The Drug Combo That Can Keep Advanced HER2-Positive Breast Cancer Under Control For Longer: Understanding The New Data

The results showed that the trastuzumab deruxtecan plus pertuzumab approach reduced the risk of disease progression or death by 44% compared to the standard.

The finding matters because it suggests many women, and the smaller group of men who share this diagnosis, can postpone harsh chemotherapy and keep their cancer under control for longer.

“That’s where the clinically meaningful and statistically significant improvement in progression-free survival matters,” Dr. Nancy Chan, director for breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, tells SurvivorNet. “…It translates into, for patients, not just a longer time period from progression, but also better quality of life.”

Why Do These Results Matter?

HER2-positive breast cancer carries more HER2 protein on the tumor surface than normal cells. That protein acts like a stuck accelerator pedal, making the cancer spread faster than most hormone-driven tumors. Twenty years ago, the outlook for stage 4 HER2-positive disease felt bleak. Then came trastuzumab (brand name: Herceptin), a targeted antibody that blocks the HER2 signal. Adding pertuzumab (Perjeta) later improved the results further.

Oncologists combined both antibodies with a taxane chemotherapy drug in a regimen made famous by the CLEOPATRA trial.

While CLEOPATRA gave patients precious months and even years without cancer progression, taxanes bring their own hardships in the form of side effects — hair loss, numb fingertips, fatigue, etc.

More recently, scientists designed antibody-drug conjugates (ADCs) that deliver a microscopic package of chemotherapy directly to HER2-laden cells. Trastuzumab deruxtecan, often shortened to T-DXd and marketed as Enhertu, is the most potent of those ADCs so far. Until today it sat in the second-line seat, offered after the cancer outgrew the standard of care drug cocktail.

DESTINY-Breast09 asked a simple question: Why wait to use the T-DXd approach?

How Does T-DXd (Enhertu) Work?

Think of T-DXd as a guided missile. The antibody part, trastuzumab, finds HER2 and locks on. Attached to the antibody is a tiny but powerful chemotherapy payload called deruxtecan. Once the drug docks on a cancer cell, the package enters, breaks apart, and releases chemo right where it hurts the tumor most.

“It’s a bioengineered drug that essentially has more of an effect on the tumor cells compared to normal cells. So use of this medication actually helps minimize some of the effects on the normal tissue, but maximize the effects on the tumor tissues,” Dr. Anupama Nehra, clinical director of hematology/oncology at the Rutgers Cancer Institute in New Jersey, told SurvivorNet.

A bit of that chemo also leaks into nearby cells that might not carry much HER2, tackling hidden pockets of disease — a “bystander” effect. “This basically means that the surrounding tumor cells are also targeted by the medication,” Dr. Nehra explains.

Doctors have already used T-DXd for breast tumors that spread after earlier treatments, and for stomach (gastric) cancers loaded with HER2. They know it shrinks tumors in roughly four of five patients, sometimes wiping out visible disease on scans.

The trade-off is a small but real risk of interstitial lung disease (ILD). ILD is inflammation in the lungs that can cause cough and breathlessness. Mild cases get better with steroids and a drug break, but serious ILD can be life-threatening, so specialists watch closely.

DESTINY-Breast09: What Did The Data Show?

Results from the DESTINY-Breast09 trial were presented at the annual ASCO conference on June 2. They showed that the trastuzumab deruxtecan (Enhertu) plus pertuzumab approach reduced the risk of disease progression or death by 44% compared to the standard taxane, trastuzumab and pertuzumab (THP) approach as a first-line (first) treatment for patients with HER2+ metastatic breast cancer.

The median progression-free survival (amount of time that disease does not progress) was 40.7 months in the group given trastuzumab deruxtecan plus pertuzumab compared to 26.9 months with THP.

Researchers were still tracking the overall survival for trastuzumab deruxtecan plus pertuzumab compared to THP, but early data looks promising for the new, targeted approach as well.

“This study actually demonstrated that we’ve now managed to find a new therapy that improved upon the standard and this will impact many patients who have HER2+ breast cancer,” Dr. Chan explains.

How Will This Change Treatment Going Forward?

For more than a decade, the combination of a taxane, trastuzumab, and pertuzumab ruled as the standard treatment approach. DESTINY-Breast09 challenges that order. Many oncologists left the session ready to offer T-DXd (brand name Enhertu) plus pertuzumab to newly diagnosed stage 4 breast cancer patients who are eligible and eager to avoid chemotherapy’s harsher toll.

However, several questions about the drug’s effectiveness remain, including:

• How long should patients be on the drug? Should people stay on T-DXd indefinitely or take it for a fixed number of cycles then coast on the antibodies alone? The trial ran continuous dosing, but some doctors wonder if an “induction” phase followed by maintenance could slash ILD risk without losing control.
• What comes after T-DXd? If T-DXd moves up, what comes second? Options include tucatinib-based triple therapy, the old CLEOPATRA trio, or antibody-drug conjugates that target different proteins. Trials are already mapping these paths.

Questions To Ask Your Doctor

• Am I a candidate for T-DXd (Enhertu) plus pertuzumab?
• How will we check for lung side effects, and how often?
• If my tumor shrinks, can we pause treatment or lower the dose?
• Will my insurance cover a newer drug?
• Could I still join a clinical trial later if the cancer grows?

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