A Phase 1 Study of TAK-676, a Novel STING Agonist, Plus Pembrolizumab Following Radiation Therapy 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)

Abstract

<h3>Purpose/Objective(s)</h3> Radiation therapy-induced cell death produces cytosolic DNA that activates the cyclic GMP-AMP synthase (cGAS)–STimulator of INterferon Genes (STING) pathway, crucial for the induction of Type I interferons (IFN-I). Checkpoint inhibitor (CPI) resistance mechanisms have been linked to impaired IFN signaling. Preclinical data have shown STING agonists to reverse CPI resistance in tumors with prior exposure, particularly when used with anti-PD-1/PD-L1 therapies. TAK-676 (a synthetic STING agonist) potently modulates the innate immune system, leading to cytokine release, adaptive immune activation, and antitumor responses in preclinical studies (Appleman et al., AACR 2022). TAK-676 is being investigated as a single agent, and in combination with pembrolizumab, for advanced solid tumors, in a first-in-human phase 1 study (NCT04420884). TAK-676 is optimally designed for intravenous (IV) delivery, with a prolonged half-life in serum and enhanced tissue permeability, allowing access to tumor sites and lymphatic tissue. Following radiation therapy, TAK-676 has the potential to stimulate T-cell mediated antitumor immunity via STING-mediated IFN-I release, particularly when used with anti-PD-1/PD-L1 therapies. Here, we present a second phase 1 study to investigate the safety and preliminary antitumor activity of TAK-676 in combination with pembrolizumab following radiation therapy, in patients with advanced or metastatic NSCLC, TNBC, or SCCHN who have progressed on CPIs (NCT04879849). <h3>Materials/Methods</h3> Patients aged ≥18 years who progressed on CPIs and have ≥2 lesions, of which one is targetable with radiation, are being enrolled. Patients receive 8 Gy x 3 followed by (after a minimum of 40 hours) escalating doses of IV TAK-676 on days 1, 8 and 15 of a 21-day cycle, and 200 mg of IV pembrolizumab on day 1 of each cycle until disease progression, intolerance, or withdrawal of consent. Dose escalation of TAK-676 will be guided by the Bayesian Optimal Interval design. At screening and between days 15–21 of cycle 1, patients with a safely accessible lesion outside of the radiation field will have paired biopsies collected once the pharmacologically active dose levels of TAK-676 have been observed. The primary objective is to determine the safety and tolerability of TAK-676 in combination with pembrolizumab following radiation therapy. Secondary objectives are to determine the recommended phase 2 dose of TAK-676 in combination with pembrolizumab following radiation therapy, and to assess the local (within the radiation field) and systemic (non-radiated lesions) preliminary antitumor activity. As of February 2022, ∼10% of the planned patients have been enrolled. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD