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.