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Plasma-based tumor mutational burden (bTMB) as predictor for survival in phase III EAGLE study: Durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum failure.
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2020
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ImmunologyR/m HnsccPathologyRecurrent/metastatic HeadImmunotherapyTumor BiologyOncologyMetronomic TherapyTumor ImmunityPlatinum FailureNeck OncologyRadiation OncologyCancer ResearchMolecular OncologyCt. BtmbImmune SurveillanceCancer TreatmentCancer GeneticsHigh BtmbBtmb ExpressionCancer ImmunosurveillanceImmune Checkpoint InhibitorHead And Neck CancerMedicine
6511 Background: In NSCLC, bTMB assessed from circulating tumor DNA shows promise as a predictive survival biomarker for immunotherapy, but its value in R/M HNSCC is uncertain. We evaluated bTMB as a predictor of survival in R/M HNSCC. Methods: EAGLE (NCT02369874) was a randomized, open-label, phase 3 trial evaluating D (anti-PD-L1), or D+T (anti-CTLA-4), vs CT in R/M HNSCC. Patients (pts) with disease progression after platinum-based CT were randomized (1:1:1) to D (10 mg/kg intravenous [IV] every 2 weeks [Q2W]), D (20 mg/kg IV Q4W) + T (1 mg/kg IV Q4W for up to 4 doses, followed by D at 10 mg/kg Q2W) or CT. bTMB was assessed in pretreatment plasma samples using the Guardant Health OMNI platform. Association of somatic loss of function mutations with OS was assessed. Results: 736 intent-to-treat pts were randomized; 247 were evaluable for bTMB (BEP). bTMB expression was not linked to HPV status, PD-L1 status, age, gender, tumor location, or ECOG PS. Smoking and progression within 6 months on multi-modality CT in localized disease trended with higher bTMB. OS and PFS HRs were significantly improved for D or D+T vs CT in pts with high bTMB (≥16 mut/Mb) vs low (<16 mut/Mb; Table). The benefit of D or D+T vs CT in pts with high bTMB generally improved with increasing cutoff. 74 pts (27 D, 20 D+T, 27 CT pts) were bTMB high. 18-month OS rates were higher for D+T (22%; 95% CI 7%–42%) and D (33%; 95% CI 17%–51%) vs CT (0%; 95% CI 0%–0%) in pts with high bTMB. Pts with mutations in KMT2D, a HNSCC tumor suppressor gene, showed improved OS for D+T vs CT (HR 0.39; 95% CI 0.18–0.85). A trend of improved OS for D+T vs CT (HR 0.19; 95% CI 0.03–1.03) was also seen in pts with ATM mutations. Conclusions: This is the first retrospective analysis of a phase 3 trial to show bTMB may be predictive of outcomes for checkpoint inhibitors in R/M HNSCC. In pts with high bTMB, D or D+T improved OS hazards by at least 60%, vs CT at cutoffs ≥16 mut/Mb. Validation of bTMB as a predictive biomarker is ongoing. Clinical trial information: NCT02369874 . [Table: see text]