LCT Fails to Improve Survival in Metastatic NSCLC After Nivolumab/Ipilimumab Failure

The LONESTAR Trial Design and Futility Closure

The open-label, single-center, randomized phase 3 trial (NCT03391869) enrolled immunotherapy-naive patients with metastatic NSCLC. Dr. Mehmet Altan of the MD Anderson Cancer Center presented the findings, explaining that participants received 12 weeks of induction therapy using nivolumab plus ipilimumab. Those who did not experience disease progression or dose-limiting toxicity were randomized 1:1 to either continued lone dual checkpoint blockade or LCT—defined as radiation to at least one disease site, alongside surgery when feasible—followed by the continuation of nivolumab and ipilimumab.

Investigators initially planned to enroll 216 participants to evaluate co-primary endpoints of overall survival (OS) in the overall population and in an oligometastatic subgroup, which was defined as having three or more metastatic lesions. Secondary endpoints tracked progression-free survival (PFS) across both the overall cohort and patients split by squamous and non-squamous histologies. However, after a data safety monitoring board (DSMB) reviewed outcomes from 166 enrolled participants, the trial was closed early for futility.

“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 stated.

Survival Outcomes and Oligometastatic Subgroup Analysis

Among the 133 patients evaluated at study closure, the median patient age in the LCT arm was 66 years. Women comprised 50.6% (n = 42) of this arm, and 75.9% (n = 63) presented with a non-squamous histology. Furthermore, roughly two-thirds of patients in the LCT group—specifically 53 individuals, or 63.9%—exhibited PD-L1 expression positivity of at least 1%. Within the LCT arm, 37 patients (44.6%) had oligometastatic disease. Most of these patients received lone radiation as their LCT modality, while 10 received a combination of radiation and surgery.

The survival data showed no significant advantages for the consolidative approach. Median OS reached 52.8 months for patients receiving lone nivolumab plus ipilimumab, compared with 43.2 months for those who received added LCT (HR, 1.14; 95% CI, 0.75-1.74; P = .54). Progression-free survival in the overall population was 32.2 months for the systemic therapy group versus 24.3 months for the LCT group, though this difference lacked statistical significance (HR, 0.79; 95% CI, 0.54-1.15; P = .220).

For the oligometastatic cohort, median OS was 75.8 months with the immunotherapy combination alone, versus 42 months when LCT was added (HR, 1.68; 95% CI, 0.87-3.26; P = .121). Progression-free survival within this specific subgroup similarly favored the patients treated without local intervention (HR, 1.38; 95% CI, 0.76-2.52; P = .284).

Safety Profile and Clinical Implications

While the addition of LCT did not trigger new safety signals or increase the incidence of grade 3 or higher treatment-related adverse events (TRAEs), specific pulmonary risks emerged. Pneumonitis developed in 9.5% of patients (n = 8) in the LCT arm. Additionally, investigators observed that absolute lymphocyte counts dropped notably when systemic therapy was restarted following local intervention.

These findings contrast with prior mid-to-late-stage trials investigating LCT following chemotherapy or targeted therapy. For instance, the phase 2 NORTHSTAR trial (NCT04479306), presented at the European Society of Medical Oncology 2024 Annual Meeting, reported that patients with EGFR-mutant NSCLC achieved a nearly 50% improvement in progression-free survival when randomized to LCT alongside osimertinib compared to lone osimertinib. Other trials like NRG-LU002 (NCT03137771) have also examined eradicating residual clones at known disease sites after systemic treatment.

Despite those precedents in other treatment contexts, the LONESTAR investigators maintain a firm stance on dual checkpoint blockade combinations. “These findings do not support the routine addition of LCT after ipilimumab/nivolumab induction for NSCLC with no AGA, outside of a clinical trial,” study authors wrote. Ongoing analyses are currently evaluating whether the specific site or type of radiation used as an LCT modality influenced these outcomes.