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Clinical Trial
. 2025 Feb;132(3):245-252.
doi: 10.1038/s41416-024-02901-6. Epub 2024 Dec 5.

Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy

Sanjay Popat  1 , Adam Januszewski  2 , Mary O'Brien  1   3 , Tanya Ahmad  4 , Conrad Lewanski  3 , Ulrike Dernedde  5 , Petra Jankowska  6 , Clive Mulatero  7 , Riyaz Shah  8 , Jonathan Hicks  9 , Tom Geldart  10 , Mathilda Cominos  11 , Gill Gray  12 , James Spicer  13 , Karen Bell  9 , Simon Roitt  14 , Clive Morris  14 , Yenting Ngai  15 , Laura Hughes  15 , Allan Hackshaw  15 , William Wilson  16
Affiliations
Clinical Trial

Long term efficacy of first-line afatinib and the clinical utility of ctDNA monitoring in patients with suspected or confirmed EGFR mutant non-small cell lung cancer who were unsuitable for chemotherapy

Sanjay Popat et al. Br J Cancer. 2025 Feb.

Abstract

Background: Here we present long-term outcomes of first line afatinib in comorbid patients with suspected or confirmed EGFR mutant NSCLC otherwise considered unsuitable for chemotherapy, and the clinical utility of serial ctDNA monitoring.

Methods: TIMELY (NCT01415011) was a multicentre, single arm, phase II trial conducted in the UK. Patients aged ≥18 were treated with daily oral afatinib (40 mg) until disease progression or unacceptable toxicity. Blood samples for ctDNA analysis were obtained at baseline and 12-weekly until treatment discontinuation. The primary endpoint was PFS.

Results: Thirty-nine patients were enrolled between March 2013 and August 2015. Median follow-up was 98 months (range 69-101). Median PFS was 7.9 months (95% CI 4.6-10.5). Seven patients (18%) continued afatinib beyond 18 months, 3 beyond 36 months and 2 were still on treatment at last follow-up 101 months post-treatment initiation. Analysis of baseline ctDNA samples identified 8 EGFR mutant cases that were not identified by tissue genotyping and ctDNA clearance was associated with improved PFS and OS.

Conclusion: Afatinib is a viable treatment option for tissue or ctDNA-detected EGFR mutant NSCLC comorbid patients, with a proportion achieving long-term clinical benefit. Plasma ctDNA testing improved EGFR mutant identification and its clearance predicted improved PFS and OS.

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Conflict of interest statement

Competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Popat’s has consulting /advisory Role with Amgen, AstraZeneca (AZ), Bayer, Blueprint, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline (GSK), Guardant Health, Incyte, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme (MSD), Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics & EQRx. He has received payment/Honoraria from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche & Takeda. He has provided expert testimony to Roche, Merck Serono. He has received meeting attendance support from Janssen & Roche. He has a leadership / fiduciary Role with the British Thoracic Oncology Group (BTOG), ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation & ETOP-IBCSG Partners Foundation Board. Dr Januszewski has received grant/holds contracts with Gilead & Roche. He has received teaching payments from AZ, Johnson and Johnson, Roche, Pfizer, MSD & Bayer. He has received meeting attendance support from Johnson & Johnson Pharmaceuticals & Roche Pharmaceuticals. He has an advisory role with BMS, AZ, Pfizer & MSD. He has a leadership/fiduciary role with BTOG. Dr Ahmad has received speaker payment from AZ. She has received payment for an advisory project from Roche and meeting attendance support from Takeda. Dr Shah has an advisory role with BI. He has received meeting attendance support from BI. He has a leadership / fiduciary role with BTOG & EGFR + UK. Dr Geldart has received honoraria from Merck and meeting attendance support from BMS. Prof Spicer has consulting compensation to author’s employer from AZ, BMS, GSK & RS Oncology; Advisory Board fees. He has an advisory role with CHM Cancer Vaccines Expert Working Group & CHM Expert Advisory Group on Oncology & Haematology. He has a leadership /fiduciary role with BTOG & Experimental Cancer Medicine Centres. He has stock/stock Options with Avacta & Epsiolgen. He has received reimbursements for treatment of trial patients from Achilles, BergenBio, BMS, Gilead, IO Biotech, Iovance, MSD, Roche, RS Oncology, Starpharma & Trizell. Dr Roitt has limited prior shares with Inivata. Dr Mulatero has stocks with Inivata. All remaining authors had no conflicts of interest to declare. Ethical approval and consent to participate: The TIMELY trial was approved by the Scotland A Research Ethics Committee. Written informed consent was obtained from all patients. The study was performed in accordance with the Declaration of Helsinki.

Figures

Fig. 1
Fig. 1. EGFR mutations.
Tumour mutations detected using baseline tissue and ctDNA for all patients.
Fig. 2
Fig. 2. Survival outcomes by EGFR mutation type (tissue and ctDNA).
a Progression-free survival and b Overall survival by EGFR mutation type, using both tissue and ctDNA.
Fig. 3
Fig. 3. Survival outcomes by ctDNA mutation clearance.
a Progression-free survival and b overall survival by whether baseline ctDNA became undetectable during serial measurements. *6 cases without serial ctDNA measurements and 15 without mutations.
Fig. 4
Fig. 4
Examples of two patients with ctDNA monitoring for disease progression. ND Not Detectable.
See this image and copyright information in PMC

References

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