Local consolidative therapy (LCT) administered after induction with nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve survival outcomes in patients with metastatic non-small cell lung cancer (NSCLC), including those with oligometastatic disease.
In the phase III LONESTAR trial, median overall survival (OS) was 43.2 months in the LCT plus nivolumab-ipilimumab arm compared with 52.8 months in the nivolumab-ipilimumab alone arm (HR 1.14, 95% CI 0.75-1.74, P=0.54), reported Mehmet Altan, MD, of the MD Anderson Cancer Center in Houston, at the World Conference on Lung Cancer (WCLC) in Seoul, South Korea.
A negative OS trend was also observed among patients with oligometastatic disease in the LCT-dual immunotherapy arm, with a median OS of 42.0 months versus 75.8 months in the nivolumab-ipilimumab alone arm (HR 1.68, 95% CI 0.87-3.26, P=0.12).
The addition of LCT also failed to yield a statistically significant improvement in progression-free survival (PFS). Among all patients, median PFS was 31.3 months in the LCT-dual immunotherapy arm versus 24.3 months in the nivolumab-ipilimumab alone arm (HR 0.79, 95% CI 0.54-1.15, P=0.22). Among patients with oligometastatic disease, median PFS was 35.7 months and 44.0 months, respectively (HR 1.38, 95% CI 0.76-2.52, P=0.284).
At a WCLC press briefing, Altan acknowledged that the LONESTAR regimen was “feasible,” but stated that the “findings do not support routine local consolidation therapy after ipilimumab and nivolumab induction in metastatic non-small cell lung cancer — without actionable genomic alteration — outside of a clinical trial.” The study was closed for futility after enrolling 166 patients.
Altan explained that the rationale for LCT is to eliminate residual or resistant clones at known disease sites following systemic therapy, with the goal of delaying progression and extending survival. In metastatic NSCLC, the addition of LCT to targeted therapy or chemotherapy has shown the ability to improve PFS, regardless of actionable genomic alteration, he noted. For instance, in the NORTHSTAR trial, osimertinib (Tagrisso) combined with LCT improved PFS in patients with EGFR-mutant locally advanced or metastatic disease.
The LONESTAR trial aimed to determine whether LCT — consisting of radiation or surgery — following dual immunotherapy would improve outcomes compared with dual immunotherapy alone in metastatic NSCLC patients with wild-type EGFR and ALK.
Eligible patients had stage IV NSCLC, were naïve to immunotherapy, and exhibited EGFR/ALK wild-type status. After 12 weeks of nivolumab-ipilimumab induction, patients without progression or dose-limiting toxicity were randomized to either continue nivolumab-ipilimumab alone or to receive LCT combined with dual immunotherapy. LCT consisted of radiation delivered to at least one disease site and surgery when clinically feasible.
Of the enrolled patients, 77 had oligometastatic disease at randomization. Sixteen patients in the LCT arm underwent surgery, and 71 patients in the LCT arm received radiation to at least one disease site.
The median age was 66 in the LCT-dual immunotherapy arm and 67 in the nivolumab-ipilimumab alone arm. Other baseline characteristics, including sex, histology, smoking status, previous chemotherapy, and PD-L1 expression, were well balanced between the two arms.
A subgroup analysis revealed that only patients under the age of 65 demonstrated an OS benefit with LCT-dual immunotherapy (HR 0.43, 95% CI 0.20-0.93).
Altan also reported that a post-hoc analysis identified a link between mediastinal radiation and increased lymphopenia in the LCT arm. “This may impair effector immune cells and blunt the benefit of consolidative therapy, although the LONESTAR study was not powered to analyze this subgroup,” he said.
Regarding safety, LCT-dual immunotherapy did not increase the overall incidence of grade 3 or higher adverse events. Pneumonitis was numerically more frequent in the LCT arm, occurring in 9.5% of patients compared with 4.9% in the nivolumab-ipilimumab alone arm.
An analysis by radiation site and type — intensity-modulated radiation therapy (RT) or stereotactic body RT — is ongoing, according to Altan.
