LCT Gains Ground in EGFR-Mutated NSCLC

Adding local consolidative therapy (LCT) to osimertinib (Tagrisso) extended median progression-free survival (PFS) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from the phase 2 NORTHSTAR trial (NCT03410043).¹ The data, which showed that surgical resection remained feasible even among patients with stage IV disease, are reshaping how oligometastatic and oligoprogressive NSCLC are managed alongside systemic therapy, according to Eric K. Singhi, MD, and Kyle G. Mitchell, MD, MSc.

“EGFR-mutated NSCLC behaves differently from other forms of lung cancer, making it particularly well suited for evaluating LCT,” Singhi said. “Osimertinib often produces deep systemic responses, but resistance frequently develops first in only a few sites, a pattern we refer to as oligoprogression. The question is whether eliminating those resistant sites with local therapy can prolong the benefit of systemic treatment.”

Singhi is the medical oncology faculty lead of the MD Anderson Young Onset Lung Cancer Program and an assistant professor of general oncology and thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. Mitchell is an assistant professor in the Department of Thoracic and Cardiovascular Surgery at The University of Texas MD Anderson Cancer Center.

In a dual interview with OncLive®, Singhi and Mitchell discussed the current standing of LCT within the lung cancer treatment landscape, notable data from the NORTHSTAR trial, and the next steps for integrating LCT into clinical practice.

OncLive: What is the present role of LCT in lung cancer?

Mitchell: Oligometastatic lung cancer is a distinct disease phenotype that is typically defined by the number of metastatic sites present either at diagnosis or later in a patient’s treatment course. Generally, these are patients with a limited number of metastases rather than widespread disease. Although definitions vary, oligometastatic disease is often considered to include 3 or fewer metastatic sites, whereas more than 5 sites is typically considered polymetastatic disease.

Over the past decade, there has been increasing interest in applying LCT to both the primary tumor and metastatic sites. This can include surgery, radiation, or ablative therapies directed at all measurable disease. The rationale is that if systemic therapy, whether [it’s] chemotherapy, immunotherapy, targeted therapy, or another approach, is effectively controlling micrometastatic disease, adding local therapy may improve survival, prolong time to progression, delay the development of new metastases, or prevent the emergence of resistant tumor clones.

Several phase 2 studies have supported this concept, demonstrating improvements in PFS and, in some cases, overall survival [OS]. These studies generally enrolled heterogeneous patient populations without restricting enrollment based on oncogenic drivers or specific systemic or local therapies. However, [data from] the [phase 2/3] NRG-LU002 trial [NCT03137771] tempered some of the enthusiasm for broadly applying LCT in an unselected patient population.

Singhi: NRG-LU002 was a randomized trial that compared maintenance systemic therapy alone with maintenance systemic therapy plus LCT in patients with limited metastatic NSCLC.² The study demonstrated that LCT should not be applied broadly to all patients. Specifically, adding LCT did not improve PFS or OS, and patients experienced higher rates of treatment-related toxicity, including grade 3 or higher pneumonitis. As a result, the phase 3 portion of the trial was not pursued.

These findings emphasize that disease biology and the type of systemic therapy patients receive are critically important. Approximately 90% of patients in NRG-LU002 received immunotherapy-based regimens, so the trial does not definitively answer whether LCT should or should not be used in every clinical setting. Rather, it highlights the importance of identifying the right patient, the right timing, and the right multidisciplinary team.

Another important question is whether patients with stage IV lung cancer who are responding well to systemic therapy should receive additional local treatment. Historically, stage IV disease was managed with systemic therapy alone. However, targeted therapies such as osimertinib can now produce deep responses, leaving only limited residual disease. That creates an opportunity to treat those remaining sites with surgery or radiation, which remains an important area of ongoing multidisciplinary investigation.

How was NORTHSTAR designed?

Mitchell: The study enrolled patients with EGFR-mutated adenocarcinoma who were either TKI-naive or had acquired a T790M mutation without prior treatment with a third-generation TKI. Patients were stratified according to prior TKI exposure, number of metastatic sites at presentation, response to therapy, and presence of brain metastases.

All patients received induction osimertinib for 6 to 12 weeks before being randomly assigned to continue osimertinib alone or receive osimertinib plus LCT. The local treatment modality—surgery, radiation, or another approach—was selected through multidisciplinary discussion. The primary end point was PFS, with secondary end points including OS, safety, perioperative outcomes, and subgroup analyses.

What are the notable data that have been reported from NORTHSTAR?

Singhi: Adding LCT to osimertinib improved median PFS by approximately 8 months compared with osimertinib alone, [at] 25.3 months [95% CI, 19.4-45.0] vs 17.5 months [95% CI, 14.5-24.3], respectively.¹ Surgical resection was feasible even in patients with stage IV disease, with 41% of patients receiving surgery as part of LCT. The benefit of LCT extended beyond patients with classic oligometastatic disease and was also observed among some patients with polymetastatic disease. Complete LCT appeared more beneficial than partial consolidation, nearly doubling PFS among patients with polymetastatic disease. Finally, there was no increase in overall toxicity, including pneumonitis, with the addition of LCT.

What factors do you weigh when considering a patient for LCT?

Singhi: When considering LCT in practice, I think about the “rule of three”: the right patient, the right time, and the right team. The right patient is someone whose goals align with pursuing aggressive local therapy, who has experienced a strong response to systemic treatment, and whose disease is well controlled. The right time is after systemic therapy has produced maximal response and disease burden is at its lowest—not at diagnosis. Finally, the right team is essential. Decisions regarding LCT should be made in a multidisciplinary setting involving medical oncology, radiation oncology, and thoracic surgery.

Mitchell: One important question is whether surgery or radiation is the preferred local therapy for the primary tumor. We don’t have definitive data because no study has been adequately powered to answer that question.

Our approach is multidisciplinary. Every patient is evaluated by the entire lung cancer team and discussed at multidisciplinary tumor board. From a surgical perspective, I use my own “rule of three”: Can we do it? Should we do it? Can we get the patient through it?

“Can we do it?” addresses technical feasibility. “Should we do it?” considers the broader oncologic context. “Can we get the patient through it?” focuses on patient-specific operative risk.

We recently presented data from 21 patients who underwent surgery following induction osimertinib. Many had characteristics that historically would have discouraged surgery, including polymetastatic disease and extensive tumor burden. Lobectomy was commonly performed, and these operations were often technically challenging because osimertinib can induce substantial fibrosis and inflammation.

Despite that complexity, perioperative outcomes were excellent. Median hospital stay was 3 days, complications were uncommon, no patients required ICU admission or reoperation, and there were no perioperative deaths. These findings suggest that carefully selected patients can safely undergo surgery despite advanced disease characteristics.

How do you identify the optimal window for integrating LCT into treatment?

Singhi: This remains an important unanswered question. In NORTHSTAR, patients received approximately 6 to 12 weeks of upfront osimertinib before consideration of LCT, but that timing reflected the study design rather than a strict clinical rule.

Ideally, patients have experienced a deep response to systemic therapy, are doing well clinically, and remain motivated to pursue additional local treatment. Determining the optimal timing requires multidisciplinary discussion for each individual patient.

Mitchell: I agree. The trial used a 6- to 12-week induction period, but we don’t consider that a rigid requirement. We frequently see patients referred after much longer periods of treatment, and we evaluate them individually.

I’ve operated on patients who received osimertinib for years before developing localized progression. The goal is to intervene with surgery or radiation before widespread resistance develops. In one recent patient, surgery revealed small cell transformation, which is an uncommon but recognized mechanism of resistance. We’re still learning what the optimal timing should be, and we’re willing to apply this treatment paradigm more broadly when appropriate.

What barriers still exist to implementing LCT as a precision treatment strategy?

Mitchell: One challenge is ensuring that every patient undergoes multidisciplinary evaluation. In many community settings, medical oncologists manage these patients independently, whereas at MD Anderson we routinely discuss these cases at multidisciplinary tumor board.

The Society of Thoracic Surgeons recently published consensus recommendations stating that patients with oligometastatic lung cancer should undergo multidisciplinary evaluation that includes a thoracic surgeon.

Another barrier is awareness. Some surgeons may view features such as malignant pleural effusion, lymphangitic spread, or extensive metastatic burden as absolute contraindications to surgery. However, our experience suggests that these features should not automatically exclude carefully selected patients from consideration. Education and multidisciplinary collaboration remain essential.

Singhi: Although we’re encouraged by the NORTHSTAR results, it’s important to remember that this was a phase 2 study, and OS data are still immature. I also don’t think NORTHSTAR closes the chapter on LCT. Rather, it reframes the discussion. The study evaluated single-agent osimertinib, but today’s treatment landscape increasingly includes combination approaches such as osimertinib plus platinum-based chemotherapy from the [phase 3] FLAURA2 trial [NCT04035486] or amivantamab-vmjw [Rybrevant] plus lazertinib [Lazcluze] from the [phase 3] MARIPOSA trial [NCT04487080]. As systemic therapies become more effective, we need to continue asking how LCT should be integrated into treatment and how it fits alongside increasingly sophisticated therapies in later lines of care.

One of the central themes of this discussion is that we’re moving away from thinking exclusively about systemic therapy, even for patients with stage IV disease. Biology matters, and the question is whether local therapy can eliminate residual resistant disease after an excellent systemic response.

The biggest challenge is ensuring patients have access to the right multidisciplinary team. Decisions about LCT should never be made by a single [provider]. Instead, they require thoughtful discussion among multiple specialists, the patient, and their family because there are many nuances involved in deciding whether LCT is appropriate.

References

1. Elamin YY, Gandhi S, Antonoff M, et al. NorthStar: a phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Ann Oncol. 2025;36(suppl 2):S1614. doi:10.1016/j.annonc.2025.09.086
2. Iyengar P, Hu C, Gomez DR, et al. NRG-LU002: randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2024;42(suppl 16):8506. doi:10.1200/JCO.2024.42.16_suppl.8506