Updated: Wednesday, February 26, 2020
Commentary by JNCCN 360 Site Editor
David S. Ettinger, MD
Alex Grass Professor of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore
In the current NCCN Clinical Practice Guidelines in Oncology for Non-Small Cell Lung Cancer,1 five category 1 oral tyrosine kinase inhibitors are listed as options for treatment of patients with non–small cell lung cancer (NSCLC) with EGFR gene mutations exon 19 and exon 21 (L858R)—osimertinib, gefitinib, erlotinib, afatinib, and dacomitinib. The latter tyrosine kinase inhibitor, dacomitinib, was approved in September 2018 by the U.S. Food and Drug Administration (FDA) based on the results of the ARCHER 1050 study, showing the drug was more effective than gefitinib.2
It should be noted that the recommended dose of gefitinib is below the maximum tolerated dose, the dose of erlotinib is at the maximum tolerated dose, and the dose of afatinib is above the maximum tolerated dose. The recommended dose of afatinib is 40 mg orally daily, although approximately 50% of patients taking it have to reduce the dose to 30 mg orally daily because of toxicity.
The FDA approved afatinib for second-line therapy of squamous cell carcinoma after failure of platinum-based chemotherapy in 2016, regardless of the mutation status based on the LUX-Lung 8 study.3 In the study, afatinib was compared with erlotinib. When tested, 6% of patients were found to have had EGFR amplification. Afatinib was reported to be superior to erlotinib in terms of improvement in both progression-free and overall survival. It should be noted that EGFR mutations occur in less than 4% of patients with squamous cell carcinoma. I would wonder how many physicians actually use it [afatinib] in the treatment of patients with squamous cell carcinoma without an EGFR mutation?
[Editor’s note: The NCCN Guidelines1 removed a previous recommendation for afatinib as subsequent therapy for advanced squamous cell NSCLC based on the LUX-Lung 8 study, which showed a low response rate (6%).3 Afatinib is less efficacious and safe compared with other options and therefore is no longer recommended in this setting. The NCCN NSCLC Panel also removed a recommendation for afatinib in patients with metastatic NSCLC who have ERBB2 (HER2) mutations because there are more effective options.
The NCCN NSCLC Panel recommends osimertinib as the preferred first-line oral tyrosine kinase inhibitor (category 1) to treat patients with metastatic NSCLC who have an EGFR mutation whether or not they have a T790M mutation. It also should be noted that osimertinib penetrates into the brain better than other tyrosine kinase inhibitors, which is important because brain metastases are not uncommon in patients with lung cancer and in those patients with EGFR mutations.]
Since May 2017, when the Spotlight on the use of afatinib in the management of NSCLC was initially posted, an expanded indication has been added that includes the treatment of patients with NSCLC whose tumors harbor uncommon EGFR alterations.4 The expanded indication was based on three LUX-Lung trials, with a confirmed overall response rate, as assessed by independent radiology review, of 66% (95% confidence interval [CI] = 47%–81%). Among the 21 responders, the proportion of patients with a response duration of at least 12 months was 52%, and the proportion with response durations of at least 18 months was 33%.5
Based on these trials—LUX-Lung 2 (ClinicalTrials.gov identifier NCT00525148), LUX-Lung 3 (NCT00949650), and LUX-Lung 6 (NCT01121393)—durable responses were reported in a subset of 32 afatinib-treated patients with metastatic NSCLC harboring nonresistant EGFR mutations (S768I, L861Q, and/or G719X) other than exon 19 deletions or exon 21 L858R substitutions.6-8 The combined study results indicated that afatinib improved objective response rate, duration of response, disease control, progression-free survival, and overall survival. The U.S. Food and Drug Administration (FDA) initially approved afatinib in 2013 for the treatment of patients with metastatic NSCLC with exon 19 deletions or exon 21 L858R substitutions.9 In 2016, the FDA expanded the indication to include patients with squamous histology following disease progression on a platinum-based chemotherapy.10
Sequential Therapy With Afatinib
In an observational study published in Advances in Therapy, afatinib therapy in sequence with osimertinib therapy in patients with NSCLC who acquired the T790M mutation was determined to be a feasible therapeutic strategy for patients who acquire the T790M mutation, particularly those with del19-positive disease or Asian patients.11 This post hoc analysis of the noninterventional, global GioTag study12 provided further evidence of a prolonged clinical benefit with sequential afatinib and osimertinib therapy, with results in patients who received the approved 40-mg starting dose of afatinib.
Of note, patients with characteristics associated with a poor prognosis, such as those with an Eastern Cooperative Oncology Group performance status of at least 2 and stable brain metastases, also derived a clinical benefit with the sequential afatinib/osimertinib strategy.
Effectiveness of Afatinib in Patients Harboring Various Mutations
In a case report, second-line therapy with afatinib was found to be efficacious in a patient with NSCLC harboring a HER2 R896G mutation who had previously received platinum-based therapy but was tyrosine kinase inhibitor–naive.13 The patient in the study was a 63-year-old man with a long smoking history, who was diagnosed with stage IV squamous cell lung cancer. The patient received afatinib at 40 mg daily and achieved a partial response after 2 months of treatment.
An international study evaluated the efficacy and tolerability of second-line afatinib in patients with EGFR mutation–positive NSCLC after chemotherapy.14 Between October 2014 and June 2017, 70 patients were enrolled across 24 sites (including Egypt, Malaysia, the Philippines, Poland, Romania, Serbia, and Thailand). All patients had EGFR mutation–positive NSCLC, either an L858R mutation (20 patients [33%]), a del19 mutation (38 patients [63%]), or both mutations simultaneously (2 patients [3%]). The current findings confirmed the efficacy of 40 mg/day of afatinib as second-line therapy for tyrosine kinase inhibitor–naive patients with EGFR mutation–positive NSCLC, after failure of first-line chemotherapy. Half of the patients had a confirmed overall response, and the median duration of response exceeded 1 year. In addition, more than 80% of patients had confirmed disease control, with a median duration of 12 months. The median progression-free survival was 11 months.
An interesting aspect of afatinib’s activity was noted in a study in which afatinib overcame pemetrexed-acquired resistance in NSCLC cells harboring an EML4-ALK rearrangement.15 The investigators noted that the activation of EGFR-HER2 contributed to the acquisition of resistance to pemetrexed in EML4-ALK–rearranged NSCLC. However, the inhibition of this alternative survival signaling pathway with RNA interference against EGFR-HER2 and with afatinib seemed to overcome this resistance.
Patients prescribed afatinib should be instructed to limit their time in the sun. Afatinib can make skin sensitive to the sun. Patients should inform their clinician if they have worsening rash or acne.16 In addition, afatinib may cause decreased fertility in women and men. Clinicians should discuss this side effect with patients who may have concerns about fertility.16
Another concern in patients receiving afatinib is liver injury, which may vary in severity from minor, transient serum enzyme elevations to acute symptomatic hepatitis and acute liver failure.17 Periodic monitoring of liver tests during afatinib therapy is recommended. Treatment should be withheld if liver function worsens and may need to be discontinued in those who develop severe hepatic impairment.
Corticosteroids have been used in some instances of acute liver injury due to EGFR inhibitors. Restarting therapy is usually, but not always, followed by recurrence of the serum enzyme elevations. There does not appear to be cross-reactivity with other tyrosine kinase receptor inhibitors, and, in some situations, switching to another protein kinase inhibitor may be appropriate.18
David S. Ettinger, MD, has received clinical research support/data safety monitoring board from Alkermes, AstraZeneca Pharmaceuticals, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb Company, and Guardant Health.
- Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 3.2020. Accessed February 12, 2020. To view the most recent version, visit org.
- Wu Y, Cheng Y, Zhou X, 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;18:1454–1466.
- Soria JC, Felip E, Cobo M, 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.
- FDA expands afatinib’s approval for lung cancer. January 14, 2018. Available at https://www.onclive.com/web-exclusives/fda-expands-afatinibs-approval-for-lung-cancer. Accessed February 21, 2020.
- U.S. Food and Drug Administration. FDA broadens afatinib indication to previously untreated, metastatic NSCLC with other non-resistant EGFR mutations. January 12, 2018. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-broadens-afatinib-indication-previously-untreated-metastatic-nsclc-other-non-resistant-egfr. Accessed February 21, 2020.
- Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 2012;13:539–548.
- Yang JC, Schuler MH, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol 2017;30(18 suppl): LBA7500.
- Wu YL, Zhou C, Hu CP, 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;15:213–222.
- FDA approves Gilotrif for late stage non-small cell lung cancer. July 12, 2013. Available at https://www.drugs.com/newdrugs/fda-approves-gilotrif-late-stage-non-small-cell-lung-cancer-3851.html. Accessed January 27, 2020.
- FDA approves Gilotrif® (afatinib) as new oral treatment option for patients with squamous cell carcinoma of the lung. April 15, 2016. Available at https://www.boehringer-ingelheim.us/press-release/fda-approves-gilotrifr-afatinib-new-oral-treatment-option-patients-squamous-cell. Accessed February 21, 2020.
- Yamamoto N, Mera T, Märten A, et al. Observational study of sequential afatinib and osimertinib in EGFR mutation-positive NSCLC: patients treated with a 40-mg starting dose of afatinib. Advances in Therapy. 2019; Dec 20. [Epub ahead of print]
- Hochmair MJ, Morabito A, Hao D, et al. Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study. Future Oncol. 2018;14:2861–2874.
- Lin L, Ge H, Yan Z, et al. Response to afatinib in a patient with non-small cell lung cancer harboring HER2 R896G mutation: a case report. Onco Targets Ther. 2019;12:10897–10902.
- Thongprasert S, Geater SL, Clement D, et al. Afatinib in locally advanced/metastatic NSCLC harboring common EGFR mutations, after chemotherapy: a phase IV study. Lung Cancer Management 2019;8:LMT15.
- Kwon JH, Kim KJ, Sung JH, et al. Afatinib overcomes pemetrexed-acquired resistance in non-small cell lung cancer cells harboring an EML4-ALK rearrangement. Cells 2019;8:1538.
- Boehringer Ingelheim Pharmaceuticals. Gilotrif (afatinib). Full prescribing information. October 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/201292s015lbl.pdf. Accessed February 21, 2020.
- ACCC, HOPA, ONS. Oral Chemotherapy Education: Afatinib. September 28, 2018. Available at https://www.oralchemoedsheets.com/sheets/Afatinib_Patient_Education.pdf. Accessed February 21, 2020.
- Ding PN, Lord SJ, Gebski V, et al. Risk of treatment-related toxicities from EGFR tyrosine kinase inhibitors: a meta-analysis of clinical trials of gefitinib, erlotinib, and afatinib in advanced EGFR-mutated non-small cell lung cancer. J Thorac Oncol 2017;12:633–643.