Kadcyla and Perjeta Before Surgery Offers More Benefits Than Standard Regimen for HER2-Positive Disease

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Results from the I-SPY 2 trial suggest that treating HER2-positive breast cancer before surgery with a combination of Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) and Perjeta (chemical name: pertuzumab) offers better pathologic complete response rates than the traditional treatment of Herceptin (chemical name: trastuzumab) and Taxol (chemical name: paclitaxel).

The study was presented at the American Association for Cancer Research Annual Meeting on April 18, 2016. Read the abstract of “Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: results from the neoadjuvant I-SPY 2 TRIAL.”

Kadcyla is a combination of the targeted therapy Herceptin (chemical name: trastuzumab) and the chemotherapy medicine emtansine. In Kadcyla, the emtansine is attached to the Herceptin. In earlier studies on Kadcyla, it was reported that the chemotherapy medicine maytansine was attached to Herceptin to form Kadcyla. Emtansine is a derivative of maytansine.

Emtansine, like some other chemotherapy medicines, disrupts the way cells grow. Emtansine isn’t a targeted medicine, which means it can affect healthy cells as well as cancer cells. In Kadcyla, the Herceptin carries the emtansine to the HER2-positive breast cancer cells.

Kadcyla is approved by the U.S. Food and Drug Administration (FDA) to treat HER2-positive metastatic breast cancer that has previously been treated with Herceptin and a taxane chemotherapy.

Perjeta is a targeted therapy medicine that is used to treat HER2-positive breast cancer. Right now, Perjeta is approved to be used in combination with Herceptin and Taxotere (chemical name: docetaxel) to treat:

  • HER2-positive, metastatic breast cancer that hasn’t been treated with either Herceptin or chemotherapy yet
  • HER2-positive, early-stage, inflammatory, or locally advanced breast cancer with a high risk of spreading to other parts of the body

Herceptin is approved by the FDA to treat advanced-stage, HER2-positive breast cancers and to lower the risk of recurrence of early-stage, HER2-positive breast cancer with a high risk of recurrence.

Taxol is a chemotherapy medicine used to treat many types of breast cancer.

HER2-positive breast cancers have too many copies of the HER2/neu gene, which make too much of the HER2 protein. HER2-positive breast cancers tend to be more aggressive than cancers that are HER2-negative.

Doctors call treatments given before surgery neoadjuvant treatments.

One way doctors judge the effectiveness of treatment given before surgery is to look at the tissue removed during surgery to see if any active cancer cells are present. If no active cancer cells are there, doctors call it a “pathologic complete response.” Some doctors believe that a pathologic complete response to neoadjuvant treatment means the cancer is less likely to come back.

Because Kadcyla and Perjeta effectively treat metastatic, HER2-positive breast cancer, researchers wondered whether the two medicines could offer a new combination treatment for earlier stages of HER2-positive disease.

This study suggests they can.

The I-SPY 2 study included women diagnosed with HER2-positive breast cancers that were 2.5 cm or larger in size. The women were randomly assigned to one of two treatments before surgery:

  • 12 weekly cycles of Herceptin plus Taxol (31 women)
  • 12 weekly cycles of Kadcyla plus Perjeta (52 women)

After those treatments, all the women received four cycles of Adriamycin (chemical name: doxorubicin) and Cytoxan (chemical name: cyclophosphamide) and then had surgery.

The women treated with Kadcyla and Perjeta had better pathologic complete response rates. Pathologic complete response rates were:

  • 52% for women treated with Kadcyla and Perjeta
  • 22% for women treated with Herceptin and Taxol

"The combination of T-DM1 and pertuzumab substantially reduced the amount of residual disease in the breast tissue and lymph nodes for all subgroups of HER2-positive breast cancers compared with those in the control group," said lead author, Angela DeMichele, M.D., professor of medicine and epidemiology at the Perelman School of Medicine at the University of Pennsylvania. "Getting a greater proportion of patients to achieve a [pathologic complete response] is the underlying goal of neoadjuvant therapy. Our results suggest a possible new treatment option for patients that can not only effectively shrink tumors in the breast, but potentially reduce the chance of the cancer coming back later. The results also show that by replacing older, non-targeted therapies with more effective and less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects."

Like most cancer medicines, both Kadcyla and Perjeta can cause side effects. Common side effects of Perjeta include:

  • hair loss
  • diarrhea
  • nausea
  • low white blood cell count

Common side effects of Kadcyla include:

  • low platelet count
  • low red blood cell count
  • fatigue
  • difficulty breathing
  • higher liver enzyme levels

Still, the combination of Kadcyla and Perjeta seems to have fewer serious side effects than the combination of Herceptin and Taxol.

"[The combination of Kadcyla and Perjeta] had a very different toxicity profile than that seen with the standard of care," said Dr. DeMichele. "Neuropathy [nerve damage in the hands and feet], hypertension [high blood pressure], and alopecia [hair loss] were much less common. I would argue that these are side effects of treatment that really matter to women that can really affect their day-to-day function. We have quality of life data that we collected concurrently that are in the midst of being evaluated."

In addition to looking at whether Kadcyla and Perjeta helped treat HER2-positive breast cancer before surgery, the I-SPY 2 study also is interesting because it uses a new and different type of study design. The researchers use what they call an “adaptive algorithm” to see which types of breast cancer respond the best to the different regimens as the study goes on. In other words, the study sees how different types of breast cancer respond to the treatments and then assigns more women diagnosed with cancers likely to respond to the treatment to that treatment arm.

When a treatment arm has added enough people, that treatment “graduates” to a larger, later phase trial. The goal of the study’s design is to figure out more quickly which types of breast cancer respond to experimental treatments and then get the treatments approved and to market more quickly and efficiently.

If you’ve been diagnosed with HER2-positive breast cancer and are planning your treatment before surgery, you might want to talk to your doctor about this study. If you’re willing to participate in a clinical trial, you may have the option of being treated with a combination of Kadcyla and Perjeta. Talk to your doctor about clinical trials that might be a good fit for you. You can visit the Breastcancer.org Clinical Trials pages for more information.

And stay tuned to Breastcancer.org’s Research News for the latest information on the Kadcyla-Perjeta combination.



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