Abstract OT2-1-02: Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases
Authors: Janosky M , Demaria S , Novik Y , Oratz R , Tiersten A , Goldberg J , Wang E , Marincola F , Fenton-Kerimian M , Maisonet O , Axelrod D , Sacris E , Levine P , Formenti S , Adams S 
Published: August 2014

Abstract
Background/Rationale: To assess the immune and systemic anti-tumor effects of the novel combination of local radiotherapy combined with imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most common tumor, excluding melanoma, to metastasize to the skin in women. Chest wall recurrence is debilitating for patients, substantially affecting quality of life. Current treatment modalities for unresectable lesions are rarely curative and patients ultimately die of visceral metastases, indicating the need for more effective therapies. Imiquimod (IMQ), a synthetic TLR-7 agonist has immunomodulatory activity with profound effects on the tumor environment and can lead to tumor regression of cutaneous breast cancer metastases (Adams et al, Clin Ca Res, Dec 15, 2012). Accumulating evidence indicates that the potential of local radiotherapy to convert the tumor into an in-situ vaccine can be enhanced by combination with immunotherapy to achieve a therapeutic synergy. We have previously shown in a mouse model of cutaneous breast cancer that topical IMQ synergizes with local RT to induce complete tumor regression (REF). Importantly, this approach used a local treatment to generate anti-tumor immune responses with ability to control the tumor systemically (Dewan et al, Clin Ca Res Dec 15, 2012). This trial was designed to test the feasibility of translating this therapeutic synergy in the clinic (clinicaltrials.gov NCT01421017).
Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. Radiation therapy is delivered to one area of skin metastases in five fractions of 6 Gy (days 1,3,5,8,10). IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks, beginning the evening of the first radiotherapy. Continuous imiquimod to all skin metastases even after completion of RT is based on our preclinical evidence of an improved effector phase of the immune response. Additional treatment cycles with IMQ/RT are permitted. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with a planned additional 25 patients. Primary endpoint is the response rate in untreated metastases, assessed by immune-related response criteria. Furthermore, the local tumor responses and safety of the combination will be determined; tumor FNA biopsies will be obtained to investigate signatures of immune-mediated rejection as recently described with IMQ mediated rejection of basal cell carcinomas; and peripheral lymphocytes will be examined for the induction/boosting of selected tumor antigen-specific T and B cell responses.
The phase I portion has been successfully completed with 6 patients without DLT. Enrollment into the phase II portion has begun. At present, a total of 11 patients have been enrolled.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-02.