EGFR tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), yet many patients still develop oligometastatic disease. Experts are exploring whether local therapies can improve outcomes in these cases, potentially extending survival and delaying disease progression.
The Role of Local Therapy
"We very often use radiation in the metastatic paradigm," said Liza Villaruz, MD, of the UPMC Hillman Cancer Center in Pittsburgh. "Often, the use of radiation extends the amount of time a patient can stay on current systemic therapy."
National Comprehensive Cancer Network (NCCN) guidelines recommend considering local radiation therapy, including stereotactic body radiation therapy (SBRT), for patients without progression on systemic therapy. Multiple trials have demonstrated that local ablative therapy like SBRT can provide additional benefits in terms of progression-free survival (PFS).
One of the first trials to address this question was by Gomez et al, with updated results reported in the Journal of Clinical Oncology. The trial demonstrated that local consolidative therapy versus maintenance therapy or observation prolonged PFS and overall survival (OS). A subset of patients with EGFR mutations also benefited from local consolidative therapy.
SINDAS Trial: A Landmark Study
Among studies specifically examining EGFR-mutant disease, many have shown benefit from radiotherapy in patients who responded well to first-line TKIs like erlotinib or afatinib followed by local consolidative therapy. For example, the phase III SINDAS trial compared first-generation EGFR-TKI therapy with or without upfront radiotherapy in 133 patients with EGFR-mutant NSCLC. Oligometastatic disease was defined as five or fewer metastases with two or fewer lesions in any one organ.
The SINDAS trial revealed that patients receiving radiotherapy had significantly improved PFS (20.2 vs 12.5 months without radiotherapy, P < 0.001) and median OS (25.5 vs 17.4 months, respectively, P < 0.001).
However, it is important to note that the treatment landscape for EGFR-mutant NSCLC has evolved since the SINDAS trial, with more effective first-line and salvage therapies now available. This raises questions about whether the benefits of radiotherapy still apply to current treatment strategies.
Combining Osimertinib and SABR
At the 2024 American Society of Clinical Oncology annual meeting, researchers presented results from a phase II trial evaluating the safety and efficacy of osimertinib plus stereotactic ablative radiation (SABR). The trial included 43 patients with disease response to osimertinib who also had persisting lesions; patients received SABR followed by continued osimertinib. With a median follow-up of almost 3 years, the median PFS was 32.6 months and median OS was 45.7 months.
Ongoing Research and Future Directions
Several ongoing trials are exploring the combination of third-generation EGFR TKIs with upfront radiotherapy in patients with oligometastatic disease.
"There is some thought that there is a synergistic effect of radiation; the radiation may make these cancer cells more susceptible to systemic treatment," said Danny Nguyen, MD, of City of Hope Orange County in Irvine, California. "The thinking is that the residual disease, after responding to initial therapy, may be more resistant to systemic treatment, so local consolidative therapy helps reduce the amount of treatment-resistant cancer cells. There's also some evidence to suggest that these residual cells may promote metastatic disease through other mechanisms, such as blood vessel formation and suppressing the immune system."
For example, the STEREO trial will evaluate osimertinib and locally ablative radiotherapy in patients with synchronous oligometastatic EGFR-mutant NSCLC. The NORTHSTAR trial will compare osimertinib with or without local consolidation therapy for patients with EGFR-mutant disease.
While surgery is not commonly used in patients with metastatic EGFR-mutant NSCLC due to the effectiveness of systemic therapies, radiotherapy remains a valuable option for local disease control. As first-line systemic regimens continue to improve, the role of radiotherapy may evolve, but further data from well-designed clinical trials will be crucial in guiding clinicians.
