Background
Phase III open-label RCT, N=1,118, treatment-naive advanced NSCLC, EGFR/ALK wt, any PD-L1 level or histology.
Interventions and follow up
Arm A: Durvalumab 20 mg/kg q4wk + tremelimumab 1 mg/kg q4wk x4 cycles
Arm B: Durvalumab 20 mg/kg q4wk until progression
Arm C: Platinum-based doublet chemotherapy x4-6 cycles (+ pemetrexed maintenance for nonsquamous)
Primary endpoints: OS (durva vs chemo) and PFS (durva+treme vs chemo) in PD-L1 TC ≥25%
mFollow up: 30 mo
Arm B: Durvalumab 20 mg/kg q4wk until progression
Arm C: Platinum-based doublet chemotherapy x4-6 cycles (+ pemetrexed maintenance for nonsquamous)
Primary endpoints: OS (durva vs chemo) and PFS (durva+treme vs chemo) in PD-L1 TC ≥25%
mFollow up: 30 mo
Results
PD-L1 ≥25% mOS (A vs B vs C): 16.3 vs 11.9 vs 12.9 mo
Durva vs chemo OS: HR 0.76, 97.54%CI 0.56-1.02; P=.04 (did not reach prespecified significance)
Durva+treme vs chemo OS: HR 0.85, 98.77%CI 0.61-1.17; P=.20
PD-L1 ≥25% mPFS (A vs B vs C): 3.9 vs 4.7 vs 5.4 mo; durva+treme vs chemo HR 1.05, 99.5%CI 0.72-1.53; P=.71
TMB ≥20 mut/Mb mOS (A vs B vs C): 21.9 vs 12.8 vs 10.0 mo
Durva+treme vs chemo (TMB≥20): HR 0.49, 95%CI 0.32-0.74
Durva vs chemo (TMB≥20): HR 0.72, 95%CI 0.50-1.05
Durva vs chemo OS: HR 0.76, 97.54%CI 0.56-1.02; P=.04 (did not reach prespecified significance)
Durva+treme vs chemo OS: HR 0.85, 98.77%CI 0.61-1.17; P=.20
PD-L1 ≥25% mPFS (A vs B vs C): 3.9 vs 4.7 vs 5.4 mo; durva+treme vs chemo HR 1.05, 99.5%CI 0.72-1.53; P=.71
TMB ≥20 mut/Mb mOS (A vs B vs C): 21.9 vs 12.8 vs 10.0 mo
Durva+treme vs chemo (TMB≥20): HR 0.49, 95%CI 0.32-0.74
Durva vs chemo (TMB≥20): HR 0.72, 95%CI 0.50-1.05
Adverse events
Treatment-related gr3-4: durvalumab 14.9%; durva+treme 22.3%; chemotherapy 33.8%
Immune-related: more common with durva+treme (colitis, hepatitis, endocrinopathy)
Discontinuation: lowest in durvalumab monotherapy arm
Immune-related: more common with durva+treme (colitis, hepatitis, endocrinopathy)
Discontinuation: lowest in durvalumab monotherapy arm
Conclusions
MYSTIC did not meet its primary OS or PFS endpoints in PD-L1 TC ≥25%. Exploratory analyses suggested OS benefit with durvalumab + tremelimumab in patients with TMB ≥20 mut/Mb.
Key Limitations
Negative trial for its primary endpoints. TMB findings are exploratory/hypothesis-generating and used blood-based TMB without prospective validation. Open-label.
Clinical Context
No FDA/EMA approval resulted from MYSTIC for first-line NSCLC. Durvalumab + tremelimumab + chemotherapy was later established in NSCLC by the positive POSEIDON trial; ESMO does not endorse the chemo-free durva+treme regimen tested here for first-line NSCLC.