Topical Imiquimod Regimen Shows Promise For Chest Wall, Cutaneous Breast Cancer Metastases

Breast cancer metastases to the chest wall show short-lived response to topical imiquimod plus albumin-bound paclitaxel

medwireNews: Topical imiquimod given alongside albumin-bound (nab)-paclitaxel resulted in a high overall response in breast cancer patients with measurable chest wall or cutaneous metastases in a phase II trial, although the duration of response was short.

Five of the 14 patients with treatment-refractory stage IV disease achieved a complete response and a further five had a partial response, giving an objective response rate of 72%, report Mary Disis, from the University of Washington in Seattle, USA, and co-workers.

But the response duration was “limited” in these patients, at a median of 12 weeks and 16 weeks, respectively. For the three patients who achieved stable disease, the response lasted a median of just 3 weeks, they write in JAMA Oncology

The toll-like receptor (TLR)-7 agonist imiquimod, at a 5% concentration, was applied to a target lesion on the skin over 12 weeks, following a pattern of once per day on days 1–4, 8–11, 15–18 and 22–25 of each 28-day cycle. In addition, participants were given nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 of each cycle and were allowed to continue with bisphosphonate and HER2-targeted or endocrine therapies.

In all, 60% of the patients completed the treatment, 20% completed two treatment cycles and 13% one cycle. The majority (92%) of adverse events were grade 1 or 2 and the remaining 8% were grade 3; three patients required nab-paclitaxel dose reduction for grade 3 neutropenia or neuropathy but none of the patients discontinued treatment because of toxicity.

“Chemoimmunotherapy is an active regimen with low toxic effects”, the team summarises.

All the patients had intratumoural T-cell infiltrates at baseline, varying from a “sparse” to “strong” infiltration, but the researchers failed to detect a “consistent trend” over treatment.

Compared with peripheral blood T-cells samples taken from volunteer donors, all patients had significantly higher pretreatment levels of programmed cell death protein-1 (PD-1)–positive CD4-positive T cells (average 6.6 vs 3.1%) and PD-1–positive CD8-positive T cells (average 7.1 vs 4.1%). And the proportion of PD-1 expressing T cells did not differ after treatment, the researchers say.

Further analysis revealed, however, that patients who achieved a complete response had similar PD-1–positive CD4 and CD8 T cells levels to the controls, whereas patients with no response or a partial response to treatment had significantly higher concentrations of both.

Monocytic myeloid derived suppressor cells (mMDSC), which inhibit CD4-positive T cell activation via the PD-1/PD-L1 axis, were also significantly associated with response, with a complete response associated with mMDSC levels similar to the controls and a suboptimal response with elevated mMDSC.

“T-cell activation could be restored in vivo in the presence of these immunosuppressive cells through the use of PD-1 blockade”, Mary Disis et al therefore hypothesize.

They conclude: “Inhibition of specific mechanisms of immune suppression, PD-1 up-regulation and mMDSC, could enhance efficacy and provide a new treatment approach to patients with refractory breast cancer in the chest wall.”

Reference

Salazar LG, Lu H, Reichow JL, et al. Topical imiquimod plus nab-paclitaxel for breast cancer cutaneous metastases. A phase 2 clinical trial. JAMA Oncol; Advance online publication 19 January 2017. doi:10.1001/jamaoncol.2016.6007

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