Kadcyla Seems Better Than Herceptin for Early-Stage, HER2-Positive Residual Breast Cancer

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Results from the KATHERINE trial suggest that Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine) improves disease-free survival compared to Herceptin (chemical name: trastuzumab) in people diagnosed with early-stage, HER2-positive breast cancer who have cancer cells found in tissue removed during surgery after neoadjuvant chemotherapy that included a taxane and Herceptin or Herceptin and Perjeta (chemical name: pertuzumab).

The research was presented on Dec. 5, 2018, at the San Antonio Breast Cancer Symposium (SABCS) and published the same day in the New England Journal of Medicine (NEJM).

Watch Marisa Weiss, M.D., chief medical officer of Breastcancer.org, discuss the KATHERINE study and its key findings.

How Kadcyla, Herceptin, Perjeta, and taxanes work

Kadcyla, Herceptin, and Perjeta are targeted therapies that work against HER2-positive breast cancer and are given intravenously, which means the medicines are delivered directly into your bloodstream through an IV or a port. A newer form of Herceptin, Herceptin Hylecta (chemical name: trastuzumab and hyaluronidase-oysk), can be given as an injection.

Kadcyla

Kadcyla is a combination of Herceptin (chemical name: trastuzumab) and the chemotherapy medicine emtansine. Emtansine, like some other chemotherapy medicines, disrupts the way cells grow. Emtansine isn’t a targeted medicine, so it can affect healthy cells as well as cancer cells.

Kadcyla was designed to deliver emtansine to cancer cells in a targeted way by attaching emtansine to Herceptin. Herceptin then carries emtansine to the HER2-positive 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.

Herceptin

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.

Perjeta

Perjeta is approved by the FDA to be used in combination with Herceptin and Taxotere (chemical name: docetaxel), a type of taxane chemotherapy, to treat HER2-positive, metastatic breast cancer that hasn’t been treated with either Herceptin or chemotherapy yet. Perjeta also is approved:

  • to be used in combination with Herceptin and Taxotere before surgery to treat HER2-positive, early-stage (the cancer must be larger than 2 cm or cancer must be in the lymph nodes), inflammatory, or locally advanced-stage breast cancer with a high risk of metastasizing or becoming fatal
  • to be used in combination with Herceptin and chemotherapy after surgery to treat HER2-positive, early-stage breast cancer with a high risk of recurrence

HER2-positive breast cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that tell the cancer to grow and spread. About one out of every four breast cancers is HER2-positive. Herceptin works by attaching to the HER2 protein and blocking it from receiving growth signals.

Taxanes

Taxane chemotherapy medicines are:

  • Taxotere
  • Taxol (chemical name: paclitaxel)
  • Abraxane (chemical name: albumin-bound or nab-paclitaxel)

Taxanes work by interfering with the ability of cancer cells to divide.

All the taxanes are given intravenously.

Neoadjuvant chemotherapy, pCR, and residual disease

Treatments given to weaken and destroy cancer cells before surgery to remove the cancer are called neoadjuvant treatments.

One way doctors judge the effectiveness of neoadjuvant chemotherapy is to look at the tissue removed during surgery to see if any actively growing cancer cells are present. If no active cancer cells are present, doctors call it a “pathologic complete response” or pCR.

If there are cancer cells present in the tissue removed, this cancer is called “residual disease.”

Disease-free survival is how long a person lives without the cancer coming back.

The KATHERINE study

Research has shown that people diagnosed with early-stage, HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy have a worse prognosis and higher risk of recurrence (the cancer coming back) than people who have a pCR after neoadjuvant chemotherapy.

Treatments given after surgery to reduce the risk of cancer recurrence are called adjuvant treatments.

Currently, adjuvant Herceptin is the standard of care for people with residual disease after neoadjuvant chemotherapy plus Herceptin or Herceptin and Perjeta.

Other research has shown that Kadcyla can help treat metastatic, HER2-positive breast cancer that has been previously treated with chemotherapy and Herceptin.

So in the KATHERINE study, researchers wanted to know if Kadcyla would be better than Herceptin to treat residual disease found after neoadjuvant chemotherapy plus Herceptin or Herceptin and Perjeta for early-stage HER2-positive breast cancer.

The analysis included 1,486 people diagnosed with early-stage, HER2-positive breast cancer between April 2013 and December 2015 that had been treated with neoadjuvant chemotherapy that included a taxane and Herceptin or Herceptin and Perjeta. All the people in the study had residual disease — cancer cells were found in the breast tissue or in the lymph nodes removed during surgery.

The people were randomly assigned to one of two treatments within 12 weeks after breast cancer surgery:

  • 743 people were treated with 14 cycles of Kadcyla
  • 743 people were treated with 14 cycles of Herceptin

Kadcyla reduced risk of recurrence more and offered longer disease-free survival than Herceptin

After about 3.3 years of follow-up:

  • 91 people (12.2%) treated with Kadcyla had a breast cancer recurrence or had died
  • 165 people (22.2%) treated with Herceptin had a breast cancer recurrence or had died

The researchers estimated 3-year disease-free survival rates to be:

  • 88.3% for people treated with Kadcyla
  • 77.0% for people treated with Herceptin

Distant or metastatic recurrence — the cancer coming back in a part of the body away from the breast, such as the bones or liver — was the first recurrence in:

  • 10.5% of people treated with Kadcyla
  • 15.9% of people treated with Herceptin

"KATHERINE will likely form the foundation of a new standard of care in this population, and increase use of neoadjuvant therapy in HER2-positive early breast cancer," said Charles Geyer, M.D., professor of medicine at Virginia Commonwealth University School of Medicine, at a media briefing at the 2018 San Antonio Breast Cancer Symposium.

The researchers also looked to see how effective Kadcyla was compared to Herceptin in specific groups:

  • cancers that were operable
  • cancers that were inoperable
  • cancers that were hormone-receptor-positive
  • cancers that were hormone-receptor-negative
  • cancers that were treated with Herceptin and chemotherapy before surgery
  • cancers that were treated with Herceptin, Perjeta, and chemotherapy before surgery

"The benefit of [Kadcyla] for invasive disease-free survival was consistent across all key subgroups," Geyer said. "Additional follow-up will be necessary to evaluate the effect of [Kadcyla] on overall survival.

“I believe these results will be practice-changing,” he continued. “The results should form the foundation of a new standard of care in patients with residual invasive breast cancer following neoadjuvant therapy. KATHERINE demonstrates that neoadjuvant therapy can be used to identify patients at increased risk for recurrence based on less than optimal response to standard neoadjuvant therapies who can benefit by switching to [Kadcyla].”

“I do think the KATHERINE study will change clinical practice,” commented Jennifer Litton, M.D., associate professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center, who was not affiliated with the study. “I think that for those patients that do not get a pathologic complete response from neoadjuvant therapy, I do think we’re going to start seeing T-DM1 in the adjuvant setting.”

Kadcyla versus Herceptin side effects

Like almost all cancer treatments, Kadcyla and Herceptin can cause side effects, some of them serious.

In this study, side effects were analyzed in:

  • 740 people treated with Kadcyla
  • 720 people treated with Herceptin

Side effects were more common in people treated with Kadcyla than in people treated with Herceptin (98.8% vs. 93.3%). Still, as the results show, almost all the people in the study had one or more side effects from treatment.

Overall, 71.4% of people treated with Kadcyla and 81.0% of people treated with Herceptin completed all 14 cycles of treatment. Of the 133 people who stopped Kadcyla treatment early, 71 switched to Herceptin, and 63 of those people completed 14 cycles of anti-HER2 therapy.

The most common side effects in people treated with Kadcyla were:

  • fatigue (49.5%)
  • nausea (41.6%)
  • low platelet count (28.5%)
  • elevated liver enzymes (28.4%)
  • headache (28.4%)
  • joint pain (25.9%)
  • neuropathy (18.6%)
  • constipation (18.6%)

The most common side effects in people treated with Herceptin were:

  • fatigue (33.8%)
  • joint pain (20.6%)
  • hot flashes (20.3%)
  • headache (16.9%)
  • nausea (13.1%)
  • constipation (8.2%)
  • neuropathy (6.9%)
  • elevated liver enzymes (5.6%)

Grade 3 or higher side effects happened in:

  • 190 people (25.7%) treated with Kadcyla
  • 111 people (15.4%) treated with Herceptin

Serious side effects happened in:

  • 94 people (12.7%) treated with Kadcyla
  • 58 people (8.1%) treated with Herceptin

Side effects that caused people to stop treatment happened in:

  • 133 people (18%) treated with Kadcyla
  • 15 people (2.1%) treated with Herceptin

For people treated with Kadcyla, the most common side effects that led to stopping treatment were:

  • low platelet count (4.2%)
  • elevated liver enzymes in the blood (5.7%)
  • peripheral neuropathy (1.5%)
  • heart problems (1.2%)

What this means for you

If you’ve been diagnosed with early-stage, HER2-positive breast cancer and did not have a pathologic complete response to treatment before surgery with chemotherapy and Herceptin or chemotherapy and Herceptin and Perjeta, you and your doctor are likely considering treatment options for the residual disease. You may want to ask your doctor about the KATHERINE study and whether treatment with Kadcyla makes sense for your unique situation.

For more information, visit the Breastcancer.org Kadcyla pages.

Editor’s Note: This article was updated with information about Herceptin Hylecta, which the FDA approved on Feb. 28, 2019. On May 3, 2019, the FDA approved Kadcyla to treat early-stage HER2-positive breast cancer after surgery if residual disease was found after neoadjuvant treatment with taxane chemotherapy and Herceptin.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser


Lilly Oncology

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