LCT After Nivolumab/Ipilimumab Induction Fails to Improve Metastatic NSCLC Survival

Added local consolidative therapy (LCT) post-induction with nivolumab plus ipilimumab did not improve neither overall nor progression-free survival (OS; PFS) in patients with non-small cell lung cancer (NSCLC), according to new data from the phase 3 LONESTAR trial (NCT03391869).¹

Research presented by Mehmet Altan, MD, of MD Anderson Cancer Center at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC) in Seoul this week showed that even patients with oligometastatic NSCLC receiving LCT following the immune checkpoint inhibitor regimen did not report improved OS nor PFS through 90 weeks.

Though added LCT did not incur new safety signals following nivolumab plus ipilimumab nor did it increase grade ≥3 treatment-related adverse events (TRAEs), LONESTAR was closed early for futility after a data safety monitoring board (DSMB) reviewed outcomes of 166 of the planned 216 trial participants.

“Adding local consolidative therapy after induction dual checkpoint blockade was feasible, but it did not improve overall survival or progression-free survival in the overall population or among patients with oligometastatic disease,” Altan said in a statement accompanying the data.

LONESTAR Design and Intent

LCT has been linked to improved outcomes in certain patients with oligometastatic NSCLC treated with chemotherapy; Altan and colleagues described multiple mid-to-late stage trials — including most recently, NORTHSTAR (NCT04479306) and NRG-LU002 (NCT03137771) — have shown using it to eradicate residual or resistant clones at known diseases sites following systemic therapy may delay progression or even extend survival.

The phase 2 NORTHSTAR, presented at the European Society of Medical Oncology (ESMO) 2024 Annual Meeting, showed patients with eGFR-mutant NSCLC randomized to LCT defined as radiotherapy and/or surgery experienced a nearly 50% increased PFS (25.4 months) versus patients randomized to lone osimertinib (17 months).²

LONESTAR was an open-label, single-center, randomized phase 3 trial that enrolled immunotherapy-naive patients with metastatic NSCLC.¹ Following 12 weeks of induction nivolumab plus ipilimumab, patients with neither progression nor dose-limiting toxicity were randomized to either continued lone nivolumab/ipilimumab or LCT — defined as ≥1 disease site radiation and surgery when feasible — followed by nivolumab/ipilimumab.

The team sought co-primary endpoints of OS among overall trial participant and OS among patients in the oligometastatic subgroup, defined as ≥3 metastatic lesions. They additionally set secondary endpoints for PFS among the overall population, as well as in squamous and non-squamous histologic patients.

What Happened in LONESTAR

Investigators sought a sample size of 216 participants randomized 1:1 to either LCT plus nivolumumab plus ipilimumab or lone nivolumab plus ipilimumab. Among the 133 enrolled at study closure, the median patient age was 66 years old in the LCT arm, with 50.6% (n = 42) being female and 75.9% (n = 63) reporting a non-squamous histology. Approximately two-thirds (n = 53 [63.9%]) of patients in the LCT arm reported ≥1% positivity for PD-L1 expression.

In the LCT arm, 37 (44.6%) patients were oligometastatic. A majority of the arm (n = 63) received lone radiation as part of their LCT; 10 received radiation plus surgery.

Prior to the study closure, investigators observed a median OS of 52.8 months among patients receiving lone nivolumab plus ipilumumab versus 43.2 months among patients receiving added LCT with the regimen (hazard ratio [HR], 1.14; 95% CI, 0.75 – 1.74; P = .54).

Median PFS was lower among patients receiving added LCT versus lone nivolumab plus ipilimumab (32.2 vs 24.3 months). However, the finding was not statistically significant (HR, 0.79; 95% CI, 0.54 – 1.15; P = .220).

In the oligometastatic cohort, investigators observed a median OS of 75.8 months with nivolumab plus ipilimumab versus 42 months with added LCT (HR, 1.68; 95% CI, 0.87 – 3.26; P = .121). PFS in the metastatic group similarly favored the combination inhibitors without LCT (HR, 1.38; 95% CI, 0.76 – 2.52; P = .284).

Regarding safety, LCT was not associated with an increased overall incidence of grade ≥3 TRAEs. About 1 in 10 patients treated with the added therapy did report pneumonitis (n = 8 [9.5%]). Absolute lymphocyte counts were notably lower when systemic therapy was restarted in the LCT arm, investigators noted.

Next Steps

Altan and colleagues concluded that adding LCT to patients with NSCLC who did not progress on ipilimumab and nivolumab induction did not improve survival.

“These findings do not support the routine addition of LCT after ipilimumab/nivolumab induction for NSCLC with no AGA, outside of a clinical trial,” investigators wrote.

Ongoing analysis is considering the impact of the site and type of radiation as an LCT modality, Altan and colleagues wrote.

References

1. Altan M, Gandhi S, Antonoff MB, Vokes N, et al. Clinical Outcomes of the Phase III Lonestar Trial: Local Consolidation Therapy After Nivolumab Plus Ipilimumab in NSCLC. Presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC). Seoul, SK. September 12 – 15, 2026.
2. Rosa K. Osimertinib Plus Local Consolidative Therapy Significantly Extends PFS in EGFR-Mutant NSCLC. OncLive. Published October 17, 2025. Accessed September 12, 2026. https://www.onclive.com/view/osimertinib-plus-local-consolidative-therapy-significantly-extends-pfs-in-egfr-mutant-nsclc