Local Consolidative Therapy After Dual Immunotherapy Fizzles in Metastatic NSCLC

Local consolidative therapy (LCT) after induction treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) failed to improve survival outcomes in patients with metastatic non-small cell lung cancer (NSCLC), including those with oligometastatic disease.

In the phase III LONESTAR trial, the median overall survival (OS) was 43.2 months with LCT plus nivolumab-ipilimumab versus 52.8 months with nivolumab-ipilimumab alone (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.

There was also a negative OS trend among patients with oligometastatic disease in the LCT-dual immunotherapy arm, with a median OS of 42.0 months compared with 75.8 months in the nivolumab-ipilimumab alone arm (HR 1.68, 95% CI 0.87-3.26, P=0.12).

The strategy also failed to provide statistically significantly 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), while 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 said the LONESTAR regimen was “feasible,” but the current “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 observed that the rationale for LCT is to eradicate residual or resistant clones at known disease sites after systemic therapy in order to delay progression and extend survival. In the case of metastatic NSCLC, regardless of actionable genomic alteration, the addition of LCT to targeted therapy or chemotherapy has been able to improve PFS, he added. For example, in the NORTHSTAR trial, osimertinib (Tagrisso) plus LCT improved PFS in patients with EGFR-mutant locally advanced or metastatic disease.

LONESTAR’s objective was to see whether LCT (radiation or surgery) after dual immunotherapy would improve outcomes versus dual immunotherapy alone in metastatic NSCLC patients with wild-type EGFR and ALK.

Eligible patients had stage IV NSCLC, were immunotherapy naïve, and had EGFR/ALK wild-type status. After 12 weeks of nivolumab-ipilimumab induction, patients without progression or dose-limiting toxicity were randomized to continue nivolumab-ipilimumab alone or to LCT-dual immunotherapy. LCT consisted of radiation to at least one disease site and surgery when feasible.

Of these patients, 77 had oligometastatic disease at randomization, 16 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 balanced between arms.

A subgroup analysis showed that only patients under age 65 saw an OS benefit with LCT-dual immunotherapy (HR 0.43, 95% CI 0.20-0.93).

Altan also reported that a post-hoc analysis demonstrated 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 adverse events. Pneumonitis was numerically more frequent in that arm in 9.5% of patients versus 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.