The field of lung cancer treatment celebrates a significant milestone this year: the 20th anniversary of the discovery of the EGFR gene mutation. This breakthrough revolutionized oncology by enabling personalized treatment strategies tailored to each patient's unique tumor profile.
The Dawn of Precision Medicine in Lung Cancer
According to Grace Dy, MD, Director of Translational Research for Thoracic Medicine at Roswell Park Comprehensive Cancer Center, the discovery of the EGFR mutation marked the beginning of precision medicine in lung cancer treatment. This pivotal finding allowed oncologists to select specific drugs based on the cancer's molecular profile, significantly increasing the likelihood of a positive treatment response compared to traditional chemotherapy.
Precision medicine hinges on identifying unique characteristics or genetic errors present only in cancer cells and developing drugs that target these specific features. In lung cancer, the development of EGFR-targeting drugs preceded the understanding of the EGFR mutation itself. Initially, drugs like gefitinib and erlotinib were used broadly for non-small cell lung cancer, based on the hypothesis that targeting the EGFR protein, commonly found in lung cancers, would be effective. However, these drugs only showed significant efficacy in a small subset of patients, termed 'exceptional responders.'
Further research, leveraging advances in DNA sequencing, revealed that these exceptional responders harbored specific mutations in the EGFR gene. This discovery demonstrated that testing for EGFR gene mutations could predict therapy response, leading to improved survival rates for patients with non-small cell lung cancer treated with gefitinib or erlotinib compared to chemotherapy. To date, over 70 types of EGFR mutations have been identified.
Targeting KRAS Mutations: A Breakthrough
While EGFR mutations are found in approximately 10-15% of lung cancers in the United States, with regional and ethnic variations, mutations in the KRAS gene are more prevalent in certain regions. For decades, the KRAS mutation was considered 'undruggable' despite its discovery in 1982. However, in 2021, the FDA approved sotorasib, the first drug targeting the KRAS G12C mutation, followed by adagrasib. These approvals marked a significant breakthrough in treating non-small cell lung cancer.
One patient, Diana Halter, benefited from adagrasib through a clinical trial at Roswell Park. Diagnosed with stage 4 lung cancer and initially given only a few months to live, Diana experienced a significant improvement in her quality of life after chemotherapy and immunotherapy failed. Her tumor was found to have the KRAS G12C mutation, the specific target of adagrasib. Four years into the clinical trial, her tumors have shrunk, and a metastatic tumor on her spine remains stable.
The Future of Lung Cancer Treatment
Roswell Park continues to conduct multiple clinical trials studying new agents for lung cancer, designed to target specific mutations. Current research focuses on next-generation KRAS G12C inhibitors to overcome resistance to sotorasib and adagrasib, a drug targeting the G12D type of KRAS mutations, and a drug that may target any type of KRAS mutation. Additionally, researchers are exploring antibody-drug conjugates and new agents against mutations for which there are currently no available drugs, such as mutations of the MTAP gene.
With improved testing platforms to identify biomarkers and guide treatment decisions, continued progress is being made, leading to better survival outcomes for lung cancer patients.
