Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer

Introduction Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. Methods This was a phase II, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to twelve weeks after completion of 60-70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and CTCAE v5.0 toxicity. Results Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n=5; two were pembrolizumab-related), disease progression (n=4), and completion of one year (n=3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI 4.2-23.7) and 22.8 months (95% CI 6.9-not reached), respectively. There was only one isolated in-field failure. Grade ≥3 toxicities occurred in 10 patients (45%); two were pembrolizumab-related. There were two grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. Conclusions In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2/22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.