Clinical Review

Safety Profile of Mutant EGFR-TK Inhibitors in Advanced Non–Small Cell Lung Cancer: A Meta-analysis

Fed Pract. 2022 August;39(3):S72-S80 | 10.12788/fp.0309

References

2. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi:10.1146/annurev-pathol-011110-130206

3. Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem. 2012;19(20):3337-3352. doi:10.2174/092986712801215973

4. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non–small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016;16(6):653-660. doi:10.1586/14737140.2016.1170596

5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X

6. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X

7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137

8. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non–small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi:10.1200/JCO.2018.78.7994

9. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi:10.1056/NEJMoa0810699

10. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non–small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. doi:10.1016/S0140-6736(15)60294-X

11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995;13(8):1880-1892. doi:10.1200/JCO.1995.13.8.1880

12. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of Stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075

13. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154

14. Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8(4):e61561. Published 2013 Apr 19. doi:10.1371/journal.pone.0061561

15. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab phase ll study in patients with advanced non–small-cell lung cancer (JO25567): updated safety results. Drug Saf. 2018;41(2):229-237. doi:10.1007/s40264-017-0596-0

16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946

18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(25):2969-2979. doi:10.1200/JCO.2016.66.9861

19. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820

20. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1

21. Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443-2450. doi:10.1093/annonc/mdx359

22. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16(8):990-998 doi:10.1016/S1470-2045(15)00121-7

23. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi:10.1200/JCO.2013.51.1816

24. Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118(24):6234-6242. doi:10.1200/JCO.2013.51.1816

25. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi:10.1016/S1470-2045(09)70364-X

26. Lee DH, Park K, Kim JH, Lee JS, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4):1307-1314. doi:10.1158/1078-0432.CCR-09-1903

27. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;22;372(9652):1809-1818. doi:10.1016/S0140-6736(08)61758-4

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

References

1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155

2. da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. doi:10.1146/annurev-pathol-011110-130206

3. Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem. 2012;19(20):3337-3352. doi:10.2174/092986712801215973

4. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non–small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther. 2016;16(6):653-660. doi:10.1586/14737140.2016.1170596

5. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X

6. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi:10.1016/S1470-2045(11)70184-X

7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137

8. Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non–small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018;36(22):2244-2250. doi:10.1200/JCO.2018.78.7994

9. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi:10.1056/NEJMoa0810699

10. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non–small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. doi:10.1016/S0140-6736(15)60294-X

11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non–small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995;13(8):1880-1892. doi:10.1200/JCO.1995.13.8.1880

12. Zhong WZ, Chen KN, Chen C, et al. Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of Stage IIIA-N2 EGFR-mutant non–small-cell lung cancer (EMERGING-CTONG 1103): a randomized phase II study. J Clin Oncol. 2019;37(25):2235-2245. doi:10.1200/JCO.19.00075

13. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154

14. Noronha V, Prabhash K, Thavamani A, et al. EGFR mutations in Indian lung cancer patients: clinical correlation and outcome to EGFR targeted therapy. PLoS One. 2013;8(4):e61561. Published 2013 Apr 19. doi:10.1371/journal.pone.0061561

15. Kato T, Seto T, Nishio M, et al. Erlotinib plus bevacizumab phase ll study in patients with advanced non–small-cell lung cancer (JO25567): updated safety results. Drug Saf. 2018;41(2):229-237. doi:10.1007/s40264-017-0596-0

16. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

17. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946

18. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(25):2969-2979. doi:10.1200/JCO.2016.66.9861

19. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 Phase III Trial. J Clin Oncol. 2021;39(7):713-722. doi:10.1200/JCO.20.01820

20. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/S1470-2045(15)00026-1

21. Shi YK, Wang L, Han BH, et al. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017;28(10):2443-2450. doi:10.1093/annonc/mdx359

22. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomized trial. Lancet Oncol. 2015;16(8):990-998 doi:10.1016/S1470-2045(15)00121-7

23. Goss GD, O’Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. doi:10.1200/JCO.2013.51.1816

24. Sun JM, Lee KH, Kim SW, et al. Gefitinib versus pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer. 2012;118(24):6234-6242. doi:10.1200/JCO.2013.51.1816

25. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi:10.1016/S1470-2045(09)70364-X

26. Lee DH, Park K, Kim JH, Lee JS, et al. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res. 2010;16(4):1307-1314. doi:10.1158/1078-0432.CCR-09-1903

27. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;22;372(9652):1809-1818. doi:10.1016/S0140-6736(08)61758-4

Safety Profile of Mutant EGFR-TK Inhibitors in Advanced Non–Small Cell Lung Cancer: A Meta-analysis

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Safety Profile of Mutant EGFR-TK Inhibitors in Advanced Non–Small Cell Lung Cancer: A Meta-analysis

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