Phase II open‐label multicenter study to assess the antitumor activity of afatinib in lung cancer patients with activating epidermal growth factor receptor mutation from circulating tumor DNA: Liquid‐Lung‐A

Abstract

Background Mutation analysis of circulating tumor DNA (ctDNA) is used for diagnosing lung cancer. This trial aimed to assess the efficacy of afatinib in treatment‐naïve patients with lung cancer harboring epidermal growth factor receptor mutations (EGFRm, exon 19 deletions or exon 21 point mutations) detected based on ctDNA. Methods The primary objective was the objective response rate (ORR) in the response evaluable (RE) population. EGFRm analysis of ctDNA was performed using PANA Mutype. Of the 331 patients screened, ctDNA was positive in 21% (68/331) in the detection of activating EGFRm. Among 81 subjects with tumor EGFRm, 48 showed matched EGFRm in their ctDNA (59% sensitivity). Results Therapy with afatinib 40 mg was initiated in 21 (female, 17; adenocarcinoma, 20) patients (intention‐to‐treat, ITT); dose modifications were made in 15 (71%). The ORR was 74% in the RE population (14/19); 11 patients showed EGFRm only in ctDNA (Group A), whereas 10 exhibited the same EGFRm in their ctDNA and tumor DNA (Group B). There was no significant difference in ORR between Groups A and B (80% and 67% RE, respectively). Median progression‐free survival (PFS) was 12.0 months, and no significant difference was observed according to the final afatinib dose, type of EGFRm, and Group A versus B. After progression, T790M mutation was found in 40% (6/15) of patients, and osimertinib was used as a second‐line treatment. Conclusions Afatinib showed similar ORR and PFS in patients with lung cancer harboring EGFRm in their ctDNA regardless of tumor EGFRm results. Key points Significant findings of the study Afatinib showed favorable ORR and PFS regardless of the tumor EGFR mutation status results, similar to the findings of previous trials assessing afatinib as first‐line treatment of EGFR‐mutated non‐small cell lung cancer based on tumor genotyping. What this study adds Our findings emphasize that the survival benefit of afatinib treatment can be achieved not only by appropriate dose reduction with frequent and detailed monitoring of toxicities, but also by using noninvasive (ctDNA) assays in a real‐world setting.

Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC?

“…Accurate molecular typing is the basis of this precise treatment; however, qualified tumor tissue specimens cannot be obtained from every patient, so liquid biopsy was developed. Many studies have prospectively verified the high specificity (92–100%) and positive predictive value (94.0–98.6%) of ctDNA-based EGFR mutation detection using tissues as a reference [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], and these two metrics have also been consistent in guiding the targeted therapy of NSCLC [ 30 , 31 , 34 , 35 ]. Recently, research on ctDNA-based next-generation sequencing (NGS) has demonstrated potential clinical utility [ 36 , 37 , 38 , 39 ].…”

“…Table 1 presents data on the association between plasma ctDNA/cfDNA EGFR mutations and the efficacy and prognosis of targeted therapy in NSCLC patients [ 28 , 30 , 31 , 32 , 33 , 34 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The BENEFIT trial prospectively demonstrated the feasibility of using liquid biopsy to guide the efficacy of first-line EGFR-TKI therapy for the first time.…”

“…Park et al evaluated the efficacy of afatinib in treatment-naïve lung cancer patients with ctDNA-based EGFR mutations (exon 19 deletion or exon 21 point mutation). The results showed that afatinib exhibited similar ORR and PFS in lung cancer patients with EGFR mutations in their ctDNA, regardless of the outcome of the tumor EGFR mutations [ 35 ]. As a second-line treatment, osimertinib showed a favorable ORR and a median PFS for patients with plasma ctDNA T790M positivity, regardless of their tissue mutation status [ 45 ].…”