Topical Imiquimod Plus Nab-paclitaxel for Breast Cancer Cutaneous Metastases: A Phase 2 Clinical Trial

Abstract

Importance: Salvage chemotherapy for recurrent chest wall lesions in breast cancer results in response rates of 20% to 30%. Preclinical studies showed significant disease regression could be induced in murine chest wall mammary cancers with a topical toll-like receptor (TLR)-7 agonist, imiquimod.

Objective: To evaluate the safety and objective response rate (ORR) of imiquimod in combination with systemic albumin bound paclitaxel in treatment-refractory breast cancer of the chest wall.

Design, setting, and particpants: A single arm phase 2 clinical trial of 15 patients with breast cancer previously treated in an academic medical center setting between 2009 and 2012 for chest wall disease that had recurred.

Interventions: Imiquimod cream, 5%, was applied topically to a designated target lesion once per day for 4 consecutive days on days 1 through 4, 8 through 11, 15 through 18, and 22 through 25 of a 28-day cycle, for 12 weeks. Albumin bound paclitaxel, 100 mg/m2, was given intravenously on days 1, 8, and 15, and repeated every 28 days over the 12-week period.

Main outcomes and measures: The primary endpoint was safety and ORR. Secondary endpoints included the generation of tumor-infiltrating lymphocytes and modulation of immune cell populations.

Results: The median age at baseline of the 15 study participants was 54 years (range, 46-92 years). Fourteen patients were evaluable. Combination therapy was associated with low-grade toxic effects. Of 358 adverse events 330 (92%) were grades 1 and 2. Five (36%) patients achieved a compete response and another 5 (36%) were partial responders for an overall response rate of 72% (10 of 14). The response duration was limited. Pretreatment levels of programmed death-1 (PD-1)+ peripheral blood T cells (PD-1+ cluster of differentiation [CD]4+; 95% CI, 2.68-6.63; P < .001 and PD-1+CD8+; 95% CI, 1.13-8.35; P = .01) and monocytic myeloid derived suppressor cells (mMDSC) (95% CI, 3.62-12.74; P = .001) greater than controls predicted suboptimal clinical response.

Conclusions and relevance: Chemoimmunomodulation with a TLR-7 agonist and albumin bound paclitaxel is effective in inducing disease regression in treatment-refractory breast cancer chest wall metastases but responses are short-lived. Preexisting levels of cells indicating either T-cell exhaustion or systemic immunosuppression may be markers of selection for responsive patients.

Trial registration: clinicaltrials.gov Identifier: NCT00821964.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Disis has a commercial research grant from EMD Serono, Seattle Genetics, Celgene, and VentiRx, and stock interest in Epithany and VentiRx. She is a patent holder at the University of Washington. Dr Lu is a full-time employee at Immune Design. No other disclosures are reported.

Figures

Figure 1.. Patient Response to Combination Chemoimmunotherapy

A patient with a complete response. A, Target lesion marked with 3 tattoos; B, complete resolution of target lesion; C, pathologic confirmation of carcinoma prior to therapy; and D, pathologic complete response and associated perivascular lymphocytic infiltration after the end of treatment. Hematoxylin-eosin stain (original magnification ×40).

Figure 2.. Pretreatment Elevated T-Cell PD1 Expression Associated With Suboptimal or No Clinical Response

A, PD1+ percent of CD3+CD4+ cells; B, PD1+ percent of CD3+CD8+ cells in controls and patients before and after treatment. C, PD1+percent of CD3+CD4+ cells; D, PD1+ percent of CD3+CD8+ cells in controls, complete response (CR), and non-CR patients before treatment. Lines represent the means of the group. aP < .05. bP < .01.

Figure 3.. Pretreatment Elevated Monocytic Myeloid-Derived Suppressor Cells Associated With Suboptimal or No Clinical Response

mMDSC indicates monocytic myeloid derived suppressor cells; Treg, regulatory T cells. A, CD14+ cells percent human leukocyte antigen (HLA) DR- cells; B, FOXP3+CD4+ cells percent of CD3+ cells in controls and patients before and after treatment. C, CD14+ cells percent HLA DR- cells; D, FOXP3+CD4+ cells percent of CD3+ cells in controls, complete response (CR), and non-CR patients before treatment. Lines represent the means of the group. aP < .05. bP < .01. cP < .001.