Meta-Analysis

Efficacy and safety of EGFR inhibitors and radiotherapy in locally advanced non-small-cell lung cancer: a meta-analysis

Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention & Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China

‡These authors have contributed equally to this work and share first authorship

Search for more papers by this author

Fang Wang^‡

Department of Radiation Oncology, Affiliated Hospital of Hebei University, Baoding, 071000, China

‡These authors have contributed equally to this work and share first authorship

Search for more papers by this author

Huijun Jia

Search for more papers by this author

Zhen Lian

Department of Emergency, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention & Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China

Search for more papers by this author

Kai Ren

Search for more papers by this author

Zhiyong Yuan

Search for more papers by this author

Ping Wang

*Author for correspondence:

E-mail Address: wangping@tjmuch.com

Search for more papers by this author

Lujun Zhao

Search for more papers by this author

Published Online:10 Aug 2022https://doi.org/10.2217/fon-2022-0491

View article

Abstract

Aim: To assess the efficacy and safety of EGFR inhibitors combined with (chemo)radiotherapy in unresectable, locally advanced non-small-cell lung cancer. Materials & methods: A systematic review and meta-analysis of prospective trials was performed. Results: Twenty-eight studies of 1640 patients were included. In patients harboring EGFR-sensitive mutations, the pooled objective response rate, 1-year overall survival rate and 1-year progression-free survival rate of EGFR-TKIs + (chemo)radiotherapy were 0.803, 0.766 and 0.554, respectively. Compared with chemoradiotherapy, the addition of EGFR inhibitors did not significantly increase the risk of grade ≥3 pneumonitis and esophagitis. Conclusion: EGFR-tyrosine kinase inhibitors combined with (chemo)radiotherapy are tolerable and the clinical benefit is promising, especially in patients with EGFR-sensitive mutations.

Plain language summary

The aim of this systemic review and meta-analysis was to assess the efficacy and safety of (chemo)radiotherapy combined with therapies targeting EGFR receptor, in unresectable, locally advanced non-small-cell lung cancer. Prospective clinical trials were searched and analyzed, and 28 studies of 1640 patients were included in this analysis. The results showed that the efficacy of (chemo)radiotherapy combined with tyrosine kinase inhibitors targeting EGFR, such as gefitinib and erlotinib, was promising, especially among patients harboring sensitive mutations in EGFR. Besides, this combination therapy was safe, which did not increase the risk of severe pneumonitis and esophagitis. Overall, tyrosine kinase inhibitors targeting EGFR combined with (chemo)radiotherapy are tolerable and the clinical benefit is promising, especially in patients with EGFR-sensitive mutations.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J. Clin. 60(5), 277–300 (2010).
MedlineGoogle Scholar
2. Antonia SJ, Villegas A, Daniel D et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379(24), 2342–2350 (2018). • Based on the results of this study, the National Comprehensive Cancer Network recommends concurrent chemoradiotherapy followed by consolidation durvalumab as the standard treatment for unresectable, locally advanced non-small-cell lung cancer.
Medline CASGoogle Scholar
3. Spigel DR, Faivre-Finn C, Gray JE et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J. Clin. Oncol. 40(12), 1301–1311 (2022).
Medline CASGoogle Scholar
4. Wang CC, Chiu LC, Ju JS et al. Durvalumab as consolidation therapy in post-concurrent chemoradiation (CCRT) in unresectable stage III non-small cell lung cancer patients: a multicenter observational study. Vaccines (Basel) 9(10), 1122 (2021).
Medline CASGoogle Scholar
5. Hellyer JA, Aredo JV, Das M et al. Role of consolidation durvalumab in patients with EGFR- and HER2-mutant unresectable stage III NSCLC. J. Thorac. Oncol. 16(5), 868–872 (2021). • Showed consolidation durvalumab after chemoradiotherapy seems to be less efficacious in patients with EGFR-mutant non-small-cell lung cancer.
Medline CASGoogle Scholar
6. Aredo JV, Mambetsariev I, Hellyer JA et al. Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy. J. Thorac. Oncol. 16(6), 1030–1041 (2021). • Showed consolidation durvalumab after chemoradiotherapy seems to be less efficacious in patients with EGFR-mutant non-small-cell lung cancer.
Medline CASGoogle Scholar
7. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 19(56), 6550–6565 (2000).
Medline CASGoogle Scholar
8. Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 10(5), 432–433 (2009).
MedlineGoogle Scholar
9. Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362(25), 2380–2388 (2010).
Medline CASGoogle Scholar
10. Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378(2), 113–125 (2018).
Medline CASGoogle Scholar
11. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J. Clin. Oncol. 28(6), 918–927 (2010).
Medline CASGoogle Scholar
12. Horn D, Hess J, Freier K, Hoffmann J, Freudlsperger C. Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma. Expert. Opin. Ther. Targets 19(6), 795–805 (2015).
Medline CASGoogle Scholar
13. Chinnaiyan P, Huang S, Vallabhaneni G et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res. 65(8), 3328–3335 (2005).
Medline CASGoogle Scholar
14. Moher D, Shamseer L, Clarke M et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 4, 1 (2015).
MedlineGoogle Scholar
15. Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann. Intern. Med. 151(4), W65–94 (2009).
MedlineGoogle Scholar
16. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8(1), 16 (2007).
MedlineGoogle Scholar
17. Walraven I, van den Heuvel M, van Diessen J et al. Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab. Radiother. Oncol. 118(3), 442–446 (2016).
MedlineGoogle Scholar
18. van den Heuvel MM, Uyterlinde W, Vincent AD et al. Additional weekly cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating. Radiother. Oncol. 110(1), 126–131 (2014).
MedlineGoogle Scholar
19. Socinski MA, Stinchcombe TE, Moore DT et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J. Clin. Oncol. 30(32), 3953–3959 (2012).
Medline CASGoogle Scholar
20. Rothschild S, Bucher SE, Bernier J et al. Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III non–small cell lung cancer: a phase I trial. Int. J. Radiat. Oncol. Biol. Phys. 80(1), 126–132 (2011).
Medline CASGoogle Scholar
21. Ramalingam SS, Kotsakis A, Tarhini AA et al. A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 81(3), 416–421 (2013).
Medline CASGoogle Scholar
22. Okamoto I, Takahashi T, Okamoto H et al. Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer 72(2), 199–204 (2011).
MedlineGoogle Scholar
23. Niho S, Ohe Y, Ishikura S et al. Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402). Ann. Oncol. 23(9), 2253–2258 (2012).
Medline CASGoogle Scholar
24. Martínez E, Rico M, Martínez M et al. Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a phase II trial. OncoTargets and Therapy 9, 1057–1066 (2016).
Medline CASGoogle Scholar
25. Liu D, Zheng X, Chen J et al. Induction chemotherapy with cetuximab, vinorelbine-cisplatin followed by thoracic radiotherapy and concurrent cetuximab, vinorelbine-cisplatin in patients with unresectable stage III non-small cell lung cancer. Lung Cancer 89(3), 249–254 (2015).
MedlineGoogle Scholar
26. Lilenbaum R, Samuels M, Wang X et al. A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). J. Thorac. Oncol. 10(1), 143–147 (2015).
Medline CASGoogle Scholar
27. Komaki R, Allen PK, Wei X et al. Adding erlotinib to chemoradiation improves overall survival but not progression-free survival in stage III non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 92(2), 317–324 (2015).
Medline CASGoogle Scholar
28. Jensen AD, Münter MW, Bischoff HG et al. Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab. Cancer 117(13), 2986–2994 (2011).
Medline CASGoogle Scholar
29. Hallqvist A, Wagenius G, Rylander H et al. Concurrent cetuximab and radiotherapy after docetaxel–cisplatin induction chemotherapy in stage III NSCLC: satellite – a phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 71(2), 166–172 (2011).
Medline CASGoogle Scholar
30. Govindan R, Bogart J, Stinchcombe T et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B Trial 30407. J. Clin. Oncol. 29(23), 3120–3125 (2011).
Medline CASGoogle Scholar
31. Dilling TJ, Extermann M, Kim J et al. Phase 2 study of concurrent cetuximab plus definitive thoracic radiation therapy followed by consolidation docetaxel plus cetuximab in poor prognosis or elderly patients with locally advanced non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 90(4), 828–833 (2014).
Medline CASGoogle Scholar
32. Choong NW, Mauer AM, Haraf DJ et al. Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. J. Thorac. Oncol. 3(9), 1003–1011 (2008).
MedlineGoogle Scholar
33. Chen Y, Moon J, Pandya KJ et al. A pilot study (SWOG S0429) of weekly cetuximab and chest radiotherapy for poor-risk stage III non-small cell lung cancer. Front. Oncol. 3, 219 (2013).
MedlineGoogle Scholar
34. Bradley JD, Paulus R, Komaki R et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 16(2), 187–199 (2015).
Medline CASGoogle Scholar
35. Blumenschein GR, Paulus R, Curran WJ et al. Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non–small-cell lung cancer: RTOG 0324. J. Clin. Oncol. 29(17), 2312–2318 (2011).
Medline CASGoogle Scholar
36. Dingemans AM, Bootsma G, van Baardwijk A et al. A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer. J. Thorac. Oncol. 9(5), 710–716 (2014).
Medline CASGoogle Scholar
37. Ready N, Janne PA, Bogart J et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: Cancer and Leukemia Group B (CALEB) 30106, a CALGB-stratified phase II trial. J. Thorac. Oncol. 5(9), 1382–1390 (2010). • Showed that the efficacy of radiotherapy and gefitinib was promising.
MedlineGoogle Scholar
38. Center B, Petty WJ, Ayala D et al. A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. J. Thorac. Oncol. 5(1), 69–74 (2010).
MedlineGoogle Scholar
39. Hughes S, Liong J, Miah A et al. A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRATCH study. J. Thorac. Oncol. 3(6), 648–651 (2008).
MedlineGoogle Scholar
40. Stinchcombe TE, Morris DE, Lee CB et al. Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer. J. Thorac. Oncol. 3(3), 250–257 (2008).
MedlineGoogle Scholar
41. Fu Z, Yang X, Wang W et al. Radiotherapy combined with gefitinib for patients with locally advanced non-small cell lung cancer who are unfit for surgery or concurrent chemoradiotherapy: a phase II clinical trial. Radiat. Oncol. 15(1), 155 (2020).
Medline CASGoogle Scholar
42. Akamatsu H, Murakami H, Harada H et al. Gefitinib with concurrent thoracic radiotherapy in unresectable locally advanced NSCLC with EGFR mutation; West Japan Oncology Group 6911L. J. Thorac. Oncol. 16(10), 1745–1752 (2021). • Showed gefitinib combined with chemoradiotherapy is promising in EGFR-mutated non-small-cell lung cancer.
Medline CASGoogle Scholar
43. Hotta K, Saeki S, Yamaguchi M et al. Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study. ESMO Open 6(4), 100191 (2021). • Showed gefitinib combined with chemoradiotherapy is promising in EGFR-mutated non-small-cell lung cancer.
Medline CASGoogle Scholar
44. Xing L, Wu G, Wang L et al. Erlotinib versus etoposide/cisplatin with radiation therapy in unresectable stage III epidermal growth factor receptor mutation-positive non-small cell lung cancer: a multicenter, randomized, open-label, phase 2 trial. Int. J. Radiat. Oncol. Biol. Phys. 109(5), 1349–1358 (2021). •• In this phase II study, survival of EGFR-mutated non-small-cell lung cancer treated by erlotinib + radiotherapy was significantly improved compared with patients treated by concurrent chemoradiotherapy.
MedlineGoogle Scholar
45. Xu K, Liang J, Zhang T et al. Clinical outcomes and radiation pneumonitis after concurrent EGFR-tyrosine kinase inhibitors and radiotherapy for unresectable stage III non-small cell lung cancer. Thorac. Cancer 12(6), 814–823 (2021). • Showed combined EGFR-tyrosine kinase inhibitors and radiotherapy did not increase the incidence of grade 4–5 radiation pneumonitis.
Medline CASGoogle Scholar
46. Satoh T, Gemma A, Kudoh S et al. Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry. Jpn J. Clin. Oncol. 44(11), 1032–1039 (2014).
MedlineGoogle Scholar
47. Nakano K, Seto A, Sasaki T et al. Incidence and risk factors of interstitial lung disease of patients with head and neck cancer treated with cetuximab. Head Neck 41(8), 2574–2580 (2019).
MedlineGoogle Scholar
48. Price L, Glynn P, Zarkar A. Interstitial lung disease secondary to cetuximab in bladder cancer: an oncologist's perspective. BMJ Case Rep. 2017, bcr2017220181 (2017).
Google Scholar

Vol. 18, No. 27

Supplemental Materials

Metrics

Downloaded 285 times

History

Received 13 May 2022

Accepted 26 July 2022

Published online 10 August 2022

Published in print September 2022

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2022-0491

Author contributions

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. X Li: conceptualization, data curation, formal analysis; F Wang: methodology, data curation, formal analysis; H Jia: investigation, writing – original draft; Z Lian: visualization; K Ren: software; Z Yuan: validation; P Wang: writing – review editing; L Zhao: supervision, project administration.

Financial & competing interests disclosure

This study was sponsored by the grant from National Natural Science Foundation of China (no. 81903121). X Li received funding to conduct this research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download