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Randomized Controlled Trial
. 2025 Jun 20;43(18):2049-2058.
doi: 10.1200/JCO-24-02007. Epub 2025 Apr 16.

Pragmatic Randomized Study of Afatinib Versus Chemotherapy for Patients With Non-Small Cell Lung Cancer With Uncommon Epidermal Growth Factor Receptor Mutations: ACHILLES/TORG1834

Satoru Miura  1 , Hiroshi Tanaka  1 , Toshihiro Misumi  2 , Hiroshige Yoshioka  3 , Takaaki Tokito  4 , Tatsuro Fukuhara  5 , Yuki Sato  6 , Yoshimasa Shiraishi  7 , Katsuhiko Naoki  8 , Hiroaki Akamatsu  9 , Ou Yamaguchi  10 , Toshihide Yokoyama  11 , Shoichi Kuyama  12 , Kazumi Nishino  13 , Naoki Furuya  14 , Takayasu Kurata  3 , Terufumi Kato  15 , Satoshi Ikeda  16 , Hidehito Horinouchi  17 , Eiki Ichihara  18 , Masahide Mori  19 , Yuichi Takiguchi  20   21 , Kentaro Tanaka  7   22 , Yasuhiro Goto  23 , Hiroaki Okamoto  24 ; Thoracic Oncology Research Group and all ACHILLES investigators
Affiliations
Randomized Controlled Trial

Pragmatic Randomized Study of Afatinib Versus Chemotherapy for Patients With Non-Small Cell Lung Cancer With Uncommon Epidermal Growth Factor Receptor Mutations: ACHILLES/TORG1834

Satoru Miura et al. J Clin Oncol. .

Abstract

Purpose: To our knowledge, the ACHILLES/TORG1834 trial is the first randomized study comparing afatinib and chemotherapy in patients with non-small cell lung cancer (NSCLC) harboring sensitizing uncommon epidermal growth factor receptor (EGFR) mutations.

Methods: This randomized, open-label study was performed at 51 Japanese institutions and recruited treatment-naïve patients with nonsquamous NSCLC with uncommon EGFR mutations, excluding exon 20 insertions and T790M mutations. Patients were randomly assigned 2:1 to receive afatinib (30 or 40 mg orally, at the treating physician's discretion) or a combination of platinum (cisplatin or carboplatin) and pemetrexed, followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, and safety. A prespecified interim analysis was planned to provide clinically meaningful information promptly, along with a crossover recommendation if necessary.

Results: A total of 109 patients were enrolled between March 2019 and February 2023. In the interim analysis, the Data and Safety Monitoring Committee recommended early study termination. The median PFS was significantly longer in patients receiving afatinib than in those undergoing chemotherapy (10.6 v 5.7 months; hazard ratio, 0.421 [95% CI, 0.251 to 0.706]; P = .0010). ORRs to afatinib were similar across the overall population and among participants with major uncommon (G719X, L861Q, and S768I), compound, and other mutations (61.7%, 55.8%, 72.7%, and 60.0%, respectively). The most common grade 3 or higher adverse events were diarrhea, paronychia, and rash for afatinib, and appetite loss and nausea for chemotherapy.

Conclusion: Afatinib should be considered the standard initial therapy for patients with NSCLC with sensitizing uncommon EGFR mutations.

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