Comprehensive genome profiling in patients with metastatic non-small cell lung cancer: the precision medicine phase 2 randomized SAFIR02-Lung trial

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.

Experimental design: SAFIR02-Lung was an open-label, randomized, phase 2 trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared to standard-of-care as a maintenance strategy in advanced EGFR, ALK wild-type (wt) NSCLC patients without progression after first line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).

Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months (95% CI 1.6-2.9) with TT vs. 2.7 months (1.6-4.1) with standard-of-care (HR 0.97, 0.7-1.36; p=0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR=0.86; 0.62-1.20; p=0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 Tumor Proportion Score (TPS) ≥ 1%, (n=29, HR=0.29; 0.11-0.75) as compared to PD-L1 <1% (n=31, HR=0.71, 0.31-1.60, interaction p= 0.036).

Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in the current study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

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