Phase 1b Study of Dazostinag Plus Pembrolizumab After Hypofractionated Radiotherapy in Patients With Select Advanced Solid Tumors

Purpose: We present the preclinical rationale and clinical data from a phase 1b trial investigating the STING agonist dazostinag plus pembrolizumab following hypofractionated radiotherapy in patients with advanced non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) whose disease had progressed on prior checkpoint inhibitors (CPIs) (NCT04879849). Patients and Methods: Eligible patients received radiation (8 Gy ×3 fractions) followed (≥40h) by pembrolizumab 200 mg every three weeks, and dazostinag in escalating doses (0.2–5.0 mg). Primary endpoints were safety and tolerability. Secondary endpoints included preliminary antitumor activity in irradiated and non-irradiated lesions, pharmacokinetics, and pharmacodynamic analyses. Results: Preclinical studies demonstrated tumor control and enhanced intratumoral immune activation in mice treated with dazostinag plus radiation. Thirty-four patients (NSCLC: 15, SCCHN: 10, TNBC: 9) with a median number of six prior treatments were enrolled. Thirty-three (97.1%) patients reported treatment-emergent adverse events (TEAEs), none were dose-limiting toxicities; the most common were fatigue (52.9%), constipation (26.5%) and cough (20.6%). Dazostinag-related TEAEs occurred in 17 patients (50.0%); the most common were fatigue (26.5%), chills (8.8%), diarrhea, arthralgia, and myalgia (5.9% each). Antitumor activity, per RECIST v.1.1, was confirmed in two (7.1%) patients (one complete response and one partial response). Pharmacodynamic analyses indicated activation of STING and interferon-γ pathways across multiple dose levels, and induced immune responses, consistent with preclinical studies. Conclusions: Dazostinag, combined with pembrolizumab after radiotherapy, was well tolerated and demonstrated clinical activity in some patients with advanced/metastatic tumors whose disease had progressed on CPIs.