Afinitor, T-DM1 and Xeloda for Metastatic Breast Cancer

Today we'll share the latest news and research on Afinitor, T-DM1 and Xeloda for metastatic breast cancer.

Afinitor plus Aromasin (phase III)

The big story this week was a phase III trial of Afinitor (everolimus) plus Aromasin (exemestane) for post-menopausal women with advanced breast cancer presented at the 2011 European Multidisciplinary Cancer Congress (EMCC). Links to the EurekAlert!, Reuters and Bloomberg articles may be found on the Afinitor page of our website.

The trial, known as BOLERO 2, involved 724 hormone-receptor positive women whose cancer had become resistant to the aromatase inhibitors Femara (letrozole) or Arimidex (anastrazole). 485 received Afinitor plus Aromasin. 239 received Aromasin alone. Progression-free survival was almost 11 months in the Afinitor group, compared to about 4 months in the Aromasin alone group.

Afinitor is also being studied in combination with other drugs for advanced breast cancer. Novartis plans to file worldwide regulatory submissions for the Afinitor/Aromasin combination by the end of 2011.

TDM-1 (phase II)

Another EMCC presentation made headlines this week. The phase II study, TDM4450g, of trastuzumab emtansine (T-DM1) as first-line therapy in women with advanced HER2 positive breast cancer was covered by Medical News Today, Bloomberg and The Telegraph (UK).

The 137 patients were treated with either T-DM1 alone or Herceptin (trastuzumab) plus Taxotere (docetaxel). The median progression-free survival was 14.2 months with T-DM1 compared to 9.2 months with Herceptin plus Taxotere. In addition, the T-DM1 group suffered fewer side effects with less hair loss and hospitalization.

Larger, phase III trials are needed before regulatory approval. Last week, The Seattle Times shared an interesting story about Jeanne Sather, a breast cancer blogger whose efforts led to a geographic expansion of a T-DM1 trial. The story may be found on our T-DM1 page.

Navelbine/Gemzar vs. Xeloda alone (phase III)

Not all research on metastatic breast cancer involves brand new drugs. Some studies experiment with combinations of existing drugs.

A September 21 phase III study from Greece in the Annals of Oncology compared Navelbine (vinorelbine) plus Gemzar (gemcitabine) to oral Xeloda (capecitabine) alone for women with metastatic breast cancer previously treated with anthracyclines and taxanes.

Progression-free survival, overall survival and overall response were similar for both groups. The authors concluded, "Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients."

At LATESTBreastCancer.com, we'll continue to follow research on treatments for metastatic breast cancer. New developments will be added to our website and database and highlighted here. Please stay tuned.

HER2 Part 3: Drugs that Target HER2

Note: This is the blog of LATESTBreastCancer.com, where you can get personalized information about the latest in breast cancer treatment.

For patients with HER2 over-expressing breast cancer, it is critical to target the HER protein. Here we'll look at an array of HER2 targeted drugs: current, new and future. If you're a patient with metastatic disease whose disease is progressing following Herceptin treatment, accessing one of these newer drugs through a clinical trial might be a reasonable option.

Herceptin (trastuzumab). "The big standard." The first drug to target HER2. Approved in 1998. Currently used for patients with all stages of HER2+ breast cancer. Picture how it works: Herceptin is a very large monoclonal antibody protein. It attaches to HER2 on the portion of the molecule that sits outside the cell. By binding to it, Herceptin effectively "flags" the cancer cell for destruction by the body's own immune system. Herceptin also seems to inhibit HER2 growth signaling more conventionally. But attracting an immune system attack is the primary way the drug works (also called, by pharma nerds, "mechanism of action" or MOA).

Tykerb (lapatinib). "The little newcomer." The second HER2 drug. Unlike Herceptin, Tykerb is a very small molecule that inhibits not only HER2 but also EGFR (HER1). Also unlike Herceptin, Tykerb attaches to EGFR and HER2 inside the cell. HER2 and EGFR still pair up with other members of the HER family, but because of Tykerb binding, the grow signal is never sent to other molecules in the "relay chain." Tykerb is used in patients with metastatic disease if they progress after using Herceptin. The other key point about Tykerb is that because it is a very small molecule, it can travel from the bloodstream into the brain, and it seems to reduce brain metastases in HER2 positive patients.

T-DM1. "Targeted AND chemotherapy." A modified version of Herceptin (trastuzumab). In this case "T" (trastuzumab) is attached to another molecule called "DM1" which is a traditional chemotherapeutic. How about this for tricky: the trastuzumab portion of the drug attaches to HER2 outside the cell. When it does, it causes HER2 to get pulled inside the cell, where there (and only there) the chemotherapy portion of the drug is released and kills the cell. So the chemotherapy only kills HER2-laden cancer cells and isn't released where it could do damage to other cells. T-DM1 appears to be doing well in clinical trials and is generating excitement.

OmniTarg (pertuzumab). "Separate, you two!" Remember that to send the grow signal inside the cell, HER family molecules on the cell membrane have to pair up. Well, Genentech has created a drug that inhibits this pairing ("dimerization"). Pertuzumab is a large monoclonal antibody like Herceptin. Like Herceptin, it binds to HER2 outside the cell. But it binds to a different part of the molecule than Herceptin, effectively inhibiting HER2 from pairing up with EGFR (HER1), HER3 and probably HER2 as well. No pairing, no growth signal. Lone HER2s just float around the cell membrane doing nothing. Cancer cell growth and proliferation slows or halts (in theory).

afatinib and neratinib "Same but (maybe) better." These two drugs are in clinical trials. They both work much like Tykerb, but they might end up being more potent and thus more effective. Like Tykerb, both are small molecules, both are taken orally as tablets, and both attach to HER2 inside the cell to inhibit growth signaling. But unlike Tykerb, they are so-called "irreversible" inhibitors of HER2. They bind and then stay attached to HER2. Tykerb is a "reversible" inhibitor that binds but sometimes detaches.

To find clinical trials for these drugs, you can go to clinicaltrials.gov. Or, better yet, try out a newer, easier-to-use site called BCTrials.org. This site provides personalized info about available clinical trials. It's sponsored by UC San Francisco.

Next: How doctors determine if you're HER2 positive