A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non–small cell lung cancer: Hoosier Cancer Research Network LUN 14‐179

Abstract

Background Five‐year overall survival (OS) for patients with unresectable stage III non–small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti–programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. Methods Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression‐free survival (PFS) and OS. Results The median follow‐up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2‐46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4‐33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1‐, 2‐, and 3‐year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). Conclusions Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

Developing and validating an integrated gross tumor volume (GTV)-TNM stratification system for supplementing unresectable locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

“…It was well recognized that consolidation chemotherapy failed to yield significant survival benefit for unresectable LANSCLC [34][35][36][37][38]. However, based on the series results of the phase III PACIFIC study and other phase II trials [39][40][41], consolidation immunotherapy following CCRT significantly improve PFS and OS with acceptable toxicities in these patients, establishing a new standard of care. In PACIFIC trial, the PFS curve of durvalumab group plateaued at a proportion surviving of 40%, indicating that certain subpopulation could achieve a potential cure.…”

Combining radiation therapy and immunotherapy for lung cancers: a narrative review

“…Pembrolizumab was also evaluated as a consolidative therapy in the phase II study conducted by the Hoosier Cancer Research Network LUN 14–179 ( 60 , 61 ). The primary endpoint was time to metastatic disease or death (TMDD).In this trial 93 patients with unresectable stage III A-B NSCLC were treated with pembrolizumab for up to a year following definitive chemoradiation.…”

Radiotherapy in the Era of Immunotherapy With a Focus on Non-Small-Cell Lung Cancer: Time to Revisit Ancient Dogmas?

“…When ICIs have been assessed as consolidation agents following standard of care definitive (chemo-)radiotherapy for locally advanced disease, RT has been delivered mostly in a conventional dose-fractionation schedule (1.8-2 Gy per fraction, one fraction per day, five days per week, to a total of 60-66 Gy for NSCLC) ( 2 , 41 , 42 ). The rationale behind this schedule is based on the linear quadratic model, whereby the optimal dose-fractionation regimen in order to kill cancer cells while sparing surrounding normal tissues may be established.…”