Checkpoint inhibitors in metastatic epidermal growth factor receptor-mutated non-small cell lung cancer patients: where we treating the wrong cancer?
Editorial

Checkpoint inhibitors in metastatic epidermal growth factor receptor-mutated non-small cell lung cancer patients: where we treating the wrong cancer?

Paul Zarogoulidis1, Vasilis Papadopoulos2, Elena Maragouli2, George Papatsibas2, Haidong Huang3

1Pulmonary Department-Oncology Unit, “Theageneio” Anticancer Hospital, Thessaloniki, Greece; 2Oncology Department, University of Thessali, Larissa, Greece; 3Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China

Correspondence to: Paul Zarogoulidis, MD. Pulmonary Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Email: pzarog@hotmail.com

Provenance: This is an invited Editorial commissioned by the Section Editor Dr. Qiuyuan Li (Department of Thoracic Surgery, Tongji University, Shanghai, China).

Comment on: Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 2017;12:403-7.


Submitted Jul 23, 2017. Accepted for publication Jul 28, 2017.

doi: 10.21037/jtd.2017.08.24


Tyrosine kinase inhibitors (TKIs) is the best treatment choice for patients with epidermal growth factor receptor mutation (EGFR) (1). However; acquired resistance is observed after 10–13 months and therefore these patients have to be investigated firstly for the mutation T790M. This investigation is currently proposed to be performed with re-biopsy in a site with disease progression (2,3). In the case where re-biopsy is not possible then liquid biopsy is proposed (4). In the case of T790M then third generation TKIS are used (5). A serious issue that treating physicians have to take under serious consideration is the possible transformation of an adenocarcinoma with EGFR positive mutation to small cell lung cancer (SCLC) (6). This is also another reason why we should choose re-biopsy instead of liquid biopsy. Tissue from a mass or lymph node with imaging findings (CT-Thorax/PET-CT) with evidence of disease relapse might reveal a transformation from adenocarcinoma to SCLC. This kind of transformation has also been observed with adenocarcinoma harboring anaplastic lymphoma kinase mutation (ALK) to SCLC (7). It has also been observed that in the same patient with adenocarcinoma harboring EGFR mutation after TKI treatment re-biopsy revealed that several hepatic metastasis and thoracic lymphnodes were transformed to SCLC, while the primary site remained adenocarcinoma (8). Transformation to squamous cell carcinoma has been also observed in EGFR positive patients even without TKI administration (9). Moreover; it has been previously observed the case where a patient with T790M mutation receiving osimertinib was transformed to SCLC (10). In the case where disease relapse in these patients cannot be treated with a TKI, then the novel checkpoint inhibitors nivolumab and pembrolizumab could be administered as second line (11). Pembrolizumab has been recently approved as first line treatment in the case where programmed death-ligand 1 (PD-L1) expression is >50% (12). However; for now in the case where patients have both EGFR positive mutation and PD-L1>50% treatment with TKIS is preferred (13). Currently data are conflicting regarding these patients and most of our knowledge is based on murine models (14). It has been observed that even the different exon mutation or EGFR wild type plays a role in the disease response with checkpoint inhibitors after TKI administration (15-17). Different response occurs possibly because of the different factors involved in the acquired resistance. Moreover; currently we are focusing on the expression of the PD-L1 in order to administer checkpoint inhibitors, however; we should consider other factors in EGFR positive mutation patients. There is definitely different immunogenicity for this subgroup of patients and therefore we should focus on investigating an additional marker before administering checkpoint inhibitors, or we could make additional studies investigating the different response to checkpoint inhibitors based on the different exon mutation or wild-type mutation. Another issue is the different percentage of PD-L1 expression, a stratification would also be useful. We could check the PD-L1 expression of the patients that received checkpoint inhibitors as second lone treatment along after disease relapse in TKI administration with the concept of two groups >50% or <50%. Furthermore; does the administration of osimertinib induce different immunogenicity in comparison to those that received just erlotinib, gefitinib or afatinib and therefore different treatment efficiency for the checkpoint inhibitors. Major issue that is unanswered do we need re-biopsy for the evaluation of PD-L1 expression. Upon diagnosis of adenocarcinoma we investigate EGFR, ALK and PD-L1 expression, what we do not know is if the PD-L1 expression changes during therapy. Does the expression of PD-L1 change throughout the treatment with checkpoint inhibitors and therefore a treatment break is necessary? Re-biopsy should be definitely considered in EGFR patients in a site that the disease response does not correlate with the rest of the imaging findings. In the case of cancer transformation the treatment should change based on the type. Finally, we are expecting results from treatment combinations with TKIS and checkpoint inhibitors after disease progression with TKIS, however; we have to consider the adverse effects of this combination (18,19). Possibly in the future we will have combination of treatments in order to avoid early acquired resistance.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Zarogoulidis K, Zarogoulidis P, Darwiche K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis 2013;5 Suppl 4:S389-96. [PubMed]
  2. Zarogoulidis P, Gaga M, Huang H, et al. Tissue is the issue and tissue competition. Re-biopsy for mutation T790: where and why? Clin Transl Med 2017;6:6. [Crossref] [PubMed]
  3. Zarogoulidis P, Rapti A, Sardeli C, et al. Re-biopsy after relapse of targeted therapy. T790M after epidermal growth factor mutation, where and why based on a case series. Respir Med Case Rep 2017;21:171-5. [PubMed]
  4. Alidousty C, Brandes D, Heydt C, et al. Comparison of Blood Collection Tubes from Three Different Manufacturers for the Collection of Cell-Free DNA for Liquid Biopsy Mutation Testing. J Mol Diagn 2017. [Epub ahead of print]. [Crossref] [PubMed]
  5. Remon J, Menis J, Hasan B, et al. The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613. Clin Lung Cancer 2017. [Epub ahead of print]. [Crossref] [PubMed]
  6. Fang L, He J, Xia J, et al. Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report. Oncol Lett 2017;14:593-8. [PubMed]
  7. Zhu YC, Liao XH, Wang WX, et al. Patients harboring ALK rearrangement adenocarcinoma after acquired resistance to crizotinib and transformation to small-cell lung cancer: a case report. Onco Targets Ther 2017;10:3187-92. [Crossref] [PubMed]
  8. Suda K, Murakami I, Yu H, et al. Heterogeneity in Immune Marker Expression after Acquisition of Resistance to EGFR Kinase Inhibitors: Analysis of a Case with Small Cell Lung Cancer Transformation. J Thorac Oncol 2017;12:1015-20. [Crossref] [PubMed]
  9. Le T, Sailors J, Oliver DH, et al. Histologic transformation of EGFR mutant lung adenocarcinoma without exposure to EGFR inhibition. Lung Cancer 2017;105:14-6. [Crossref] [PubMed]
  10. Li L, Wang H, Li C, et al. Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report. Oncotarget 2017;8:18609-14. [PubMed]
  11. Meng X, Liu Y, Zhang J, et al. PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: New development and challenges. Cancer Lett 2017. [Epub ahead of print]. [Crossref] [PubMed]
  12. Hui R, Garon EB, Goldman JW, et al. Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial. Ann Oncol 2017;28:874-81. [Crossref] [PubMed]
  13. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
  14. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 2013;3:1355-63. [Crossref] [PubMed]
  15. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
  16. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-50. [Crossref] [PubMed]
  17. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387:1837-46. [Crossref] [PubMed]
  18. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [Crossref] [PubMed]
  19. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2008;14:2895-9. [Crossref] [PubMed]
Cite this article as: Zarogoulidis P, Papadopoulos V, Maragouli E, Papatsibas G, Huang H. Checkpoint inhibitors in metastatic epidermal growth factor receptor-mutated non-small cell lung cancer patients: where we treating the wrong cancer? J Thorac Dis 2017;9(9):2771-2773. doi: 10.21037/jtd.2017.08.24