Purpose: A Phase 2 trial of stereotactic radiation therapy and in situ cytotoxic virus therapy in metastatic triple-negative breast cancer (mTNBC) patients followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mTNBC patients. Methods: In this single-arm, open-label Phase 2 trial, mTNBC patients were treated with ADV/HSV-tk (5 x 1011 vp) intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200mg, Q3w). The primary endpoint was clinical benefit rate (CBR, CR, PR or SD≥ 24 weeks per RECIST version1.1 at non-irradiated site). Secondary endpoints included duration on treatment (DoT), OS and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: 28 patients were enrolled and treated. CBR was seen in 6 patients (21.4%) including two CR (7.1%), one PR (3.6%) and three SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with CyTOF and IMC revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated mTNBC patients. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

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