N et al (2019a) Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 7:387–401
Qin Sk, Ren Zg, Feng Y, et al. (2020) Efficacy and safety of atezolizumab + bevacizumab vs sorafenib in Chinese patients with unresectable HCC in the phase III IMbrave150 study[R]. Liver Cancer Summit OP02–03
Reck M, Mok TSK, Makoto N et al (2019b) Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 7:387–401
Reck M, Rodriguez-Abreu D, Robinson AG et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833
Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350–1355
Rini Brian I, Thomas P, Atkins Michael B et al (2019) Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet 393:2404–2415
Rittmeyer A, Barlesi F, Waterkamp D et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265
Siegel RL, Miller KD, Jemal A et al (2020) Cancer statistics, 2020. CA Cancer J Clini 70(1):7–30
Socinski MA, Jotte RM, Cappuzzo F et al (2018b) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301
Socinski MA, Jotte RM, Cappuzzo F et al (2018a) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301
Teele K, Laurence A, Bernard E et al (2017) Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis 20:205–215
Wallin JJ, Bendell JC, Funke R et al (2016a) Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Commun 7:12624
Wallin JJ, Bendell JC, Funke R et al (2016b) Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 7:12624
Yuhui H, Jian** Y, Elda R et al (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA 109:17561–17566
Funding
This work was supported by the National Key R&D Program of China (No. 2017YFC0907900/2017YFC0907904).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethics approval
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 approved by the institutional review board of the People's Liberation Army General Hospital, Bei**g, China (approval number: S2018-092–01).
Consent to participate
Written informed consent was signed up by all patients involved in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Huang, D., Cui, P., Huang, Z. et al. Anti-PD-1/L1 plus anti-angiogenesis therapy as second-line or later treatment in advanced lung adenocarcinoma. J Cancer Res Clin Oncol 147, 881–891 (2021). https://doi.org/10.1007/s00432-020-03380-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-020-03380-x