Other specified malignant neoplasms of bronchus or lung ICD11 code: 2C75.Y
Oral > Solid: 100 mg ; 150 mg
Adolescents and adults
Main patents have expired but secondary patents might remain active in some jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPal.org
Read more about patents.
Expert Committee recommendation
The Committee endorsed the recommendations of the EML Cancer Medicine Working Group with regard to the proposed threshold of four to six months of overall survival benefit as a guiding principle for prioritizing cancer medicines for inclusion on the EML, and applied this principle to the consideration of the tyrosine kinase inhibitors afatinib, erlotinib and gefitinib. The Committee noted that afatinib, erlotinib and gefitinib were all scored as 4/5 on the ESMO-MCBS v1.1 for this indication. The Expert Committee recommended the addition of erlotinib with a square box to the complementary list of the EML for first-line treatment of EGFR mutation-positive advanced non-small cell lung cancer. Afatinib and gefitinib should be considered as therapeutically equivalent alternatives. The Committee noted that these medicines are associated with relevant survival benefits for patients, acceptable toxicity and improvements in quality of life compared to chemotherapy. The Committee also noted that since these medicines were considered for inclusion on the EML in 2015, generic versions of these medicines are more widely available, as are quality-assured diagnostic molecular tests for EGFR mutations.
The application requested the addition of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to the complementary list of the EML for first-line treatment of EGFR mutation positive, non-small cell lung cancer. EGFR TKIs have been considered and rejected for inclusion on the EML on two previous occasions in 2015 and 2017. In each case, the Expert Committee acknowledged that individual patients with a drug-sensitive EGFR mutation may derive benefit from TKI therapy, which has been associated with similar efficacy and more favourable tolerability compared to cytotoxic chemotherapy. However, the requirements to screen patients for suitability for treatment must be taken into account by health systems (1, 2). Cytotoxic chemotherapy currently included on the EML for treatment of non-small cell lung cancer (NSCLC) includes carboplatin, cisplatin, etoposide, gemcitabine, paclitaxel and vinorelbine.
Public health relevance
Lung cancer is the most commonly diagnosed cancer globally, and the leading cause of cancer death, with estimated 2 million new cases and 1.7 related deaths in 2018. The economic impact of lung cancer has been estimated at around US$ 8 billion in lost productivity in the BRICS countries (Brazil, Russia, India, China and South Africa) (3). Moreover, in the absence of wide coverage of effective screening programmes on a global scale, lung cancer diagnoses occur in advanced stage in more than 60% of cases, with highly regional variability (4, 5). The mutational pattern of NSCLC varies across the different regions, with a higher prevalence in Asia Pacific (up to 76% of patients) and the lowest registered in Oceania (12%). Africa, Europe and North America registered the same rate of EGFR-mutated NSCLC, at around 20% (6–8). Non-squamous NSCLC has been linked to gene mutations in EGFR. This disease, given its incidence, comprises a high burden and leads to a high mortality. However, with advances in cancer gene-directed treatment, the outcome of the disease has improved. The response rate doubled as compared to chemotherapy, the progression free survival (PFS) doubled and the median survival time increased to nearly three years if patients receive both the targeted medicines and chemotherapy together (the median survival time for patient receiving chemotherapy only is approximately 10 months, in historical series).
The application reported the findings and recommendations for EGFR-mutated NSCLC from the 2018 European Society For Medical Oncology (ESMO) Clinical Practice Guidelines for diagnosis, treatment and follow up of metastatic nonsmall cell lung cancer (9). The ESMO guidelines state that EGFR-TKIs are the standard of care for first-line treatment for advanced EGFR-mutated NSCLC (level of evidence: I; grade of recommendation: A). EGFR mutation as an oncogenic target has proven predictive power in NSCLC from multiple Phase III trials of EGFR-TKIs versus platinum-based chemotherapy (10–15). The improvement in objective response rate (ORR) and progression free survival (PFS) is consistent across all age groups, genders, smoking status and performance status. However, none of the above studies demonstrated an overall survival benefit for a EGFR-TKI over platinum-based chemotherapy, likely due to the high level of crossover (16). The use of EGFR-TKI as first-line therapy has been associated with a greater benefit than as second-line treatment after chemotherapy for PFS (12.9 months vs 9.0 months (HR 0.78, 95%CI 0.61 to 0.98. p=0.034)), ORR (67.8% and 55.6%, respectively, p=0.001). Overall survival in patients receiving first-line TKI followed by second-line chemotherapy was longer than in patients receiving TKI second-line after chemotherapy (30.7 months vs 27.2 months (HR 0.69, 95%CI 0.50 to 0.94, p=0.02) (17). Evidence supports the continuation of EGFR-TKI treatment beyond radiological progression in patients who are clinically stable (18). EGFR-TKI use in combination with local radiation therapy in patients with oligoprogressive disease, has also been shown to be associated with significantly longer PFS (19). The IMPRESS trial tested the continuation of gefitinib plus chemotherapy with placebo plus chemotherapy in patients with EGFR mutation-positive advanced NSCLC with progression after first-line gefitinib (20). The trial failed to show a benefit of the continuation strategy of the EGFR-TKI as add-on strategy; the continuation of gefitinib plus cisplatin and pemetrexed was detrimental to OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio [HR] 1.44, 95%CI 1.07 to 1.94; p=0.016; median OS, 13.4 v 19.5 months). Therefore, continuous use of EGFR-TKI in combination with chemotherapy is not recommended. The NEJ009 trial evaluated the efficacy of a combination of gefitinib and carboplatin/pemetrexed in untreated advanced NSCLC patients with EGFR mutations (21). Carboplatin/pemetrexed/gefitinib demonstrated better PFS (mPFS: 20.9 vs 11.2 months, HR 0.49, 95%CI 0.39 to 0.62) and OS (mOS: 52.2 vs 38.8 months, HR 0.69, 95%CI 0.52 to 0.92) compared with gefitinib monotherapy in advanced EGFR mutated NSCLC, representing a first-line therapy option. The choice between first- (gefitinib or erlotinib, (reversible)) and second-generation (afatinib, (irreversible)) EGFR-TKIs was investigated in two randomized studies. The Phase IIB LUX-Lung 7 trial compared afatinib with gefitinib (22). The study reported similar tumour ORR and a modest nonclinically meaningful difference in PFS (mPFS 11.0 vs 10.9 months; HR 0.73, 95%CI 0.57 to 0.95, p=0.0165). OS was not statistically different (23). There was no difference in OS in patients with EGFR exon 19 mutation, contrary to earlier claims of benefit in this sub-group from the pooled analysis of LUX-Lung 3 and LUX-Lung 6 studies (24). ARCHER 1050 is a randomized Phase III study that compared dacomitinib (a second-generation EGFR-TKI) with gefitinib in stage IV EGFRmutated lung cancer patients without central nervous system (CNS) metastasis (25, 26). The study showed an improved PFS in the dacomitinib arm (mPFS 14.7 vs 9.2 months; HR 0.59, 95%CI 0.47 to 0.74, p<0.0001). The mOS was 34.1 months with dacomitinib vs 26.8 months with gefitinib (HR 0.76, 95%CI 0.58 to 0.993, p<0.04). The OS probabilities at 30 months were 56.2% and 46.3% with dacomitinib and gefitinib, respectively.
The toxicity profile of EGFR-TKIs is generally clinically manageable, with 6% of toxicity-related treatment discontinuation reported in one pooled analysis (27, 28). The use of EGFR-TKI was favoured over chemotherapy in quality of life (QoL) analyses, reporting a longer time to clinical deterioration and maintained overall QoL (29–31). For afatinib, an extensive investigation of patient-reported symptoms and health-related QoL benefits have been reported, showing that afatinib delayed the time to deterioration for cough (HR 0.60, 95%CI 0.41 to 0.87; p=0.007) and dyspnoea (HR 0.68, 95%CI 0.50 to 0.93; p=0.015), with more patients on afatinib (64%) versus chemotherapy (50%) experiencing improvements in dyspnoea scores (p=0.010), the cardinal symptom for lung cancer patients (32). For erlotinib, a secondary analysis from the OPTIMAL (CTONG-0802) Phase III clinical trial, showed that patients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group, across different scales to assess general outcome and lung-specific subscales (33). Data for gefitinib are still consistent with the findings for the other two EGFR-TKIs: time to deterioration in physical and life well-being favoured gefitinib over chemotherapy (HR of time to deterioration, 0.34, 95%CI 0.23 to 0.50; p<0.0001 and HR 0.43, 95%CI 0.28 to 0.65; p<0.0001, respectively) (29).
Cost / cost effectiveness
A cost-effectiveness analysis performed by the Institute for Clinical and Economic Review showed that the use of each of the first-line EGFR-TKI regimens resulted in a 0.84 life-year gain in survival relative to chemotherapy. Quality-adjusted life-years (QALYs) gained versus chemotherapy were also very similar, ranging from 0.60 for gefitinib to 0.62 for afatinib and erlotinib. Incremental costs versus chemotherapy were lower for gefitinib (approximately US$ 66 000) than for the other EGFR-TKIs, as a function of a shorter duration of time spent in the progression-free state (and a consequently shorter duration of treatment). Cost-effectiveness estimates were similar across the EGFR-TKIs, ranging from approximately US$ 110 000 to US$ 150 000 per QALY gained (34). In another cost-effectiveness analysis, two different strategies were compared: the ‘EGFR testing strategy’, in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the ‘notesting strategy,’ in which genetic testing was not conducted and all patients were treated with standard chemotherapy. The authors concluded that the combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin-paclitaxel for the treatment for NSCLC in Japan (35). Technology appraisal guidance issued by National Institute for Health and Care Excellence (NICE) for first-line EGFR-TKIs gefitinib, erlotinib and afatinib state that these medicines are recommended treatment options people with locally advanced or metastatic EGFR mutation-positive NSCLC if the manufacturers provide the drugs at agreed fixed or discounted prices (36–38).
Originator brands of afatinib, erlotinib and gefitinib are manufactured by Boehringer Ingelheim, Roche and AstraZeneca, respectively. Generic brands are becoming available.
Comments on the application were received from the WHO Department of Management of NCDs, Disability, Violence and Injury Prevention. The technical unit advised that it supported the inclusion of EGFR TKIs on the EML, stating that there is sufficient evidence that these medicines are equivalent or superior to existing listed medicines, based on updated meta-analysis and real-world data, particularly in middle-income countries. Based on the results of the LUX-Lung 3 study (14, 32), afatinib received a score of 4 on the ESMO-Magnitude of Clinical Benefit Scale (MCBS, v1.1) for first-line use in metastatic EGFR+ NSCLC (39). Based on the results of the OPTIMAL (40) and EURTAC (13) studies, erlotinib received a score of 4 on the ESMO-MCBS v1.1 for use in metastatic EGFR+ NSCLC (39). Based on the results of the IPASS study (10, 41), gefitinib received a score of 4 on the ESMO-MCBS v1.1 for first-line use in metastatic EGFR+ NSCLC (39).
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2015 (including the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines for Children) (WHO Technical Report Series, No. 994). Geneva: World Health Organization; 2015. Available from https://apps.who.int/iris/bitstream/handle/10665/189763/9789241209946_eng.pdf, accessed 30 October 2019. 2. The selection and use of essential medicines. Report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children) (WHO Technical Report Series, No. 1006). Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/handle/10665/259481/9789241210157-eng.pdf, accessed 30 October 2019. 3. Pearce A, Sharp L, Hanly P, Barchuk A, Bray F, de Camargo Cancela M et al. Productivity losses due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): A population-based comparison. Cancer Epidemiol. 2018;53:27–34. 4. Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME. The International Epidemiology of Lung Cancer: Latest Trends, Disparities, and Tumor Characteristics. J Thorac Oncol. 2016;11(10):1653–71. 5. Morgensztern D, Ng SH, Gao F, Govindan R. Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol. 2010;5(1):29–33. 6. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892–911. 7. Benbrahim Z, Antonia T, Mellas N. EGFR mutation frequency in Middle East and African non-small cell lung cancer patients: a systematic review and meta-analysis. BMC Cancer. 2018;18(1):891. 8. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):95867. 9. Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Supplement_4):iv192–iv237. 10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. 11. Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122–8. 12. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8. 13. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E 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):239–46. 14. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34. 15. Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22. 16. Nan X, Xie C, Yu X, Liu J. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget. 2017;8(43):75712–26. 17. Xu J, Zhang X, Yang H, Ding G, Jin B, Lou Y et al. Comparison of outcomes of tyrosine kinase inhibitor in first- or second-line therapy for advanced non-small-cell lung cancer patients with sensitive EGFR mutations. Oncotarget. 2016;7(42):68442–8. 18. Park K, Yu CJ, Kim SW, Lin MC, Sriuranpong V, Tsai CM et al. First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study. JAMA Oncol. 2016;2(3):305–12. 19. Jiang T, Chu Q, Wang H, Zhou F, Gao G, Chen X et al. EGFR-TKIs plus local therapy demonstrated survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC patients with oligometastatic or oligoprogressive liver metastases. Int J Cancer. 2018; 144(10):2605–2612. 20. Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ et al. Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses. J Clin Oncol. 2017;35(36):4027–34. 21. Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol. 2018;36(15_suppl):9005. 22. Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577–89. 23. Paz-Ares L, Tan EH, O'Byrne K, Zhang L, Hirsh V, Boyer M et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28(2):270–7. 24. Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-51. 25. Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S 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):2244–50. 26. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–66. 27. Takeda M, Nakagawa K. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor gene mutation-positive lung cancer. Mol Clin Oncol. 2017;6(1):3-6. 28. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74–9. 29. Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H et al. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863–70. 30. Metro G. EGFR targeted therapy for lung cancer: are we almost there? Transl Lung Cancer Res. 2018;7(Suppl 2):S142–s5. 31. Kohler J, Schuler M. Afatinib, erlotinib and gefitinib in the first-line therapy of EGFR mutation-positive lung adenocarcinoma: a review. Onkologie. 2013;36(9):510–8. 32. Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3342–50. 33. Chen G, Feng J, Zhou C, Wu YL, Liu XQ, Wang C et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol. 2013;24(6):1615–22. 34. Treatment options for advanced non-small cell lung cancer: Effectiveness, value and value-based price benchmarks. Evidence Report. Boston: Institute for Clinical and Economic Review; 2016. [Available late-2019]. 35. Narita Y, Matsushima Y, Shiroiwa T, Chiba K, Nakanishi Y, Kurokawa T, et al. Cost-effectiveness analysis of EGFR mutation testing and gefitinib as first-line therapy for non-small cell lung cancer. Lung Cancer. 2015;90(1):71–7. 36. Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. Technology appraisal guidance [TA192]. London: National Institute for Health and Care Excellence; 2010. Available from https://www.nice.org.uk/guidance/ta192, accessed 29 September 2019. 37. Afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer. Technology appraisal guidance [TA310] 23 April 2014. London: National Institute for Health and Care Excellence; 2014. Available from https://www.nice.org.uk/guidance/TA310, accessed 29 September 2019. 38. Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small-cell lung cancer. Technology appraisal guidance [TA258]. London: National Institute for Health and Care Excellence; 2012. Available from https://www.nice.org.uk/guidance/TA258, accessed 29 September 2019. 39. ESMO-Magnitude of Clinical Benefit Scale. The ESMO-MCBS Score Card. Lugano: European Society for Medical Oncology. Available from https://www.esmo.org/score/cards, accessed 29 September 2019. 40. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C 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):735–42. 41. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–74.