Posted: Wednesday, May 10, 2017
Afatinib is an irreversible pan-ErbB inhibitor, including EGFR (ErbB1), developed to treat lung cancers of different types, including those with epidermal growth factor receptor (EGFR) mutations. The LUX-Lung series of studies1-3 have evaluated the efficacy and toxicities of afatinib in both treatment-naïve patients with metastatic disease and in those with previously treated non-small cell lung cancer (NSCLC). The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration in 2013 for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.4,5 Afatinib is commonly referred to as an EGFR tyrosine kinase inhibitor (TKI).
Approximately 15% to 20% of patients with NSCLC will be identified as having activating EGFR mutations in their tumors, and this percentage may be even higher among non-smokers with adenocarcinomas. For patients with EGFR-mutant tumors, targeted therapy can yield high response rates, long periods of disease control, and improved quality of life compared with chemotherapy.7,8
Although it is the most recently approved EGFR TKI for first-line treatment of metastatic NSCLC, afatinib is one of the best studied agents, with excellent comparative data versus both chemotherapy and other TKIs, said Gregory J Riely, MD, PhD, a lung cancer expert and associate attending physician at Memorial Sloan-Kettering Cancer Center in New York City.
Explaining Treatment Choice to Patients: Why Afatinib?
One of the newest issues to arise in clinical practice relates to questions from patients and families about immunotherapy and why an EGFR TKI is being considered instead of immunotherapy. “Media is saturated with advertisements for immunotherapy whereas there are few, if any, advertisements for EGFR TKIs. So, offering targeted therapy takes some explanation,” Dr Riely observed. “I usually start with the relatively uncommon incidence of EGFR mutations in the general lung cancer population—ie, much of what patients know about lung cancer in general doesn’t necessarily apply to their particular situation.” According to Dr Riely, the key piece of information is that the response rate for patients with EGFR mutations who are treated with an appropriate EGFR TKI—such as erlotinib, gefitinib, or afatinib--is much higher than for those treated with immunotherapy. “I also point out that this is the beginning of our treatment plan…this is what we recommend to start with. Nevertheless, as treatment proceeds, we might decide to switch to a number of different options and immunotherapy may be a reasonable treatment down the road.” Additionally, Dr Riely pointed out that some subset analyses from immunotherapy trials have shown that patients with EGFR mutations benefit less from immunotherapy than those with wild-type EGFR.9
Finding the Right Dose for Every Patient
There is a sense among community oncologists that afatinib may be more difficult for patients to tolerate than earlier generation sensitizing EGFR TKIs such as erlotinib or gefitinib, noted Lecia V. Sequist, MD, Associate Professor of Medicine, Harvard Medical School. This is not necessarily true, Dr Sequist pointed out, although successful treatment with afatinib may require a different approach by the medical team.
The challenge when initiating therapy, explained Dr Riely, is finding the right dose and managing the usual toxicities of EGFR TKIs in a proactive way. Most clinicians initiate treatment with the recommended starting dose but there are idiosyncrasies in the toxicities for every patient that may signal the need for dose modification. The rates of dose modification may be slightly higher in patients on afatinib, Dr Riely said, “but we can almost always identify a tolerable dose for every patient.”
Confirming the notion that dose reduction is appropriate, “it’s important for clinicians to know that about 50% of patients who start afatinib at the approved starting dose (40 mg) will ultimately benefit from dose reduction,” Dr Sequist said. “I usually tell patients upfront, ‘We’re going to start with the approved dose but it’s hard to predict side effects merely on the basis of body weight, age, gender, etc. Different patients metabolize the drug differently. Overall, there is a 50-50 chance that we will need to reduce the dose. So we will start here, but we will have a low threshold to dose reduce if you start having difficulty. Recent data confirm that outcomes on afatinib are equally good for patients who underwent dose reduction compared with those who did not.’ ”10
Treatment Choice and Molecular Typing
There are some provocative data to suggest that afatinib might have some benefits compared with other TKIs, but nothing conclusive, Dr Riely observed. For instance, in a head-to-head trial of afatinib versus gefitinib, those who received afatinib had better outcomes with regard to some endpoints, including progression-free survival (PFS) and time-to-treatment failure, compared with gefitinib.11 Nevertheless, there was no significant overall survival difference between the 2 therapies. According to analyses from 2 additional trials that compared afatinib with chemotherapy, afatinib shows an overall survival advantage for patients with the exon 19 deletion mutation in EGFR, but this effect was not seen in those patients with the L858R EGFR mutation.12 Neither gefitinib nor erlotinib have demonstrated an overall survival advantage versus chemotherapy for patients with any EGFR mutation subtype. “So, one of the common views is that afatinib is the preferred drug for patients with exon 19 deletions, although we don’t really know if erlotinib, for instance, wouldn’t be equally effective,” Dr Riely pointed out. “The efficacy data are not sufficiently different that I would make treatment decisions based on molecular typing. Large bodies of data suggest that they’re roughly the same.”
Dr Sequist agreed that the data are not conclusive on this point. “My personal practice tends to be to favor afatinib in the case of exon 19 deletion, as well as for some specific other rare EGFR mutations, including G719X, L861Q, or L858RS768I,” she said. Dr Sequist, whose clinical work is at the Massachusetts General Hospital Cancer Center in Boston, noted, “Those are specific mutations for which there are good efficacy data with afatinib.”13,14 (Editor’s Note: According to afatinib approval and prescribing information, “safety and efficacy of afatinib have not been established in patients whose tumors have other EGFR mutations” [other than exon 19 deletions or exon 21 (L858R) substitution mutations]).
Preventing and Managing Afatinib Toxicities
Illustrating his overarching attitude toward EGFR TKI-induced adverse effects, Dr Riely explained, “Most patients will have some degree of rash, but what I emphasize is that we need to find a tolerable level of rash. I explain that our goal is to continue the therapy for many months and even years. This side effect [eg, severe rash] is not something, therefore, that we want patients to ‘tough out.’ We need to find the right management strategy and the right dose.”
With proper education of both the clinicians and patients, Dr Sequist observed, using afatinib is quite feasible. “I don’t restrict the use of afatinib to any particular tumor criteria, gender, or age cut-off, but patients should have a good performance status and not be frail. Anectodally, I have the most trouble with it in very thin and petite older women (>70 yrs).”
The 2 most common adverse effects with afatinib –and all EGFR TKIs—are rash and diarrhea.
Treatment-related rash takes longer to develop and is slower to respond to intervention compared with diarrhea. It is important to address and control rash as early as possible, as soon as it is identified, by beginning topical agents and oral antibiotics. Although the rash is acne-like, patients should be informed that the rash is not acne and therefore it should not be treated with over-the-counter agents for acne, which can exacerbate the rash. Dr Riely described his approach, saying, “I usually give patients a prescription for a topical corticosteroid that they can fill as soon as rash starts. If the rash becomes significant, the patient is asked to come in for evaluation. If the rash is serious, we may consider a course of oral antibiotics, typically doxycycline or minocycline.”
Dr Sequist advocates taking a more proactive strategy with respect to afatinib-associated rash by prescribing a course of prophylactic antiobiotics. “I start everyone who goes on afatinib on an antibiotic (minocycline, doxycycline, or ciprofloxacin), with instructions to begin the antibiotic about 4 to 5 days after the afatinib (to distinguish the cause of any nausea). This is not included in the PI,” she noted, but “in my opinion, it should be a universal recommendation for patients to be on a concurrent antiobiotic for at least the first 4 to 6 weeks of afatinib treatment, as it really seems to help with rash,” she said.
“I usually schedule a ‘teaching session’ with patients and instruct them to call us if they are having trouble at home on the medication rather than just waiting for their next scheduled appointment. I also schedule that first visit about 10 to 14 days after they’ve started afatinib because that’s when the rash emerges and I can get a good visual assessment of how things are going,” she said.
Some patients on chronic treatment with afatinib or any EGFR TKI, struggle with paronychia. In general, “they should be cautioned about having debriding procedures, which are often done at a podiatrists’ office and can worsen the condition,” Dr Sequist observed. Topical corticosteroid can be helpful and, in refractory cases, a dermatologist can perform an avulsion, removing the lateral edges of a toenail, which tends to be very successful but is a permanent alteration of the toenail.
“Holding” Drug is Often Best Advice
When a patient is struggling with an adverse effect of an oral drug—whether it is rash or diarrhea or mouth sores—sometimes the best thing to do when the symptom is first reported by phone, according to Dr Sequist, is to advise them to just “hold” the medicine.
If patients are having trouble with moderate symptoms when they first start afatinib, “I tell them to hold the dose for about 5 to 7 days. This is for those situations where the side effect is substantial enough to be uncomfortable but not serious enough to signal a medical issue.” In some circumstances, it will be clear that dose reduction is required. Often, though, after about a week off medicine, Dr Sequist explains that patients can re-start without the same level of side effects occurring again. “The same dose is often better tolerated the second time around,” she commented.
Our goal is to continue the therapy for many months and even years. This side effect is not something, therefore, that we want patients to ‘tough out.’ We need to find the right management strategy and the right dose.
Sometimes patients will modify oral regimens on their own, thinking that they’ve figured out a well tolerated schedule. Perhaps they take drug for 5 days and then take 2 days off. This is particularly the case when they’ve been on treatment for several months. After a period of time, the safety profile can change. “You might not get the acute symptoms like rash or diarrhea, but you’ll see nail changes or stomatitis,” Dr Sequist said. The clinician needs to ask at each visit whether the patient is taking pills every day. “Although ‘stop dose and hold’ is a great strategy for dealing with acute toxicities, a chronic pattern of holding doses is not generally a good long-term approach,” she explained. Frequent cycling on and off medication can result in more rapid development of resistance.15 It is better to dose reduce to a more tolerable dose than to take the medication intermittently. If necessary, it is important to educate patients about the risks for resistance associated with intermittent dosing.
One of the ongoing trials looking at optimal first-line treatment for patients with EGFR mutations is afatinib monotherapy versus afatinib plus cetuximab.16 A second-line trial that explored the combination in patients who had developed resistance to a TKI showed that those who received the 2-drug combination had a response rate on the order of 30% to 40%.17 The premise of the current trial is to determine whether the demonstrated effectiveness of afatinib plus cetuximab in the resistant setting will translate to the first line. In addition, although response rates with EGFR inhibitor TKIs in the first line may be as high as 60% to 70%, the duration of PFS is 12 months or less. The goal of using a combination regimen would be to extend the duration of the PFS.
A second issue that arises is how long to continue treatment with an EGFR TKI after disease progression. Oncologists frequently recommended continuing the EGFR TKI indefinitely and added different chemotherapy regimens over time, as needed. However, according to findings from the IMPRESS trial, which studied this approach, there was no value in continuing the TKI beyond progression, especially when a standard platinum-based chemotherapy doublet is initiated.18
To avoid the “flare” that occurs in about 25% of patients when they come off TKIs, Dr Riely recommended “a minimal wash out during the period before chemotherapy begins; it may even be ok to continue the TKI very briefly after chemotherapy is started.”
Describing typical sequential treatment for EGFR-mutated advanced NSCLC, Dr Riely explained that most patients begin with a sensitizing EGFR TKI in the first line—typically afatinib, erlotinib, or gefitinib--and then move to a platinum-based doublet—typically carboplatin or cisplatin with pemetrexed—on progression.19 However, about 60% of patients with progression may have an acquired mutation in T790M; targeted therapy with osimertinib is recommended for these patients.20 Then, for third- line treatment, they might be offered either immunotherapy or docetaxel. “There’s some evidence that, from an efficacy perspective, docetaxel is superior to immunotherapy in this setting but the toxicity profile for immunotherapy is easier. Many patients prefer, therefore, to try immunotherapy first,” he said.
“One of my key messages to oncologists is that dose reduction is OK,” Dr Riely concluded. “These agents were originally developed for use in patients with wild-type EGFR and were dosed at their maximal tolerable dose. We now know that lower doses of EGFR TKIs are likely to be just as efficacious in these patients. Identifying a tolerable dose where patients can live relatively normal lives with less rash and less diarrhea is the best approach,” he observed.
Gregory J Riely, MD, PhD, has disclosed no relevant relationships.
Lecia V. Sequist, MD, has disclosed that she has received consulting fees from AstraZeneca, Genetech, Ariad Pharmaceuticals, Inc, and Bristol-Myers Squibb.
- Boehringer Ingelheim. LUX-Lung clinical trial programme. Available at: http://www.inoncology.com/pipeline/our-trials/our-trials/non-small_cell_lungcancer/lux-lung-programme.html. Accessed March 20, 2017.
- Joshi M, Rizvi SM, Belani C, et al. Afatinib for the treatment of metastatic non-small cell lung cancer. Cancer Manag Res 2015;7:75-82.
- Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-3334.
- NIH. National Cancer Institute. FDA approval for afatinib dimaleate. Available at: https://www.cancer.gov/about-cancer/treatment/drugs/fda-afatinibdimaleate. Accessed March 20, 2017.
- FDA approves afatinib. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm. Accessed March 20, 2017.
- Boehringer Ingelheim Pharmaceuticals, Inc. Gilotrif (afatinib). Full Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf. Accessed March 14, 2017.
- Sequist LV, Bell DW, Lynch TJ, et al: Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007; 25:587-595.
- Moran T. Timing of epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung cancer with EGFR mutations. J Clin Oncol 2007; 25:587-595.
- Lee CK, Man J, Lord S, et al. Checkpoint inhibitors in metastatic EGFR-mutated non–small cell lung cancer—a meta-analysis. J Thorac Oncol 2016; 12:403-407.
- Yang JC-H, Sequist LV, Zhou C, et al. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol 2016;27:2103-2110.
- Paz-Ares L, et al. Afatinib (A) vs gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC): overall survival (OS) data from the phase IIb trial LUX-Lung 7 (LL7) [abstract]. Presented at the European Society for Medical Oncology (ESMO) 2016 Congress, October 7-9, 2016; Copenhagen, Denmark. # LBA43.
- Yang JC, Wu Y-l, Schuler M, 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 randomized, phase 3 trials. Lancet Oncol 2015;16:141-151.
- Helgener DF, Schumann C, Sebastian M, et al. Afatinib in non-small cell lung cancer harboring uncommon EGFR mutations pretreated with reversible EGFR inhibitors. Oncologist 2015;20:1167-1174.
- Yang C-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830-838.
- Foo J, Chmielecki J, Pao W, Michor F. Effects of pharmacokinetic processes and varied dosing schedules on the dynamics of acquired resistance to erlotinib in EGFR-mutant lung cancer. J Thorac Oncol 2012;7:1583-159.
- Afatinib dimaleate with or without cetuximab in treating patients with newly diagnosed stage IV or recurrent, EGFR mutation positive non-small cell lung cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02438722. Accessed March 20, 2017.
- Janjigian YY, Smit EF, Groen HJM, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014;4:1036–1045.
- Soria J-C, Wu Y-L,Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015; 16:990-998.
- Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer, v4.2017. Available at https://www.nccn.org/. Accessed April 17, 2017.
- Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-1699.