Sunitinib plus a taxane active in advanced breast cancer

SAN ANTONIO-Pilot studies presented at the 2007 San Antonio Breast Cancer Symposium have found robust activity for the multi-targeted tyrosine kinase inhibitor sunitinib (Sutent) when given with docetaxel (Taxotere) (abstract 6079) or paclitaxel (abstract 6078) as first-line treatment for patients with advanced breast cancer.

Sunitinib/docetaxel

European investigators evaluated the pharmacokinetic profile, safety, and preliminary efficacy of sunitinib plus docetaxel in 22 advanced breast cancer patients. Docetaxel 75 mg/m2 was given on day 1 every 3 weeks and sunitinib 37.5 mg/d was started on day 2 and given for 2 weeks, followed by 1 week off.

When docetaxel was discontinued for reasons other than progressive disease, patients received continuous dosing with sunitinib, with treatment breaks and dose reductions as needed for tolerability concerns. Sunitinib doses were escalated to 50 mg/d if well tolerated. Patients received a median of eight cycles of sunitinib and six of docetaxel.

Of 18 evaluable patients, 13 (72.2%) responded (all partial responders), and 5 patients (27.7%) achieved stable disease. Nine patients experienced tumor shrinkage after just two cycles of therapy, several of whom had visceral disease. Five of six patients with triple-negative tumors (negative for estrogen and progesterone receptors and HER2 overexpression) responded, reported Luca Gianni, MD, of the Istituto Nazionale Tumori, Milan, Italy, lead author of the study.

Treatment with the combination was generally well tolerated. The most commonly reported severe adverse event was grade 4 transient neutropenia, which occurred in 11 patients (50%). Grade 3 adverse events were few and included one case each of fatigue, diarrhea, stomatitis, and hand-foot syndrome. Eleven patients discontinued treatment because of lack of efficacy (5), non-treatment-related reasons (4), and toxicity (2).

Co-investigator Gabriella Mariani, MD, commented that the good tolerability allows for sunitinib to be continued indefinitely without a problem.

“We can usually give full doses, and it is also possible to increase the dose of sunitinib,” Dr. Mariani said. “We now have one patient continuing on sunitinib after 12 cycles-6 on the combined regimen and 6 with single-agent sunitinib. Last week we evaluated her and the disease was still stable, after a good response. We have seen some fairly dramatic responses.”

A phase III study of this combination compared with docetaxel alone in the first-line metastatic setting is underway.

Sunitinib/paclitaxel

A phase I study by US investigators found that sunitinib had good activity when combined with paclitaxel in the first-line metastatic setting.

The study included 22 patients who initially received 25 mg/d of sunitinib and were dosed continuously, with tolerability-dependent escalation to 37.5 mg/d or reduction to 12.5 mg/d as necessary, plus paclitaxel 90 mg/m² per week (reduced to 65 mg/m² per week when necessary) for 3 weeks on and 1 week off treatment. Patients received a median of five cycles.

In 21 evaluable patients, objective responses were documented in 7 patients (33.3%). This included two complete responses (9.5%) and five partial responses (23.8%). The objective response rose to 38.8% (7 of 18) in patients with measurable disease.

Stable disease of 8 weeks or longer was observed in 12 patients (57.1%) and 24 weeks or longer in 3 (14.3%). Only 2 patients (9.5%) had progressive disease as their best response, reported Mark Kozloff, MD, of the Cancer Research Center, Ingalls Memorial Hospital, Harvey, Illinois.

“Responses were documented in three of eight patients with triple-negative receptor status and measurable disease. Stable disease lasting at least 6 months was observed in three patients (all with nonmeasurable disease). Responses were reported in patients with lung, liver, lymph node, and superficial involvement,” Dr. Kozloff said.

Patients with superficial disease were often observed to have rapid regression of lesions after the start of therapy, that is, a reduction in lesions was observed within the first cycle of treatment, he said.

A phase III trial is underway in patients with advanced breast cancer comparing first-line treatment with sunitinib plus paclitaxel vs bevacizumab (Avastin) plus paclitaxel.

Neither study showed a pharmacokinetic drug-drug interaction.