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  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  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


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 Publication29-Dec-2017

Correspondence Address:
Dr. B Biswas
Department of Medical Oncology, Tata Medical Centre, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_589_17

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 » Abstract 


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 2019 Aug 21];54, Suppl S1:55-64. Available from: http://www.indianjcancer.com/text.asp?2017/54/5/55/221927





 » Introduction Top


Lung cancer is the leading cause of cancer deaths globally.[1] 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.[2] The estimated incidence of lung cancer in India was 70,275 in both sexes and all ages as per the GLOBOCAN 2012 report.[3] More than 80% of lung cancers are detected at an advanced stage where curative treatment is not possible.[4] 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.[5]

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.[6] EGFR mutations in lung adenocarcinoma are higher among Asian population than Whites, with an incidence ranging from approximately 20%–80% among Asians.[7],[8],[9],[10] 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.[6],[11]

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.[11] While EGFR TKIs have demonstrated superiority over chemotherapy as first-line agents in the treatment of EGFR-mutant NSCLC,[12],[13] their role in patients who do not harbor activating mutations (wild-type EGFR) is controversial.[11] 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.[14] 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.[15]

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 Top


Erlotinib

Erlotinib has shown efficacy as second- or third-line agent in the previously treated NSCLC patients [16] as well as first-line agent in patients with EGFR-mutated advanced NSCLC.[13],[17],[18],[19] [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.
Table 1: Adverse events with erlotinib across various clinical trials

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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.[17] 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.[22]

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.[13] 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.[21]

Gefitinib

Gefitinib has better safety profile compared to chemotherapy when used as a first-line agent in NSCLC patients.[12],[23],[24] [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.
Table 2: Adverse events with gefitinib across various clinical trials

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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.[24] 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).[23]

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.[12]


 » Adverse Events With Second-Generation Tyrosine Kinase Inhibitors Top


Afatinib

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.[31] 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 [32] [Table 3].
Table 3: Adverse events with afatinib across various clinical trials

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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.[31]

Dacomitinib

Dacomitinib is an irreversible pan-human EGFR TKI and has shown improved progression-free survival in patients with advanced NSCLC as compared to erlotinib [37] [Table 4].
Table 4: Adverse events with dacomitinib across various clinical trials

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 » Adverse Events With Third-Generation Tyrosine Kinase Inhibitors Top


Osimertinib

Osimertinib irreversibly and selectively targets both sensitizing and resistant T790M EGFR mutations while demonstrating less activity toward wild-type EGFR.[40] 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 [41] [Table 5].
Table 5: Adverse events with osimertinib across various clinical trials

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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.[43]

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.[45] 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.[46]

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.[47]


 » Comparison of Adverse Events between Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Inhibitors Top


[Table 6] summarizes some of the common AEs with EGFR TKIs across various trials.[12],[13],[17],[23],[31],[33],[43]
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.[48]

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.[36]

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.[39]

Osimertinib versus erlotinib/gefitinib

Trials comparing osimertinib with the first-generation EGFR TKIs in patients with advanced NSCLC are ongoing.[49],[50] 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.[51]

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 Top


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).[52] 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.[53] 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%).[54] In terms of skin toxicity, gefitinib was observed to have a better safety profile as compared to erlotinib among Indian patients.[55]


 » Prevention and Management of Adverse Events With Tyrosine Kinase Inhibitors Top


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.[56]

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.[57] Lotions need to be avoided as they contain alcohol and creams and ointments should be preferred.[58]

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.[58] The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.[59]
Table 7: Management of acneiform rash in patients taking epidermal growth factor receptor tyrosine kinase inhibitors

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Paronychia

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.[57]

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.[58]

Diarrhea

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.[56] 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.[60] The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.[59]
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.[57]

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.[58] The grading of toxicity is based on U.S. National Cancer Institute's Common Terminology Criteria for AEs.[59]
Table 8: Management of stomatitis/mucositis in patients taking epidermal growth factor receptor tyrosine kinase inhibitors

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Hepatotoxicity

Majority of patients with levels of aminotransferases (less than CTCAE grade 3)[59] 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.[56]

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.[56]


 » Conclusion Top


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.

Acknowledgments

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.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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