Survival analysis
The cut-off date for survival analysis was July 2022, and the median follow-up period for all patients was 26.6 months (range, 0.8–71.6 months). The median follow-up periods among patients who received gefitinib/erlotinib, afatinib, and osimertinib were 25.9 (range, 0.2–136.1) months, 37.2 (range, 0.8–71.6) months, and 24.1 (range, 3.2–45.4) months, respectively. Per Kaplan–Meier analysis, the median PFS was 15.7 months (95% CI: 13.9–17.5) in the GPS = 0 group, 10.0 months (95% CI: 7.2–12.8) in the GPS = 1 group, and 6.3 months (95% CI: 2.4–10.2) in the GPS = 2 group (Fig. 2); patients with a GPS of 0 had significantly more favorable PFS than those with a GPS of 1 (P = 0.03) or 2 (P < 0.001).
The median OS was 40.1 months (95% CI: 35.0–45.2) in the GPS = 0 group, 25.8 months (95% CI: 11.0–40.6) in the GPS = 1 group, and 14.4 months (95% CI: 8.2–20.6) in the GPS = 2 group; again, patients with a GPS of 0 had significantly longer OS than those with a GPS of 1 (P = 0.001) or 2 (P < 0.001) (Fig. 3).
On univariate analysis, a poor PS score of 2 or 3 (HR 2.36 P < 0.001), gefitinib/erlotinib treatment (HR 2.03, P < 0.001), a GPS of 1 (HR 1.44, P = 0.034), and a GPS of 2 (HR 1.40, P < 0.001) were associated with a significantly short PFS, whereas postoperative recurrence (HR 0.53, P < 0.001) and the lack of brain metastasis (HR 0.68, P = 0.006) were significantly associated with a long PFS (Table 3). On multivariate analysis, a poor PS score (HR 2.00, P < 0.001), afatinib treatment (HR 1.79, P = 0.01), gefitinib/erlotinib treatment (HR 2.40, P < 0.001), and a GPS score of 2 (HR 1.91, P < 0.001) were associated with a significantly short PFS, whereas postoperative recurrence (HR 0.69, P = 0.033) was significantly associated with a long PFS (Table 3).
Table 3
Cox proportional hazards analyses of factors potentially associated with progression-free survival
| Univariate analysis | | Multivariate analysis |
Variable | Hazard ratio (95% CI) | P-value | | Hazard ratio (95% CI) | P-value |
Sex Male Female | 1 (Ref.) 0.88 (0.769–1.14) | 0.34 | | 1 (Ref.) 0.94 (0.70–1.27) | 0.68 |
Age (years) <75 ≥75 | 1 (Ref.) 1.10 (0.85–1.41) | 0.48 | | 1 (Ref.) 1.002 (0.76–1.32) | 0.99 |
ECOG PS score 0–1 2–3 | 1 (Ref.) 2.36 (1.80–3.10) | < 0.001 | | 1 (Ref.) 2.00 (1.45–2.70) | < 0.001 |
Smoking status Current or former smoker Never smoker | 1 (Ref.) 0.79 (0.62–1.02) | 0.07 | | 1 (Ref.) 0.76 (0.55–1.04) | 0.085 |
Stage IV Postoperative recurrence | 1 (Ref.) 0.53 (0.39–0.70) | < 0.001 | | 1 (Ref.) 0.69 (0.49–0.97) | 0.033 |
Brain metastasis Positive Negative | 1 (Ref.) 0.68 (0.51–0.89) | 0.006 | | 1 (Ref.) 0.80 (0.59–1.09) | 0.16 |
Histology Adenocarcinoma Other | 1 (Ref.) 1.61 (1.00–2.62) | 0.51 | | 1 (Ref.) 1.62 (0.91–2.88) | 0.10 |
EGFR alteration Exon 19 deletion L858R point mutation | 1 (Ref.) 1.19 (0.93–1.52) | 0.16 | | 1 (Ref.) 1.25 (0.97–1.61) | 0.082 |
EGFR-TKI Osimertinib Afatinib Gefitinib/erlotinib | 1 (Ref.) 1.30 (0.93–1.81) 2.03 (1.47–2.82) | 0.13 < 0.001 | | 1 (Ref.) 1.79 (1.15–2.78) 2.40 (1.70–3.39) | 0.01 < 0.001 |
GPS 0 1 2 | 1 (Ref.) 1.44 (1.03–2.01) 1.40 (1.20–1.64) | 0.034 < 0.001 | | 1 (Ref.) 1.21 (0.84–1.72) 1.91 (1.37–2.67) | 0.30 < 0.001 |
CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; GPS: Glasgow prognostic score; TKI: tyrosine kinase inhibitor |
With respect to OS, univariate analysis revealed that a poor PS score (HR 3.05, P < 0.001), lack of brain metastases (HR 0.67, P = 0.0011), gefitinib/erlotinib treatment (HR 1.50, P < 0.001), a GPS of 1 (HR 1.82, P = 0.001), and a GPS of 2 (HR 1.58, P < 0.001) were associated with a significantly poor OS, whereas postoperative recurrence (HR 0.56, P = 0.001) was associated with a significantly long OS (Table 4). On multivariate analysis, a poor PS score (HR 2.22, P < 0.001), gefitinib/erlotinib treatment (HR 2.50, P < 0.001), and a GPS of 2 (HR 2.03, P < 0.001) were associated with significantly short OS (Table 4).
Table 4
Cox proportional hazards analyses of factors potentially associated with overall survival
| Univariate analysis | | Multivariate analysis |
Variable | Hazard ratio (95% CI) | P-value | | Hazard ratio (95% CI) | P-value |
Sex Male Female | 1 (Ref.) 0.85 (0.65–1.12) | 0.26 | | 1 (Ref.) 0.91 (0.65–1.28) | 0.57 |
Age (years) <75 ≥75 | 1 (Ref.) 1.13 (0.85–1.50) | 0.41 | | 1 (Ref.) 1.15 (0.85–1.57) | 0.36 |
ECOG PS score 0–1 2–3 | 1 (Ref.) 3.05 (2.30–4.05) | < 0.001 | | 1 (Ref.) 2.22 (1.54–3.09) | < 0.001 |
Smoking status Current or former smoker Never smoker | 1 (Ref.) 0.77 (0.59–1.02) | 0.07 | | 1 (Ref.) 0.66 (0.46–0.95) | 0.026 |
Stage IV Postoperative recurrence | 1 (Ref.) 0.56 (0.40–0.78) | 0.001 | | 1 (Ref.) 0.75 (0.50–1.11) | 0.15 |
Brain metastasis Positive Negative | 1 (Ref.) 0.67 (0.49–0.91) | 0.011 | | 1 (Ref.) 0.92 (0.65–1.32) | 0.66 |
Histology Adenocarcinoma Other | 1 (Ref.) 1.19 (0.71–2.02) | 0.51 | | 1 (Ref.) 1.14 (0.61–2.13) | 0.69 |
EGFR alteration Exon 19 deletion L858R point mutation | 1 (Ref.) 1.23 (0.94–1.61) | 0.13 | | 1 (Ref.) 1.26 (0.95–1.67) | 0.11 |
EGFR-TKI Osimertinib Afatinib Gefitinib/erlotinib | 1 (Ref.) 1.56 (0.81–2.99) 1.50 (1.20–1.87) | 0.18 < 0.001 | | 1 (Ref.) 1.28 (0.71–2.33) 2.50 (1.61–3.87) | 0.41 < 0.001 |
GPS 0 1 2 | 1 (Ref.) 1.82 (1.26–2.63) 1.58 (1.34–1.87) | 0.001 < 0.001 | | 1 (Ref.) 1.25 (0.83–1.87) 2.03 (1.42–2.90) | 0.29 < 0.001 |
CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; GPS: Glasgow prognostic score; TKI: tyrosine kinase inhibitor |
The PFS and OS, according to the GPS (0–1 vs. 2), were analyzed separately among patients with poor PS scores (2–3). The PFS of those with a GPS of 0–1 and 2 were 6.7 months (95% CI: 5.6–7.8) and 1.9 months (95% CI: 0.3–3.5), respectively; the former group tended to have a longer PFS than the latter (P = 0.07) (Fig. 4a). Moreover, the OS of patients with a GPS of 0–1 and those with a GPS of 2 were 14.4 months (95% CI: 9.0–19.8) and 3.4 months (95% CI: 0.0–7.4), respectively; this difference was significant (P = 0.008) (Fig. 4b).