Systemic single-agent or combination treatment incorporating targeted agents, immune checkpoint inhibitors (ICIs), and/or chemotherapy is the mainstay of frontline therapy for patients with metastatic non-small cell lung cancer (NSCLC).

Mehmet Altan, MD, Associate Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, who presented data from the phase III LONESTAR trial at the 2026 World Conference on Lung Cancer, explained that the objective of local consolidative therapy (LCT) is to “eradicate residual or resistant clones at known disease sites after systemic therapy, with the goal of delaying progression, and in some settings, extending survival.”

The Breakthrough Immunotherapy for Advanced NSCLC

Clinical Outcomes of the Phase III Lonestar Trial: Local Consolidation Therapy After Nivolumab Plus Ipilimumab in NSCLC

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LCT was applied as an intensive, direct radiation- or surgery-based approach to target detectable residual disease. The addition of LCT to targeted therapy has been shown to prolong survival in patients with metastatic NSCLC harboring actionable genomic alterations. The value of LCT in tumors lacking actionable alterations, however, remains controversial.

LCT following first-line induction with ICIs in metastatic NSCLC without actionable alterations has yielded mixed results, Dr. Altan said, citing NRG-LU002.

In LONESTAR, a single-center, open-label, randomized controlled study, Dr. Altan and colleagues evaluated the value of LCT, based on radiation to ≥ 1 residual site, with or without surgery, in patients who received frontline nivolumab and ipilimumab induction therapy for metastatic NSCLC with wild-type EGFR or ALK genomic alterations.

After dual immune checkpoint blockade, 166 patients who did not have progressive disease were randomly assigned at a ratio of 1:1 to continue the ipilimumab-nivolumab combination for up to two years (ICI-only) or undergo LCT followed by the combination ICI therapy for up to two years (ICI+LCT).

The primary endpoint was overall survival (OS); if the primary endpoint failed to show significant differences, a coprimary endpoint of OS in patients with oligometastatic disease was planned. Progression-free survival (PFS) and safety were secondary endpoints.

Dr. Altan said the demographic, clinical, and tumor characteristics of patients in the two treatment arms were well balanced, with no notable differences in smoking status, programmed death protein ligand 1 (PD-L1) expression in tumors, the proportion of patients with oligometastatic versus polymetastatic disease, or response to induction therapy.

In the ICI+LCT arm, 62 of the 83 patients received radiation alone as LCT, eight received surgery alone, and nine received radiation and surgery. Four patients in the ICI+LCT arm did not receive LCT for various reasons.

There were no significant differences in median OS between the treatment arms; median OS was 43.2 months in the ICI+LCT arm, compared with 52.8 months in the ICI-alone arm, with a hazard ratio (HR) of 1.14 (95% confidence interval [CI], 0.75-1.74; P=0.54).

The coprimary endpoint of OS in the subset of patients with oligometastatic disease also did not differ significantly between arms; median OS in ICI+LCT recipients was 42 months, compared with 75.8 months in patients who received ICI alone (HR, 1.68; P=0.12).

The addition of LCT did not improve PFS in the full cohort or in the subset with oligometastatic disease. Median PFS was 21.3 months with LCT versus 24.3 months without LCT in the full cohort (HR, 0.79; P=0.22) and 35.7 months versus 44 months for patients with oligometastatic disease (HR, 1.38; P=0.284).

“Unlike in actionable genomic alteration-positive NSCLC treated with targeted therapy or in chemotherapy-treated metastatic NSCLC, adding LCT after dual ICI induction therapy in metastatic NSCLC did not improve OS or PFS,” Dr. Altan said.

While the overall profile of adverse events (AEs) was comparable, with similar rates of ≥ grade 3 treatment-related AEs, pneumonitis rates were higher in LCT recipients than in ICI-alone recipients (9.5% vs. 4.9%). Also, at the time of reinitiation of ICI therapy, lymphopenia rates were markedly higher in the LCT arm (54.6% vs. 7.5%).

A post-hoc subgroup analysis showed that eight of the 17 (47%) patients in the ICI+LCT arm who underwent surgery achieved complete pathologic response. The median time to resume dual ICI therapy was longer in patients who underwent surgery than in recipients of ICI alone (58 days vs. 0 days).

Receipt of mediastinal radiotherapy was associated with higher rates of lymphopenia in the subset who received radiation within the LCT than in those who did not; ≥ grade 2 lymphopenia rates were 70% in mediastinal radiation recipients, compared with 28% in patients who did not receive mediastinal radiation.

Some have speculated that lymphocyte depletion associated with XRT may have compromised the efficacy of subsequent ICI therapy.  Corey Langer, MD, FACP and Editor of ILCN worries that this significant drop in lymphocytes linked to XRT, especially mediastinal XRT, may have robbed immunotherapy of its intended target.

Dr. Altan reminded the audience that LONESTAR was not powered for the subgroup analysis.

Overall, while LONESTAR showed that LCT is “feasible,” the findings “do not support the routine utilization of LCT after ipilimumab and nivolumab induction in metastatic NSCLC outside of a clinical trial,” he said.

Further analysis of LONESTAR data by radiation site, type, and completion/noncompletion of LCT is ongoing.