Median age of 125 patients was 63.1 (37.0-86.0). Exon 18, exon 20 and complex mutations rates were 60% (75 patients), 16% (20 patients) and 24% (30 patients), respectively. Exon 18 and complex mutations were observed more in males, and the frequency of exon 20 mutations was equal in both genders (p=0.196). There were 75 patients (60%) treated with erlotinib and 50 patients (40%) with afatinib. EGFR-TKI was the first line treatment in 53.6% of the patients, second line in 39.2%, third line in 6.4% and fourth line in 0.8%. General characteristics of the patients are presented in Table 1.
The median follow-up time of all patients was 16.7 months (1.3-112.7). Follow-up period was 16.5 months in the erlotinib arm and 17.4 months in the afatinib arm.
OS of all patients was 21.4 months (95%CI: 16.1-26.6), while PFS was 7.2 months (95%CI: 5.1-9.3). When PFS and OS were compared according to the type of TKI used, PFS was 8.0 months (95%CI: 4.7-11.3) in the erlotinib arm and 7.0 months (95%CI: 4.4-9.6) in the afatinib arm. OS seemed longer in the afatinib arm than in the erlotinib arm (24.8 months vs. 20.0 months, respectively). However, no statistically significant difference was found between the two groups in both PFS and OS comparisons (Figure 2A,2B).
PFS in the Exon 18, Exon 20 and complex mutation groups were 7.0 months (95%CI 5.9-8.1), 4.3 months (95%CI 2.1-6.5) and 17.3 months (95%CI 8.5-26.1), respectively, and there was a statistically significant difference between these 3 groups (p=0.036) (Figure 3).
The distribution of rare mutations is presented in figure 4.
Exon 18 G719X point mutation was the most mutation. This mutation was found alone in 85%, and it was also found together with exon 19 deletion in 3% and with exon 21 mutation in 12% of patients. Thirty-six exon 18 G719X positive patients received erlotinib and 24 patients received afatinib. The survival rates are shown in Table 2.
When insertions of exon 20 was excluded, the second most common mutation was S768I, which was usually positive alone. Nine patients with this mutation received erlotinib and 6 received afatinib (Table 2).
When the PFSs were evaluated according to the TKI types of the patients in the exon groups, statistical significance was not found in all groups, although the PFS was longer in those who received afatinib than those who received erlotinib. Similar results were also observed in OS. The results are presented in Table 2.
When OSs were compared according to exon subgroups, the longest OS was found to be 32.5 months in complex mutations, while it was 21.0 and 21.2 months seen in Exon 18 and exon 20 mutations, respectively (p=0.323).
Exon 19 or exon 21 mutations were present in 22 patients in the complex mutation group, and PFS time of these patients was 17.4 months (95% CI 6.6-28.2) and OS was 24.3 months (95% CI 0.0-89.4). In patients without exon 19 and/or exon 21 alterations, PFS was 8.3 months (95% CI 0.0-21.4) and OS was 11.5 months (95% CI 0.0-42.5). In the complex mutation group, there was no difference in terms of PFS and OS between erlotinib or afatinib treatments, regardless of exon 19 or exon 21 status.
Overall response rate of the patients was similar in the erlotinib and afatinib arms (53.3% vs 52%, p= 0.218) (Table 3).
There was no difference between the TKI treatment groups in terms of gender and metastatic status. In the erlotinib arm, PFS of the patients who had never smoked was statistically longer than those who were ex-smokers and current smokers (12.0 vs 8.0 vs 3.5 months, p= 0.008), while no statistical difference was found in the afatinib arm (9.6 vs 6.0 vs 8.5 months, p= 0.087).
There were no difference between the exon groups, when sex and metastasis status were compared. However, in exon 18 mutation-positive patients, the PFS was longest in the never-smoker group, and a statistical difference was found compared to the patients who quit smoking and are still smoking (9.6 vs 6.6 vs 3.7 months, p=0.013). There were no PFS difference between smoking status in exon 20 and complex mutations (p:0.118 vs p:0.331)
Patients received TKIs mostly as first line treatment, and the PFS in the first line was 8.9 months, 7.1 months in the second line, 3.4 months in the third line, and 3.5 months in the fourth line (p= 0.009). There were no OS difference between the line of treatment (p=0.233).
Results of patients with exon 20 insertion
Since exon 20 insertion is associated with TKI resistance, this mutation was analysed in itself. Of those 18 patients with exon 20 insertion, 10 patients were male, and 50% were non-smokers. In this group, 7 patients (38.3%) received erlotinib, 6 patients (33.3%) afatinib, and 5 patients (27.7%) gefitinib. Median PFS of the whole group was 8.7 months (95% CI 3.1-14.3). In those who received erlotinib PFS was 7.0 months (95% CI 1.0-14.2), in afatinib treated patients PFS was 8.7 months (95% CI 1.0-20.5), and in gefitinib 15.0 months (95% CI 1.0-24.1) (p=0.479). Median OS was 26.4 months (95% CI 20.0-32.8) for the entire group. It was 24.0 months (95% CI 20.7-27.3) with erlotinib, 31.4 months (95% CI 22.7-40.1) with afatinib, and 28.5 months (95% CI 11.1-46.0) with gefitinib. There was no statistically significant difference between the TKIs. In this patient group, only the PFS values of male patients were found to be significantly longer than female patients (12.0 months vs. 3.2 months, p=0.003).
Most common adverse event in the erlotinib arm was rash (54.6%), followed by mucositis (41.3%), anemia (32.0%), diarrhea (28.0%), and elevated transaminase (20%). Rash (66%), diarrhea (58%), anemia (36%), mucositis (28%), and elevated transaminases (24%) were observed frequently with afatinib.
The incidence of grade 3-4 adverse events was 13.3% in the erlotinib arm, and 20% in the afatinib arm. Due to side effects, treatment was interrupted in 20 (16.0%) patients and dose reduction was made in 17 (13.6%) patients. In 7 patients (5.6%), the treatment was permanently discontinued. Side effects that led to treatment discontinuation were rash, elevated transaminases, and interstitial lung disease. Interstitial lung disease was observed only in 1 patient (2%) with afatinib, and treatment was permanent discontinued.
When the relationship between side effects and survival was evaluated, PFS was longer in patients with mucositis (14.2 months vs. 6.0 months, p= 0.004), and OS was longer in patients with rash (24.7 months vs 17.8 months, p= 0.080).