Treatment of Oligometastatic EGFR-Mutant Lung Cancer

EGFR tyrosine kinase inhibitors (TKIs) are effective treatments for EGFR-mutant non-small cell lung cancer (NSCLC). However, even after undergoing systemic therapy, patients may have oligometastatic disease.

“A lot of patients respond well to current treatment options — whether it is osimertinib [Tagrisso] with or without platinum-based chemotherapy or amivantamab [Rybrevant] with lazertinib [Lazcluze] — but trials have shown despite that response, some will still have residual disease left behind,” said Danny Nguyen, MD, of City of Hope Orange County in Irvine, California.

Oligometastatic disease is heterogenous and has been defined differently across trials, Nguyen explained. Generally the term refers to a limited number of existing or new metastatic sites, with five or fewer sites often used as the definition in clinical trials.

“The question is, for those patients who respond well to treatment, is there something else they can do to better control and contain the disease that allows the patient to live longer?” Nguyen said.

The answer may be yes.

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 the use of local radiation therapy, including stereotactic body radiation therapy (SBRT), to the primary tumor and oligometastatic sites for patients without progression on systemic therapy.

“There have been multiple trials spanning decades that have looked at the role of local ablative therapy like SBRT that have shown if we treat patients in that manner that they get additional benefit in terms of progression-free survival [PFS],” Villaruz said.

One of the first trials to tackle this question was by Gomez et al, with updated results reported in the Journal of Clinical Oncology in 2019; the trial demonstrated that local consolidative therapy versus maintenance therapy or observation prolonged PFS and overall survival (OS). There were a few patients with EGFR mutations who also benefited from local consolidative therapy.

Among those studies that looked specifically at EGFR-mutant disease, “a lot of the studies showed benefit [to radiotherapy] in patients who responded well to [first-line TKIs] erlotinib [Tarceva] or afatinib [Gilotrif] who then got local consolidative therapy,” Nguyen said.

For example, the phase III SINDAS trial compared first-generation EGFR-TKI therapy in first-line 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. Patients assigned to receive radiotherapy had significantly improved PFS (20.2 vs 12.5 months with no radiotherapy, PP

However, it should be acknowledged that treatment of EGFR-mutant NSCLC has evolved since the SINDAS trial, with more effective first-line therapies and salvage therapies, leaving it unclear if the benefit of radiotherapy applies to current treatments.

Still an Option?

At the 2024 American Society of Clinical Oncology annual meeting, researchers presented results of a phase II trial looking at 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.

Other trials underway are also combining 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,” Nguyen said. “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, STEREO will evaluate osimertinib and locally ablative radiotherapy in patients with synchronous oligometastatic EGFR-mutant NSCLC; NORTHSTAR will compare osimertinib with or without local consolidation therapy — including surgery — for patients with EGFR-mutant disease.

According to Villaruz, though, surgery is not often used in patients with metastatic EGFR-mutant NSCLC.

“These patients do so well on systemic therapy that we don’t typically do any surgery,” she said. “At the end of the day, it is a systemic disease and there is always going to be micrometastatic disease somewhere in the body. We typically reserve surgery for the curative paradigm.”

Currently available first-line systemic regimens, and options for subsequent lines of therapy, are providing patients with dramatic tumor response, including central nervous system response. With these continued gains, the role of radiotherapy may be further diminished in the future; however, only additional time and data from well-done clinical trials will provide clinicians with further guidance.