To the best of our knowledge, this retrospective trial is the largest evaluation of patients receiving 30 mg afatinib daily as the starting dose for treatment of metastatic lung adenocarcinoma harboring exon 21 L858R point mutations and exon 19 deletions. We demonstrated that patients who received 30 mg afatinib as their starting dose had non-inferior RRs, PFS and OS compared with patients who received 40 mg afatinib as their starting dose, and they also had fewer severe ADRs.
Those patients receiving 30 mg afatinib daily as the initial dose tended to be older, female, weigh less, have a lower BMI and have fewer metastatic sites on their initial diagnosis of lung cancer, compared with patients receiving 40 mg afatinib. These results are similar to previous studies [23, 29]
The patients initially using 30 mg afatinib daily had similar RRs to the 40 mg afatinib group, and the RR was comparable with previous studies (61–74%). In two phase 3 clinical trials, Lux-Lung 3 and Lux-Lung 6, the median PFS among patients who harbored EGFR mutations and took 40 mg afatinib as their initial dose was 10.9 and 13.6 months, respectively. A real word practice study in Japan that enrolled 128 patients reported a median PFS of 17.8 months , while a phase 2 study which used a lower starting dose of 20 mg afatinib that increased in 10-mg increments up to 50 mg/day, reported a PFS of 15.2 months . Another phase 2 study that enrolled 40 elderly patients had a shorter PFS of 12.9 months . The current study revealed that the median PFS of patients who harbored exon 19 and exon 21 mutations and took afatinib 30 or 40 mg afatinib as their starting dose was 14.5 and 14.8 months, respectively; no significant difference in PFS was observed between the two groups, the result is similar to our previous small-scaled study.
In terms of OS, the phase 3 Lux-Lung 3 and Lux-Lung 6 trials reported that the median OS was 31.4 and 33.3 months, respectively. Tanaka et al presented a real-world study of first line afatinib in Japan, with a reported median OS of 39.5 months . In the Giotag trial, all patients initially received 40 mg afatinib, followed by osimertinib if T790M acquired resistance was reported; the median OS was 41.3 months and the OS was as long as 45.7 months in patients with an exon 19 deletion . In the present study, the OS was 34 and 25.2 months, respectively in the 30 mg and 40 mg groups which was not statistically significant. These results indicate that the clinical efficacy of 30 mg afatinib as a starting dose was not inferior to 40 mg afatinib as a starting dose in this multicenter retrospective study.
It should be noted that the current study enrolled patients from May 2014, however only 13 patients (13%) in the 30 mg group and 5 patients (6%) in the 40 mg group received osimertinib as a 2nd line therapy. This is likely because osimertinib is very expensive and was not reimbursed by the Taiwanese National Health Insurance until April 2020. Therefore, the majority of patients with acquired-resistance to afatinib chose to receive platinum-based chemotherapy as their 2nd line therapy as opposed to osimertinib.
In the current study, the independent predicting factors for PFS were 1) number of metastatic sites and 2) dose reduction due to severe ADRs. The independent predictive factors for OS were male gender, initial poor ECOG and number of metastatic sites. In Liang et al, patients with significant pretreatment weight loss (>10.0% in 6 months) had a shorter median PFS, and patients with brain metastases had a poorer ECOG status and were associated with a shorter median PFS . Tanaka et al also showed that patients with dose reduction had a significantly longer PFS than those without dose reduction in a real-world study (18.5 vs. 7.9 months, respectively; p=0.018) . However, the average daily dose of <20 mg afatinib had a significantly shorter PFS compared with the other higher dose (p = 0.049) . Another study of afatinib in Taiwan showed that OS was not affected by reductions in the afatinib dosage; they also indicated that brain metastases at diagnosis and treatment response to afatinib are two important prognostic factors for OS .
Previous clinical trials recommended that 40 mg afatinib daily should be the starting dose in patients who harbor EGFR mutations, however, this dosage was often accompanied by serious ADRs and up to 28 to 53.3% of patients required dose reduction in the Lux-Lung 3 and Lux-Lung 6 studies [14, 18]. In a real-world study in Japan, 48% of patients receiving standard 40mg afatinib had dose reduction and 23% of patients discontinued treatment due to ADRs .
In fact, many clinicians had experienced more severe ADRs in patients who received standard 40 mg afatinib than those who received 1st generation EGFR TKIs, such as gefitinib or erlotinib. There is an urgent need to find a reliable strategy for reducing ADRs associated with afatinib, whilst maintaining its clinical efficacy for the management of lung cancer. Therefore, in clinical practice many clinicians prescribe a lower starting dose of afatinib [22, 23] or perform dose modification [19, 21] to try and improve patient outcomes and adherence. In a non-interventional, observational study  of patients who started on 40 mg afatinib daily, 67.1% underwent dose reduction, 86.5% of which occurred in the first 6 months. Dose reductions were more common in females, East Asian individuals, and those with a low body-weight . In a post-marketing, observational study of afatinib in Japan , low-dose initial treatment was observed at a higher rate in females compared with males, and more often in patients with lower body weights compared with patients with higher body weights. A study by Imai et al enrolled 40 patients with a median age of 77 years (range, 70-85 years old) and all of them received 30 mg afatinib as the starting dose; their RR and median PFS were similar to the present study and their ADRs were also acceptable .
Our study revealed that clinicians tended to prescribe 30 mg afatinib to lung cancer patients with either a lower BSI, lower body weight or increased age. Recently, a prospective phase 2 clinical trial, which enrolled 46 patients assessed the efficacy and safety of low starting doses of afatinib followed by dose modification, according to its toxicity in patients with EGFR mutation-positive NSCLC. The study had a median PFS of 15.2 months (95% CI: 13.2–not estimable) and the 1-year OS rate was 95.6% (95% CI: 89.7%–100%) .
Since severe ADRs may discontinue the use of afatinib or lead to dose reduction, one must pay close attention to the incidence and severity of ADRs in the treatment of lung adenocarcinoma harboring exon 19 or exon 21 mutations. Of patients who received 40 mg afatinib as their starting dose in the phase 3 Lux-Lung 3 and Lux-Lung 6 trials, 73.0 and 80.6%, respectively experienced grade 3 or higher treatment-related ADRs; the incidence of ADRs dropped to 11.9 and 20.5%, respectively after the dosage was lowered [13, 14, 18]. In a real-world study, grade 3 or higher ADRs occurred in 30.4% of patients . The present study demonstrated that skin rash and/or acne, diarrhea, dry skin and paronychia were the most common ADRs and fewer events were observed in the 30 mg group compared with the 40 mg group, which is in keeping with the findings of our previous study . Furthermore, patients who received 30 mg afatinib daily had a significantly lower incidence of moderate to severe ADRs, including diarrhea, stomatitis, dry skin, acne and/or rash and pruritis; their overall incidence of moderate or severe ADRs was also significantly reduced. Fewer severe ADRs will lead to better drug compliance and a better overall quality of life for the patient. Besides, there was no increased incidence of recurrent central nervous system metastasis in patients receiving 30 mg afatinib as the starting dose compared with those receiving 40 mg in the current study.
Limitations First, although the study enrolled patients from three hospitals, the retrospective design of this study makes the results less reliable than standard prospective clinical trials. Second, the number of cases enrolled in the study was relatively low for a retrospective study. However, the number of patients enrolled receiving 30 mg afatinib as the starting dose is the largest of any study to date. Third, patients with recurrent lung cancer were excluded from the current study. Fourth, we only enrolled lung adenocarcinoma patients and excluded those with squamous cell carcinoma or other rare types of lung cancer. Almost 99% of residents in Taiwan are covered by the Taiwan National Health Insurance bureau and only adenocarcinoma harboring susceptible EGFR mutations is reimbursed by the National Health Insurance bureau. Fifth, only 13% of patients in the 30 mg group and 6% of patients in the 40 mg group received osimertinib as their 2nd line therapy. This is because osimertinib is expensive and was not reimbursed by the National Health Insurance in Taiwan until April 2020. Therefore, the majority of lung cancer patients with acquired-resistance to afatinib chose to receive platinum-based chemotherapy instead of osimertinib as a salvage therapy.