(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

Objective Circulating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)‐mutated non‐small‐cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status. Methods A retrospective analysis was performed using 91 ctDNA samples from a cohort of 28 patients who were diagnosed with EGFR‐mutated NSCLC and treated with EGFR‐TKIs, including 14 patients treated with first‐/second‐generation TKIs and 14 treated with osimertinib. Blood samples at baseline (BL), within 4 weeks after TKI initiation (Week4), within 12 weeks before progression (pre‐PD), and at progression were collected. The relationship alternatives in ctDNA status, ctDNA EGFR status and response to EGFR‐TKIs as well as progression‐free survival (PFS) were analyzed. Results We categorized 20 BL‐ctDNA positive patients with available Week4‐ctDNA into two groups: ctDNA‐clearance (N = 7, 35%) and ctDNA‐non‐clearance (N = 13, 65%). The ctDNA‐clearance group had better PFS than the ctDNA‐non‐clearance group (ctDNA‐clearance vs. ctDNA‐non‐clearance, p = 0.091, hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.15–1.19). According to Week4‐EGFR status, we observed that PFS was significantly longer in EGFR‐clearance patients than EGFR‐non‐clearance groups, (p = 0.011, HR = 0.23, 95% CI = 0.08–0.72). We then categorized patients into three subgroups according to Week4‐ctDNA and Week4‐EGFR status: non‐clearance (N = 9), only‐EGFR‐clearance (concomitant alterations non‐clearance) (N = 4), and all‐clearance (N = 7). The nonclearance group had a significantly worse PFS than the all‐clearance group (median PFS = 5.07 vs. 11.40 months, p = 0.029, HR = 3.45, 95% CI = 1.05–11.49). The only‐EGFR‐clearance group had a similar PFS to the all‐clearance group (p = 0.607), which was longer than that of the non‐clearance group (median PFS = 9.20 vs. 5.07 months, p = 0.060, HR = 0.25, 95% CI = 0.05–1.18). We found that the all‐clearance group had a similar objective response rate (ORR) to the only‐EGFR‐clearance group (p = 1.000) and a higher ORR than the non‐clearance group (p = 0.012). Conclusion Monitoring of EGFR clearance in ctDNA is promising and cost‐effective in assessing response and predicting survival in EGFR‐mutated NSCLC patients treated with EGFR‐TKIs, with similar predictive value to ctDNA surveillance.

<p>The TMB distribution of all primary and metastases samples. The total TMB (defined as the number of nonsynonymous mutations) in each group.</p>