There has been remarkable progress in treating EGFR-variant lung adenocarcinoma with tyrosine kinase inhibitors such as gefitinib, erlotinib, osimertinib, and afatinib. However, several important issues remain unresolved, including whether there remains a role for chemotherapy, who should receive a tyrosine kinase inhibitor, when to start treatment, how to monitor efficacy, and when to stop therapy.
Although there are reasonably large data on the results of tyrosine kinase inhibitor therapy for EGFR-variant lung adenocarcinoma, there are considerably more data using tyrosine kinase inhibitors to treat chronic myeloid leukemia (CML). In a recent article in JAMA Oncology, I reviewed how the data on the use of tyrosine kinase inhibitors in CML might inform the use of these drugs for EGFR-variant lung adenocarcinoma.1
Comparing Tumor Types
There seem few similarities between EGFR-variant lung adenocarcinoma and CML, but this is misleading. Both cancers arise from a variant causing increased tyrosine kinase activity. In lung cancer, this typically results in an in-frame EGFR exon 19 deletion or a point mutation in exon 21. Increased tyrosine kinase activity in CML results in a chromosome translocation (t[9;22]) forming the BCR::ABL1 fusion gene, which encodes a 210 kD oncoprotein.
However, there are also important differences between EGFR-variant lung adenocarcinoma and CML. CML is caused by one mutation—BCR::ABL1—present in everyone with this diagnosis and necessary and sufficient to cause the cancer. Although some people have additional variants, they are not necessary to develop CML.
Can knowledge learned from tyrosine kinase inhibitor therapy for CML inform therapy for operable EGFR-variant lung adenocarcinoma? Perhaps in the future but not now.— Robert Peter Gale, MD, PhD, DSc (hc), FACP, FRCP, FRCPI (hon), FRSM
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This contrasts with EGFR-variant lung adenocarcinoma, where different people can have different mutations, most people have at least 20 other mutations, and the EGFR variant is necessary but not sufficient to cause the cancer. Moreover, EGFR variants are found in rare lung cells in healthy people, implying something else is needed, perhaps air pollution.2 Also, although people with both cancers may develop resistance to tyrosine kinase inhibitors, the rate of such resistance is 20% to 30% in EGFR-variant lung adenocarcinoma vs 5% in CML.
There are also differences in diagnostic criteria. Having BCR::ABL1 is the sine qua non for diagnosis of CML, whereas diagnosis of EGFR-variant lung adenocarcinoma is based on histology followed by DNA analyses.3
What about therapy? Everyone with CML receives a tyrosine kinase inhibitor starting at diagnosis, whereas people with operable stage IB–IIIA lung adenocarcinoma and an EGFR variant typically receive surgery with or without adjuvant chemotherapy and/or a tyrosine kinase inhibitor as neoadjuvant treatment, adjuvant treatment, or both.
An important difference between therapy with tyrosine kinase inhibitors for EGFR-variant lung adenocarcinoma and CML is how efficacy is monitored. In CML, monitoring is by quantifying the blood concentration of BCR:ABL1 RNA transcripts, whereas in lung adenocarcinoma, monitoring is by serial computed tomography and positron-emission tomography scans. There is recent progress testing cell-free DNA for the EGFR-variant lung adenocarcinoma, but this is in an early stage and not standard of care.
Therapy Duration
An important question is how long to continue tyrosine kinase inhibitor therapy for these cancers and when to stop treatment. In CML, tyrosine kinase inhibitor therapy is continued indefinitely or until a sustained deep molecular response is achieved, after which about 20% of people are able to permanently discontinue therapy without leukemia recurrence. This is termed therapy-free remission. In responders to tyrosine kinase inhibitors, we and others reported the possibility of decreasing the dose without leukemia recurrence.4 The important point is although when therapy is stopped, about one-half of people have molecular evidence of leukemia recurrence, but this is easily reversed by restarting tyrosine kinase inhibitor therapy.
In EGFR-variant lung adenocarcinoma, the major clinical questions are who should receive tyrosine kinase inhibitors; when; and when, if ever, to stop treatment. Surgery with or without chemotherapy cures about one-half of people with operable EGFR-variant lung adenocarcinoma. Obviously, persons who are already cured cannot benefit from receiving tyrosine kinase inhibitor therapy but can be harmed. Unfortunately, we cannot accurately identify people who are cured from those who are not unless we wait for recurrence. Moreover, there are no data showing that waiting for recurrence before starting therapy with tyrosine kinase inhibitors is detrimental.
Furthermore, if someone is to receive therapy with a tyrosine kinase inhibitor, should it be given as a neoadjuvant, adjuvant, or both? Also how long should tyrosine kinase inhibitor therapy be given? In the ADAURA trial, osimertinib was given for 3 years.5 Whether a briefer or longer therapy interval might be better is unknown. A phase II trial is testing the use of 5 years of osimertinib, but it has no comparator arm. Unfortunately, there are no data from a prospective trial suggesting that assaying cell-free DNA for EGFR mutations during tyrosine kinase inhibitor therapy is an accurate way to assess efficacy or indicate when to stop treatment.
Remaining Questions and Challenges
So, can knowledge learned from tyrosine kinase inhibitor therapy for CML inform therapy for operable EGFR-variant lung adenocarcinoma? Perhaps in the future, but not now. What are the major differences? One is the complexity of EGFR-variant lung adenocarcinoma compared with CML. A second is our much better understanding of the pathophysiology of CML compared with EGFR-variant lung adenocarcinoma. And third is the imprecision in monitoring the efficacy of tyrosine kinase inhibitors in EGFR-variant lung adenocarcinoma compared with CML.
Therapy with tyrosine kinase inhibitors such as osimertinib for lung adenocarcinoma is a huge advance, substantially extending progression-free survival and probably survival.6 However, not all survivors are progression-free, and most receive subsequent therapies such as immune therapy. There are important remaining questions and challenges in optimizing therapy with tyrosine kinase inhibitors for EGFR-variant lung adenocarcinoma. Knowledge from treating CML suggests progress depends on developing biomarkers such as cell-free DNA analyses to monitor and direct therapy.
Dr. Gale is with the Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London.
DISCLOSURE: Dr. Gale is a consultant to Antengene Biotech LLC; Medical Director, FFF Enterprises; a speaker for Janssen Pharmaceuticals and Jiangsu Hengrui Pharmaceuticals; on the Board of Directors for the Russian Foundation for Cancer Research Support; and on the scientific advisory board for StemRad.
Acknowledgement: Dr. Gale is supported by the UK National Institute of Health Research Biomedical Research Centre funding scheme.
REFERENCES
1. Gale RP: Can knowledge from treating chronic myeloid leukemia inform therapy of EGFR-mutant lung adenocarcinoma? JAMA Oncol. February 20, 2025 (early release online).
2. Hill W, Lim EL, Weeden CE, et al: Lung adenocarcinoma promotion by air pollutants. Nature 616:159-167, 2023.
3. Williamson DFK, Marris SRN, Rojas-Rudilla V, et al: Detection of EGFR mutations in non-small cell lung cancer by droplet digital PCR. PLoS One 17:e0264201, 2022.
4. Li Z, Zhang X, Zhao Y, et al: Imatinib dose reduction after major molecular response in chronic-phase chronic myeloid leukemia. Cancer 131:e35565, 2025.
5. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.
6. Tsuboi M, Herbst RS, John T, et al; ADAURA Investigators: Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 389:137-147, 2023.
