|Year : 2017 | Volume
| Issue : 5 | Page : 55-64
A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients
B Biswas1, N Ghadyalpatil2, MV Krishna3, J Deshmukh4
1 Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Medical Oncology, Yashoda Hospitals, Hyderabad, Telangana, India
3 Department of Medical Oncology, Apollo Cancer Institutes, Hyderabad, Telangana, India
4 Medical Affairs, AstraZeneca Pharma Limited, Bengaluru, Karnataka, India
|Date of Web Publication||29-Dec-2017|
Dr. B Biswas
Department of Medical Oncology, Tata Medical Centre, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-mutant nonsmall cell lung cancer (NSCLC). These EGFR TKIs demonstrate a different adverse event (AE) profile as compared to conventional chemotherapy agents. They are more commonly associated with cutaneous AEs and diarrhea while hematological AEs occurred commonly with chemotherapy agents. These AEs are the extension of pharmacological effect and occur as a result of blockade of EGFR-regulated pathways in the skin and gastrointestinal tract. This review article sheds light on the safety profile of first-, second-, and third-generation EGFR TKIs based on data obtained from several clinical trials conducted in NSCLC patients and highlights trials comparing these agents with the conventional chemotherapy agents. The strategies to manage EGFR TKI-related AEs are also reviewed.
Keywords: Adverse events, epidermal growth factor receptor, nonsmall cell lung cancer, tyrosine kinase inhibitors
|How to cite this article:|
Biswas B, Ghadyalpatil N, Krishna M V, Deshmukh J. A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients. Indian J Cancer 2017;54, Suppl S1:55-64
|How to cite this URL:|
Biswas B, Ghadyalpatil N, Krishna M V, Deshmukh J. A review on adverse event profiles of epidermal growth factor receptor-tyrosine kinase inhibitors in nonsmall cell lung cancer patients. Indian J Cancer [serial online] 2017 [cited 2021 Jul 31];54, Suppl S1:55-64. Available from: https://www.indianjcancer.com/text.asp?2017/54/5/55/221927
| » Introduction|| |
Lung cancer is the leading cause of cancer deaths globally. In India, lung cancer is responsible for 9.3% of all cancer-related deaths and constitutes 6.9% of all new cancer cases in both sexes. The estimated incidence of lung cancer in India was 70,275 in both sexes and all ages as per the GLOBOCAN 2012 report. More than 80% of lung cancers are detected at an advanced stage where curative treatment is not possible. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer. There has been a shift in the pathological distribution of NSCLC in India with adenocarcinoma being the most common histological type over the earlier predominant squamous cell carcinoma.
Genomic profiling in NSCLC has led to the identification of actionable driver genes such as epidermal growth factor receptor (EGFR) mutations, which can enable genotype-directed biomarker-driven type of treatment in lung cancer. The targetable genetic mutations in lung adenocarcinoma include EGFR, BRAF, and HER2 mutations, while actionable genetic rearrangements include anaplastic lymphoma kinase rearrangements, ROS1, and RET rearrangements. EGFR mutations in lung adenocarcinoma are higher among Asian population than Whites, with an incidence ranging from approximately 20%–80% among Asians.,,, The two most common EGFR-activating mutations in NSCLC include in-frame deletion around the LREA motif of exon 19 and L858R substitution mutation in exon 21.,
The discovery of mutant EGFR paved the way for targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. These agents such as gefitinib and erlotinib act as reversible competitive inhibitors of adenosine triphosphate (ATP) for the tyrosine kinase domain of EGFR. The inhibition of mutant EGFR results in blockade of downstream signaling pathways such as RAS-RAF-MEK-ERK or MAPK pathway and the PI3K-AKT-mTOR pathways. This results in the inhibition of tumor cell proliferation and survival. While EGFR TKIs have demonstrated superiority over chemotherapy as first-line agents in the treatment of EGFR-mutant NSCLC,, their role in patients who do not harbor activating mutations (wild-type EGFR) is controversial. The tumor cells eventually develop resistance to the TKIs and will have tumor progression. The most common cause of acquired resistance to first- and second-generation EGFR TKIs is the T790M mutation. This mutation alters the affinity of EGFR TKIs for ATP-binding site leading to failure of therapy. In the patients with EGFR T790M mutation resistance to first- or second-generation EGFR TKIs, third-generation EGFR TKI osimertinib has been approved for treatment of NSCLC patients in many countries including India.
While EGFR TKIs have transformed the treatment landscape of NSCLC, they have also introduced unique challenges in terms of a different side effect profile from conventional chemotherapy. In this review, we discuss the adverse events (AEs) due to EGFR TKIs obtained from clinical trials. In addition, we provide a brief overview on the management of these adverse effects.
| » Adverse Events With The first-Generation Tyrosine Kinase Inhibitors|| |
Erlotinib has shown efficacy as second- or third-line agent in the previously treated NSCLC patients  as well as first-line agent in patients with EGFR-mutated advanced NSCLC.,,, [Table 1] lists the number of grade ≥3 AE, common AE, percentage of treatment-related serious AEs (SAEs), AE leading to dose modification or permanent discontinuation, and number of AE leading to death with erlotinib.
Erlotinib versus chemotherapy
In the EURTAC trial comparing first-line erlotinib with standard chemotherapy in advanced NSCLC patients, the incidence of grade 3 or 4 AE was 67% in standard chemotherapy group as compared to 45% in erlotinib group. Treatment-related SAEs and AE leading to discontinuation occurred at a higher rate in standard chemotherapy group as compared to erlotinib group (20% vs. 6%). The incidence of pneumonitis was similar between the groups and neutropenia did not occur in the erlotinib group. Wu et al. also reported higher rate of grade 3 or more AE and treatment-related SAEs in gemcitabine/paclitaxel (10.6%) group as compared to erlotinib (2.7%) group. While the most common grade 3 or 4 AE in erlotinib group was rash, neutropenia occurred most commonly in chemotherapy group.
The OPTIMAL study reported a higher incidence of neutropenia, thrombocytopenia, and anemia of any grade in gemcitabine and carboplatin group as compared to erlotinib group. These events of grade 3 or more severity did not occur in erlotinib group. Erlotinib group experienced lesser grade 3 or 4 AEs, treatment-related SAEs, rate of dose reduction, and discontinuation in comparison to chemotherapy group. In chemo-naïve elderly patients with advanced NSCLC, decreased appetite occurred more frequently in vinorelbine group, and skin rash, mouth ulceration, and diarrhea were more frequent in erlotinib group which was significant.
Gefitinib has better safety profile compared to chemotherapy when used as a first-line agent in NSCLC patients.,, [Table 2] lists the number of grade ≥3 AEs, common AE, percentage of treatment-related SAEs, AE leading to dose modification or permanent discontinuation, and number of AE leading to death with gefitinib.
Gefitinib versus chemotherapy
In the first-SIGNAL trial, the incidence of grade 3 or 4 AEs was higher in gemcitabine and cisplatin group as compared to gefitinib group (68% vs. 28.9%). While hematological AEs, fatigue, alopecia, and nausea were more frequent in the chemotherapy group, skin rash and elevated liver enzymes were more common in gefitinib patients. Two patients in gefitinib arm who had underlying comorbidities died after developing interstitial lung disease (ILD) while one patient died due to pulmonary thromboembolism in chemotherapy group. Similarly, Mok et al. also reported a lower rate of grade 3 or 4 AEs with gefitinib as compared to carboplatin and paclitaxel chemotherapy. The rate of AEs leading to treatment discontinuation or dose modification was also lower in gefitinib group. ILD events occurred more commonly in gefitinib as compared to chemotherapy group (2.6% vs. 1.4%, respectively).
Grade 3 or more reactions were less frequent with gefitinib treatment except for elevated liver enzymes as reported by Mitsudomi et al. ILD leading to death was also reported in one gefitinib-treated patient while no death occurred in cisplatin plus docetaxel group.
| » Adverse Events With Second-Generation Tyrosine Kinase Inhibitors|| |
Afatinib exerts sustained and broad-spectrum anti-mitogenic effects by covalently and irreversibly binding to proteins of the ErbB receptor family. Afatinib has shown efficacy as a first-line agent in treatment of EGFR-positive advanced NSCLC in terms of improvement in progression-free survival as compared to gemcitabine and cisplatin chemotherapy. In patients with EGFR-mutant-positive advanced NSCLC, the progression-free survival, time to treatment failure, and overall response rate significantly improved with afatinib as compared to gefitinib  [Table 3].
Afatinib versus chemotherapy
In the LUX-Lung 6 trial comparing the first-line afatinib with cisplatin plus gemcitabine in patients with advanced NSCLC, the rate of AEs of grade 3 or more was higher in the chemotherapy group (60.2%) as compared to afatinib group (36%). The incidence of treatment-related AEs leading to permanent discontinuation was greater in the chemotherapy group, and treatment-related SAEs were reported by 39.8% of patients in chemotherapy group as compared to 5.9% in afatinib group. One patient in the afatinib group developed interstitial pneumonitis that was treatment-related. Afatinib and chemotherapy group reported one sudden death and a death due to cardiac failure, respectively.
Dacomitinib is an irreversible pan-human EGFR TKI and has shown improved progression-free survival in patients with advanced NSCLC as compared to erlotinib  [Table 4].
| » Adverse Events With Third-Generation Tyrosine Kinase Inhibitors|| |
Osimertinib irreversibly and selectively targets both sensitizing and resistant T790M EGFR mutations while demonstrating less activity toward wild-type EGFR. In patients with disease progression after previous EGFR TKI therapy, osimertinib was found to be highly effective in terms of overall response rate and progression-free survival in patients harboring EGFR T790M mutation  [Table 5].
Osimertinib versus chemotherapy
Grade 3 or more AEs were reported by fewer patients in osimertinib group (23%) as compared to platinum-pemetrexed group (47%). While the most frequent AEs in osimertinib group were diarrhea, rash, dry skin, and paronychia, the common AEs with chemotherapy group were nausea, decreased appetite, constipation, and anemia. Osimertinib was associated with lower rate of AEs leading to permanent discontinuation as compared to platinum-pemetrexed group. Osimertinib was associated with ILD-like AEs (4%) and prolongation of QT interval (4%). The rate of these AEs was lower in chemotherapy group as compared to osimertinib group.
Other third-generation epidermal growth factor receptor-tyrosine kinase inhibitors
Rociletinib is an irreversible EGFR TKI inhibitor that binds covalently and selectively inhibits mutant EGFR without inhibiting wild-type EGFR. It has shown promise in treatment of T790M mutant NSCLC in preclinical models. By its selective action on mutant EGFR, toxicities associated with inhibition of wild-type EGFR is avoided. Sequist et al. reported mild and less frequent treatment-related AEs with rociletinib and hyperglycemia was the most predominant grade 3 AE. Rociletinib was also associated with grade 3 prolongation of QTc interval (5%) and the development of rociletinib was stopped in 2016.
Olmutinib, a third-generation EGFR TKI, is associated with treatment-related AEs such as diarrhea, decreased appetite, rash, pruritus, dry skin, skin exfoliation, and nausea. The most commonly occurring AEs with nazartinib include diarrhea, rash, pruritus, and stomatitis.
| » Comparison of Adverse Events between Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Inhibitors|| |
[Table 6] summarizes some of the common AEs with EGFR TKIs across various trials.,,,,,,
|Table 6: Adverse events with erlotinib, gefitinib and afatinib across various trials|
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Erlotinib versus gefitinib
A phase III randomized controlled trial conducted in patients with EGFR-mutant advanced NSCLC showed no significant difference in the incidence of grade ≥3 AEs between erlotinib and gefitinib. The common treatment-emergent AEs with erlotinib were rash, cough, and nail changes and with gefitinib were rash, cough, and diarrhea. There were no reports of ILD in both the groups.
Afatinib versus erlotinib
In the LUX-Lung 8 trial, the proportion and severity of AEs and SAEs were similar in the afatinib and erlotinib groups. Ninety-three percent of patients in afatinib group experienced drug-related AEs with most commonly occurring AEs being diarrhea, fatigue, stomatitis, and rash or acne. Treatment-related AEs occurred in 81% of patients in erlotinib group and the most frequent AEs in this group were diarrhea, fatigue, rash or acne, and pruritus. While the incidence of grade 3 rash was higher with erlotinib, grade 3 stomatitis and diarrhea were higher with afatinib treatment. AE leading to dose reduction occurred in 27% and 14% of patients in afatinib and erlotinib groups, respectively. Six treatment-related deaths occurred in afatinib group and five occurred in erlotinib group.
Dacomitinib versus erlotinib
In a pooled analysis of two randomized trials, ARCHER 1009 and A7471028, Ramalingam et al. reported that stomatitis, paronychia, diarrhea, and mucosal inflammation occurred more frequently in dacomitinib group compared with erlotinib group.
Osimertinib versus erlotinib/gefitinib
Trials comparing osimertinib with the first-generation EGFR TKIs in patients with advanced NSCLC are ongoing., In a planned primary analysis, 34% patients on osimertinib experienced grade 3 or more AEs compared to 45% patients on erlotinib/gefitinib as presented in European Society for Medical Oncology 2017 congress recently.
A graphical representation of frequency of grade ≥3 AEs across various trials of erlotinib, gefitinib, afatinib, and osimertinib is shown in [Figure 1].
|Figure 1: Percentage of grade ≥3 adverse reactions with erlotinib, gefitinib, afatinib, and osimertinib|
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| » Clinical Experience With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Indian Lung Cancer Patients|| |
Singh et al. identified skin rash (17.6%) and diarrhea (10.6%) to be the most common AEs occurring in 76 newly diagnosed NSCLC patients treated with oral EGFR TKIs. Skin rash was observed to be an independent and significant predictor of objective response rate and overall survival. A better response to treatment and median overall survival was observed in patients with skin rash as compared to patients without skin rash (100% and median not reached versus 23.1% and 178 days, respectively). A retrospective analysis of tolerability data of Indian patients treated with gefitinib in ISEL trial revealed that gefitinib was associated with lower incidence of withdrawals due to AEs, lower incidence of AEs of all grades as well as grade 3/4 AEs, and lower incidence of deaths due to AEs as compared to placebo. The tolerability data of Indian patients was consistent with overall population, except for frequency of deaths due to AEs, which was slightly higher than overall ISEL population (11% vs. 5%). However, this was less likely to be treatment related. When compared to pemetrexed carboplatin doublet chemotherapy, first-line gefitinib in patients with advanced adenocarcinoma was associated with more grade 3/4 acneiform rash (69.7% vs. 28.4%) and diarrhea (46.2% vs. 27.7%) and less grade 3/4 anemia (53.1% vs. 78.7%), neutropenia (2.8% vs. 37.6%), and thrombocytopenia (6.9% vs. 40.4%). In terms of skin toxicity, gefitinib was observed to have a better safety profile as compared to erlotinib among Indian patients.
| » Prevention and Management of Adverse Events With Tyrosine Kinase Inhibitors|| |
Cutaneous adverse events
The blockade of EGFR function by EGFR TKIs affects the differentiation and maturation of skin and stimulates the release of pro-inflammatory cytokines. This results in changes in the structure of dermis and impairs the epithelium to produce cutaneous AEs.
Cutaneous AEs can be prevented by intensively moisturizing the skin using emollients and protecting the skin from sunlight by covering the exposed areas and by using sunscreens. Products such as soaps that dehydrate the skin should be avoided. Lotions need to be avoided as they contain alcohol and creams and ointments should be preferred.
The acneiform rash which typically occurs on face, shoulders, upper chest, and back should be closely monitored every week for the first 6 weeks. It is important to educate the patients regarding EGFR TKI-induced rash before starting treatment and to contact healthcare provider if the rash becomes troublesome. [Table 7] shows the treatment algorithm for management of acneiform rash with EGFR TKIs. The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.
|Table 7: Management of acneiform rash in patients taking epidermal growth factor receptor tyrosine kinase inhibitors|
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It is important to avoid skin irritants, to avoid soaking of hands and feet for prolonged time period in soapy water, and to make sure that feet is dry before putting on shoes. Care should be taken while cutting nails and cotton gloves should be used to protect hands while washing.
The strategies for local care in paronychia include cushioning of the involved areas, use of emollients such as petroleum jelly, and antimicrobial soaks of the affected areas. For paronychial inflammation of up to grade 2 severity, betamethasone valerate should be applied two to three times as needed and EGFR TKI can be continued at the current dose. However, for grade 3 paronychia, EGFR TKI has to be temporarily discontinued for 2 weeks and restarted upon improvement (grade 1 or less) at a dose based on treating doctor's judgment. Clobetasol cream has to be applied for severe paronychia. In case there is no improvement, EGFR TKI has to be permanently discontinued.
The administration of EGFR TKIs may cause impairment of intestinal crypts and also cause excess secretion of chloride into the lumen which can lead to diarrhea in patients. In patients on EGFR TKI treatment experiencing diarrhea, greasy, spicy, fried food items, and food that are difficult to digest such as cabbage should be avoided. A diet consisting of bananas, rice, toast, and apple sauce can be consumed until symptoms start to resolve. A fluid intake of 3–4 l daily is essential with some fluids containing sugar and salt to combat dehydration, hyponatremia, and hypokalemia. [Figure 2] depicts the treatment algorithm for EGFR TKI-induced diarrhea. The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.
|Figure 2: Management of diarrhea in patients taking epidermal growth factor receptor tyrosine kinase inhibitor. (a) Starting dose is 4 mg followed by 2 mg to a maximum of 20 mg daily. Adapted from: Hirsh V. Managing treatment-related adverse events associated with epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall-cell lung cancer. Curr Oncol 2011;18:126-38|
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Stomatitis and mucositis
Stomatitis/mucositis can be prevented by consuming foods that are easier to chew and swallow, taking lot of fluids, supplementing meals with high protein or calorie drinks, and maintaining good oral hygiene by using nonalcoholic mouthwash and by avoiding spicy, rough, and acidic foods.
Oral care should be performed every 2–3 h by patients with mild stomatitis and every 1–2 h in patients with moderate-to-severe symptoms. Oral care regimen consists of use of soft-bristle brush for brushing teeth and tongue, rinsing, flossing, and moisturizing. [Table 8] depicts the management of various grades of stomatitis/mucositis induced by EGFR TKIs. The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.
|Table 8: Management of stomatitis/mucositis in patients taking epidermal growth factor receptor tyrosine kinase inhibitors|
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Majority of patients with levels of aminotransferases (less than CTCAE grade 3) are asymptomatic and do not require adjustment of EGFR TKI treatment. However, in those with grade 3 or higher level of aminotransferases, EGFR TKI therapy has to be discontinued temporarily after ruling out other etiologies of liver dysfunction. It can then be reintroduced once the toxicity grade drops to grade 1 or less. In case the event recurs, dose modification needs to be done.
Interstitial lung disease
The underlying mechanism for the occurrence of ILD in patients administered EGFR TKIs is not clear but may be attributed to the decrease in the protective function of EGFR that are localized in type 2 pneumocytes. In patients with suspected ILD, treatment with EGFR TKI should be discontinued until the diagnosis is confirmed. Once confirmed, treatment should be stopped irrespective of severity of ILD and the patient should be started on methylprednisolone 1 g daily intravenously over 3 days. It is then switched to an oral dose of 60 mg/day and gradually taper the dose by 10 mg/week.
| » Conclusion|| |
EGFR TKIs have revolutionized the treatment of EGFR-positive advanced NSCLC. The AEs with EGFR TKIs are generally mild to moderate and are associated with low rates of discontinuation. The AEs are manageable, and if managed appropriately, unnecessary dose reductions or discontinuation of these effective therapies can be prevented.
We acknowledge AstraZeneca Pharma India Ltd and Indegene Lifesciences for medical writing and editing support.
Financial support and sponsorship
Financial support to authors - Nil.
The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94.
Malik PS, Raina V. Lung cancer: Prevalent trends & emerging concepts. Indian J Med Res 2015;141:5-7.
] [Full text]
Noronha V, Pinninti R, Patil VM, Joshi A, Prabhash K. Lung cancer in the Indian subcontinent. South Asian J Cancer 2016;5:95-103.
] [Full text]
Chatterjee S, Misra S, Das I, Chakraborty R, Saha K, Kundu S, et al
. A cross-sectional study on different time intervals from the appreciation of symptoms to final diagnosis in inoperable primary lung cancer: An Eastern Indian experience. J Assoc Chest Physicians 2016;4:63. [Full text]
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George K, et al.
Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer 2012;49:74-81.
] [Full text]
Okimoto RA, Bivona TG. Recent advances in personalized lung cancer medicine. Per Med 2014;11:309-21.
Raparia K, Villa C, DeCamp MM, Patel JD, Mehta MP. Molecular profiling in non-small cell lung cancer: A step toward personalized medicine. Arch Pathol Lab Med 2013;137:481-91.
Li C, Sun Y, Fang Z, Han X, Fang R, Zhang Y, et al.
Comprehensive analysis of epidermal growth factor receptor gene status in lung adenocarcinoma. J Thorac Oncol 2011;6:1016-21.
Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al.
The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 2005;11:1167-73.
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;5:2892-911.
Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future. Transl Lung Cancer Res 2015;4:36-54.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, 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, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.
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;12:735-42.
Sacher AG, J, Open-Label, Randomised, Phase 3 Study. Lancet Oncol 2011;12:735-4growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer. Cancer 2014;120:2289-98.
TAGRISSO prescribing information.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previously treated non-small-cell lung cancer. N
Engl J Med 2005;353:123-32.
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;13:239-46.
Costa C, Molina MA, Drozdowskyj A, Gimskyjlina MA, abel, Randomised Phase 3 Trial. Lancet et al.
The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 2014;20:2001-10.
Goto K, Nishio M, Yamamoto N, Chikamori K, Hida T, Maemondo M, et al.
Aprospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). Lung Cancer 2013;82:109-14.
Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al.
First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): A double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2012;13:1161-70.
Chen YM, Tsai CM, Fan WC, Shih JF, Liu SH, Wu CH, et al.
Phase II randomized trial of erlotinib or vinorelbine in chemonaive, advanced, non-small cell lung cancer patients aged 70 years or older. J Thorac Oncol 2012;7:412-8.
Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al.
First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-9.
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;361:947-57.
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;30:1122-8.
Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al.
Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial RIANTACT 1. J Clin Oncol 2004;22:777-84.
Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al.
Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial RIANTACT 2. J Clin Oncol 2004;22:785-94.
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005;366:1527-37.
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al.
Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809-18.
Crindomised phase III trial. Lancet 2008;372:1809-18.-small-cell et al.
Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): A randomized, phase II study. J Clin Oncol 2008;26:4253-60.
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al.
First-line gefitinib in caucasian EGFR mutation-positive NSCLC patients: A phase-IV, open-label, single-arm study. Br J Cancer 2014;110:55-62.
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;15:213-22.
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;28:270-7.
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;31:3327-34.
Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al.
LUX-lung 4: A phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013;31:3335-41.
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;17:577-89.
Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al.
Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-lung 8): An open-label randomised controlled phase 3 trial. Lancet Oncol 2015;16:897-907.
Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, et al.
Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2012;30:3337-44.
Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, et al.
Aphase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer 2014;120:1145-54.
Ramalingam SS, O'Byrne K, Boyer M, Mok T, Jänne PA, Zhang H, et al.
Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): Pooled subset analyses from two randomized trials. Ann Oncol 2016;27:423-9.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al.
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.
J61.046-61.n irreversible EPlanchard D, Ohe Y, Ramalingam SS, et al.
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N
Engl J Med 2015;372:1689-99.
Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, et al.
Osimertinib for pretreated EGFR thr790Met-positive advanced non-small-cell lung cancer (AURA2): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2016;17:1643-52.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al.
Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N
Engl J Med 2017;376:629-40.
Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, et al.
Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol 2017;35:1288-96.
Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al.
Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 2013;3:1404-15.
Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al.
Rociletinib in EGFR-mutated non-small-cell lung cancer. N
Engl J Med 2015;372:1700-9.
Barnes TA, O'Kane GM, Vincent MD, Leighl NB. Third-generation tyrosine kinase inhibitors targeting epidermal growth factor receptor mutations in non-small cell lung cancer. Front Oncol 2017;7:113.
Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, et al.
Aphase III randomised controlled trial of erlotinib vs. gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017;116:568-74.
Remon J, Menis J, Hasan B, Peric A, De Maio E, Novello S, 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;18:583-8.
Singh N, Vishwanath G, Aggarwal AN, Behera D. Clinical experience on use of oral EGFR-TKIs as first-line treatment of advanced NSCLC from a tertiary care centre in North India and implications of skin rash. Indian J Chest Dis Allied Sci 2014;56:149-52.
Parikh P, Chang AY, Nag S, Digumarti R, Bhattacharyya GS, Doval DC, et al.
Clinical experience with gefitinib in Indian patients. J Thorac Oncol 2008;3:380-5.
Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R, et al.
Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open 2017;2:e000168.
Udupa KS, Rajendranath R, Sagar T, Thomas J. Differential toxicities of tyrosine kinase inhibitors in the management of metastatic lung cancer. Indian J Med Paediatr Oncol 2017;38:15-7.
] [Full text]
Pdupa KS, Rajendranath R, Sagar T, Thomas J. Differential toxicities of tyrosine kinase inhibitors in the management of
Califano R, Tariq N, Compton S, Fitzgerald DA, Harwood CA, Lal R, et al.
Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK. Drugs 2015;75:1335-48.
Melosky B, Leighl NB, Rothenstein J, Sangha R, Stewart D, Papp K, et al.
Management of egfr tki-induced dermatologic adverse events. Curr Oncol 2015;22:123-32.
Hirsh V. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol 2011;18:126-38.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]
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|[Pubmed] | [DOI]|