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 (RT) 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 (CPI; NCT04879849).

[PATIENTS AND METHODS] Eligible patients received radiation (8 Gy × 3 fractions) followed (≥40 hours) by pembrolizumab 200 mg every 3 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 nonirradiated lesions, pharmacokinetic analyses, 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, and TNBC: 9) with a median number of six prior treatments were enrolled. Thirty-three (97.1%) patients reported treatment-emergent adverse events (TEAE), 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 IFNγ pathways across multiple dose levels and induced immune responses, consistent with preclinical studies.

[CONCLUSIONS] Dazostinag, combined with pembrolizumab after RT, was well tolerated and demonstrated clinical activity in some patients with advanced/metastatic tumors whose disease had progressed on CPIs.

[SIGNIFICANCE] Dazostinag, an intravenous STING agonist, combined with radiation, demonstrated tumor control and enhanced intratumoral immune activation, preclinically. In phase 1b, dazostinag plus pembrolizumab following RT had a manageable safety profile and provided clinical benefit for some heavily pretreated patients with advanced/metastatic solid tumors whose disease had progressed on CPIs.