SORAFENIB FOR BREAST CANCER

December 14, 2009 (San Antonio, Texas) — The targeted agent sorafenib (Nexavar, Onyx/Bayer), currently approved for use in kidney and liver cancer, has shown activity in breast cancer in phase 2 clinical trials, and a large registration phase 3 trial is planned for next year.

The results from the latest studies of sorafenib were presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

Two of these studies investigated the use of the drug in combination with chemotherapy, either capcitebine or paclitaxel, in women with locally advanced or metastatic HER2-negative breast cancer. But perhaps the most intriguing results come from a third study, which suggests that sorafenib can overcome resistance to aromatase inhibitors (AI) in postmenopausal estrogen-receptor-positive breast cancer.

Overcoming Resistance to AI?

The study of overcoming resistance was presented at the meeting by Claudine Isaacs, MD, clinical director of the breast cancer program at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. Resistance to AIs appears to involve the Ras–Raf–MAPK pathway, and sorafenib was investigated because it is an inhibitor of multi(Raf)-kinase, she explained.

The trial involved 35 postmenopausal women with hormone-receptor-positive metastatic breast cancer who had received more than 2 previous chemotherapy regimens, and who had disease recurrence or progression on the AI anastrozole (Arimidex, AstraZeneca). They continued taking anastrozole, but also received sorafenib, either 200 mg or 400 mg twice daily.

Dr. Isaacs reported that 20% of women showed a clinical benefit — complete or partial response — or stable disease for at least 6 months. She said this result was "encouraging" and worthy of further study.

It appears that sorafenib is acting to reverse resistance to AIs, because this type of response would not be expected with either drug used alone, Dr. Isaacs said. Sorafenib has shown "negligible activity" as a single agent in metastatic breast cancer, she added, although it has shown activity in combination with chemotherapy.

"We believe that sorafenib might disrupt the machinery created by the tumor to grow without the estrogen," she said in a statement. "After the machinery is destroyed, the aromatase inhibitor can do its work again."

"To manage breast cancer long-term, it's apparent that we may need to continually switch drugs to keep up with how a cancer evolves and evades each approach," she added.

Adverse effects were common, and included hand and foot syndrome, skin rash, fatigue, nausea/vomiting, diarrhea, and hypertension. However, most were mild or were managed by reducing the dose, Dr. Isaacs said.

In Combination With Chemotherapy

The other phase 2 trials with sorafenib reported at the meeting each involved more than 200 women with locally advanced or metastatic HER2-negative breast cancer. Both were funded by the manufacturer and are part of the Trials to Investigate the Effects of Sorafenib in Breast Cancer (TIES) program.

One trial looked at first-line treatment in women who had not received any previous chemotherapy in this setting. They were randomized to receive 1 of 2 treatment regimens: sorafenib 400 mg twice daily plus paclitaxel 90 mg/m² weekly for 3 weeks, followed by a week of rest; or paclitaxel plus a placebo.

This trial results were presented at the meeting by William Gradishar, MD, from the Feinberg School of Medicine, Northwestern University, in Chicago, Illinois. He said the results "demonstrated a trend in favor of the combination arm."

The primary end point of progression-free survival was not significantly different in the 2 treatment groups (6.9 months in the combination group vs 5.6 months in the paclitaxel group; P = .0875). However, one of the secondary end points, time-to-progression, did reach significance (8.1 vs 5.6 months; P = .017).

The other trial investigated a similar patient population, but some of the women had received 1 previous chemotherapy in this setting. This trial compared the combination of sorafenib plus capecitabine 100 mg/m² with capecitabine plus placebo.

Known as SOLTI-0701, this trial was presented at the meeting by José Baselga, MD, from the Vall d'Hebron University Hospital in Barcelona, Spain

In this case, the primary end point of progression-free survival did reach statistical significance (median, 6.4 months in the combination group vs 4.1 months in the capecitabine group; P = .0006).

A post hoc subgroup analysis split the participants into those who had not previously been treated with a previous chemotherapy (i.e., first-line therapy) and those who had received a previous chemotherapy (i.e., second-line therapy). The improvements in progression-free survival were statistically significant in both groups.

These findings for sorafenib plus paclitaxel "are the basis for a registrational phase 3 program that is expected to begin next year," according to the manufacturer.

In the meantime, 2 other phase 2 trials with sorafenib in breast cancer are ongoing, although they were not discussed at the meeting. One is exploring sorafenib plus gemcitabine or capecitabine in a second-line setting following progression on bevacizumab, and the other is evaluating sorafenib plus docetaxel and/or letrozole in the first-line setting.

The 400 mg twice-daily dose of sorafenib used in these trials was associated with frequent adverse effects, including hand and foot syndrome and hypertension. Dr. Isaacs said that "there is activity, but at this dose, there is a fair amount of toxicity." But she noted that in her own study, the adverse effects were manageable when the dose was reduced. "There is a lot of interest in sorafenib because it is an oral drug and it appears to increase the response to chemotherapy. There would be a benefit to taking it if it improved progression-free survival and the quality of life was good," she added.

In the SABCS Medscape Oncology blog, Lida Mina, MD, from the Indiana University School of Medicine, in Indianapolis, noted that the SOLTI-0701 trial of sorafenib plus capecitabine was "very promising, with a near 40% increase in progression-free survival, but unfortunately the toxicity was humungous, with a 45% grade 3 hand and foot syndrome." Commenting more generally on trials with sorafenib, as well as on other new targeted therapies, all with some antiangiogenic properties, she said these trials "do send a signal of efficacy," but it appears to be "somewhat diluted."

The study of overcoming resistance was funded by the Avon Patients for Progress Award, and partly funded by Bayer. Both of the chemotherapy combination studies were funded by the manufacturer of sorafenib, Onyx/Bayer. Dr. Isaacs reports serving on a speaker's bureau for Pfizer, Abraxis Oncology, Genentech, GlaxoSmithKline, and Novartis. Dr. Gradishar reports acting as a consultant for Bayer. Dr. Baselga reports acting as a consultant for Merck, Novartis, Roche, and Exelixis, and receiving grant support from GlaxoSmithKline.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 44, 45, 3090. Presented December 11, 2009.