LBA66 - Afatinib versus chemotherapy for treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation: A phase III study (ACHILLES/TORG1834)

Background

EGFR mutations are diverse and include major uncommon and compound mutations. There is no conclusion on whether EGFR-TKI is the optimal treatment for these diverse mutations. Herein we report results on the first phase III ACHILLES trial, where treatment with afatinib and chemotherapy were compared in sensitizing uncommon EGFR mutant non-small cell lung cancer (NSCLC).

Methods

In this open-label phase III study, treatment-naïve patients with sensitizing uncommon EGFR mutant NSCLC were randomized 2:1 to oral afatinib (30 or 40 mg daily) or the combination of platinum (cisplatin 75 mg/m² or carboplatin AUC 5 or 6) and pemetrexed (500 mg/m²), followed by pemetrexed maintenance therapy every three weeks. The primary endpoint was progression-free survival (PFS) per RECIST 1.1. The sample size (n = 106) was based on 75% power to detect a hazard ratio of 0.6 in PFS with α= 0.05, which was pre-planned upon completion of enrollment. The analysis was adjusted for multiple testing with the Lan-DeMets alpha-spending function, using the O’Brien and Fleming method.

Results

A total of 109 patients were enrolled between Feb 2019 and Feb 2023. The median follow-up time was 12.5 months. The patient’s backgrounds were well-balanced. The median PFS was significantly longer with afatinib treatment than with chemotherapy (10.6 vs. 5.7 months; hazard ratio for death or disease progression, 0.422; 95% confidence interval, 0.256–0.694; p = 0.0007). The data and safety monitoring committee recommended an early study termination. The objective response was similar in both groups: 61.4% with afatinib treatment and 47.1% with chemotherapy (p = 0.2069). The rate of grade ≥3 treatment resulting in adverse events in both groups was 43.8% and 37.1%, respectively. The most common adverse events in the afatinib arm were diarrhea, rash, and paronychia. One treatment related death due to pneumonitis was observed in the afatinib arm.

Conclusions

Afatinib is superior to platinum doublet chemotherapy as an initial treatment for uncommon or compound EGFR mutation-positive advanced NSCLC.

Clinical trial identification

jRCTs 031180175.

Editorial acknowledgement

Legal entity responsible for the study

Thoracic Oncology Research Group (TORG).

Funding

Boehringer-Ingelheim.

Disclosure

S. Miura: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Boehringer-Ingelheim Japan, Pfizer, Novartis, MSD, Kyowa Hakko Kirin, Daiichi Sankyo, Nippon Kayaku, Amgen, Merck, Takeda Pharmaceutical. H. Tanaka: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai pharmaceutical, Boehringer Ingelheim, Eli Lilly, MSD, Ono pharmaceutical, Merck, Novartis, Takeda pharmaceutical, Pfizer, DaiIchi Sankyo pharmaceutical, Taiho pharmaceutical, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Chugai pharmaceutical, Merck, AstraZeneca, MSD, Eli Lilly, Ono pharmaceutical, Bristol Myers Squibb, Merck, Takeda pharmaceutical, Taiho pharmaceutical, Pfizer, Daiichi Sankyo pharmaceutical, AbbVie. H. Yoshioka: Financial Interests, Personal, Invited Speaker, Lecture fee: Eli Lilly Japan K.K., Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisor: Delta-Fly Pharma; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Jannsen Pharmaceutical, MSD, Novartis Pharma, Delta-Fly Pharma, Boehringer Ingelheim. T. Kurata: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Pfizer, Bristol Myers, Takeda, Eli Lilly, Chugai, Nipponkayaku, Yansen, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: MSD, Takeda. T. Fukuhara: Financial Interests, Institutional, Research Grant: MSD, Bristol Myers Squibb, Novartis. Y. Sato: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Bristol Myers Squibb, Eli Lilly, Takeda, Kyowa Kirin. Y. Shiraishi: Financial Interests, Personal, Invited Speaker: Chugai Pharma, Ono Pharmaceutical, Bristol Myers Squibb Company, AstraZeneca, Taiho Pharmaceutical; Financial Interests, Institutional, Invited Speaker: Chugai Pharma; Non-Financial Interests, Principal Investigator: Chugai Pharma. S. Teraoka: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Thermo Fisher Scientific K.K.; Financial Interests, Personal, Advisory Board: Pfizer R&D Japan G.K.. T. Kato: Financial Interests, Personal, Advisory Board, speaker, consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, speaker: Pfizer; Financial Interests, Personal, Other, consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, consultancy, speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis; Financial Interests, Personal, Advisory Board: BeiGene, Glaxo; Financial Interests, Personal, Full or part-time Employment, Family member: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Chugai, MSD, Pfizer, AstraZeneca, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biophama, Haihe Biopharma, Blueprint Medicines, Turning Point. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie, Roche/Chugai; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku; Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, ONO pharmaceutical, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AbbVie. Y. Takiguchi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Daiichi Sankyo, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Lilly, Pfizer, Novartis, Kyowa Kirin International, MSD, Eisai, Takeda, Amgen; Financial Interests, Personal, Other, Member of Ethics Committee: Oncolys BioPharma; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Lilly, Chugai Pharma, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: MSD Oncology, AstraZeneca, AbbVie. Y. Goto: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., AstraZeneca K.K., GSK K.K., Pfizer Japan Inc., Takeda Pharmaceutical CO., LTD., Nippon Kayaku Co.,Ltd., Novartis Japan, Bristol-Myers Squibb K.K., Kyowa Hakko Bio Co., Ltd., Eli Lilly Japan K.K.. S. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Ono, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono, Bristol Myers Squibb, Taiho, Eli Lilly, Pfizer, Boehringer Ingelheim, Takeda; Financial Interests, Research Grant: AstraZeneca, Chugai. E. Ichihara: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Takeda Pharmaceutical, MSD, Novartis, Ono pharmaceutical, BMS, Chugai pharmaceutical, Eli Lilly Japan, Janssen Pharmaceutical K.K.; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: MSD, Takeda Pharmaceutical, Janssen Pharmaceutical K.K., Giliad; Non-Financial Interests, Institutional, Product Samples: Janssen Pharmaceutical K.K.. H. Okamoto: Financial Interests, Institutional, Research Grant: MSD, Taiho, Bristol Myers Squibb. All other authors have declared no conflicts of interest.