Concurrent chemoradiotherapy with or without simultaneous integrated boost for unresectable stage III non-small-cell lung cancer: a randomized phase II trial with exploratory EGFR and PD-L1 analyses.

BACKGROUND AND PURPOSE: Based on the assumption that radiation dose escalation to the primary tumor improves local control and therefore produces survival benefits under the condition of limiting the dose to the organ at risk (OAR), we launched a study to evaluate the effect of simultaneous integrated boost (SIB) radiotherapy implemented in stage III locally advanced non-small cell lung cancer (LA-NSCLC) patients.

MATERIALS AND

METHODS

A prospective, single-center, open-label, randomized phase II trial was performed in patients with stage III LA-NSCLC. Patients were randomized to receive SIB thoracic radiation: 50 Gy in 25 fractions of 2.0 Gy for planning target volume (PTV), 55 Gy in 25 fractions of 2.2 Gy for clinical target volume (CTV), 60-70 Gy in 25 fractions of 2.4-2.8 Gy for gross tumor volume (GTV), or control group: 30 fractions of 2.0 Gy for PTV. A platinum based concurrent chemotherapy was administered to patients in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), failure patterns, and treatment-related toxicities. Exploratory analyses of epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) were performed for PFS and OS.

RESULTS

From April 2015 to April 2018, 168 patients were included in the analysis, with 84 in the control group and 84 in the SIB group. The median PFS was 21.0 months in the SIB group and 11.0 months in the control group (P < 0.001, Hazard Ratio (HR) 0.48, 95% CI 0.34-0.68). The median OS was 42.0 months and 26.0 months(P = 0.002, HR 0.55, 95% CI 0.37-0.81) in the SIB group and the control group, respectively. The SIB group had a significantly lower risk of brain and other distant metastasis, with adjusted sub-distribution HR of 0.35 (95% CI, 0.14-0.87, P = 0.025) and 0.65 (95% CI, 0.45-0.94, P = 0.023), respectively. There was lower radiation-related pneumonitis (P = 0.015) in the SIB group because of the lower dose for the irradiated lung (irradiated-lung V5, 55.38±18.11 Gy vs. 61.95±15.45 Gy, P = 0.015). Most other OAR doses and incidences of grade ≥2 disease were similar between the two arms. Exploratory biomarker analysis reveals a trend toward superior survival benefit from SIB in patients with PD-L1 ≥1% or EGFR-mutant.

CONCLUSIONS

We demonstrated that the routinely adaptive SIB strategy could significantly improve PFS and OS and reduce the dose to the irradiated lung without increasing the risk of tumor recurrence. Exploratory analyses of EGFR mutation status and PD-L1 expression suggested potential differences in treatment outcomes across biomarker-defined subgroups. This strategy represents a potentially feasible regimen to improve survival outcomes for patients with stage III LA-NSCLC eligible for definitive concurrent chemoradiotherapy and warrants further validation in larger prospective trials.