Enhertu Moves Toward First-Line Treatment for HER2-Low Metastatic Breast Cancer

HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that promotes cell growth and division. HER2-positive breast cancer produces excessive amounts of this protein. In 1998, trastuzumab (Herceptin) became the first FDA-approved treatment for HER2-positive breast cancer. This was a turning point both for molecularly targeted cancer treatment and for HER2-positive breast cancer, changing the outlook for this disease. Since then, many HER2-targeted drugs have been developed, revolutionizing breast cancer treatment.

One of the latest examples of these targeted treatments, with a bispecific structure, is trastuzumab deruxtecan (T-DXd, brand name Enhertu). T-DXd is notable for its effectiveness not only in HER2-positive patients but also in HER2-low disease. This article examines how research is positioning this promising treatment as a first-line option for HER2-low metastatic breast cancer.

When a pathologist examines breast cancer tissue under a microscope, special immunohistochemical (IHC) stains determine the tumor's HER2 status. Under the conventional approach, IHC staining is interpreted as follows:

• 0 HER2 is "negative"
• 1+ HER2 status is " low-positive" = "negative",
• 2+ HER2 status is " equivocal-positive", requiring HER2 testing by FISH for confirmation. A positive or negative FISH result determines the final HER2 status. 
• 3+ HER2 status is considered "positive."

Before Enhertu, patients with a HER2 result described as "low-positive" and (IHC 1+, IHC 2+ / FISH-negative) breast cancer did not receive HER2-targeted therapy. However, clinical trials demonstrated Enhertu's effectiveness in HER2-low breast cancer. Patients with HER2-low tumors account for 50% of all breast cancer patients , making this a major development.

T-DXd: An Effective Treatment for HER2-Low Metastatic Breast Cancer

The antibody–drug conjugate trastuzumab deruxtecan (T-DXd, brand name Enhertu) is emerging as an effective first-line treatment for HER2-low metastatic breast cancer, providing an additional 5 months of progression-free survival (PFS) compared with chemotherapy.

Results from DESTINY-Breast04 in 2022 demonstrated T-DXd's effectiveness as second-line chemotherapy for HER2-low metastatic breast cancer, and it received FDA approval in August 2022.

New findings presented this year at the ASCO 2024 annual meeting from the eagerly anticipated phase 3 DESTINY-Breast06 trial support an earlier role for T-DXd in HER2-low cancer treatment. They also show benefit in a group called HER2-ultralow. These patients have cancers with HER2 expression that is only faintly detectable by current tests.

Details of the DESTINY-Breast06 Trial

Dr. Giuseppe Curigliano of the University of Milan and European Institute of Oncology presented the DESTINY-Breast06 findings. He and his colleagues randomized patients with metastatic breast cancer —866 in total—to two groups:

• 436 patients received intravenous T-DXd, and
• 430 received investigator-selected capecitabine, nab-paclitaxel or paclitaxel chemotherapy.

Investigators chose capecitabine in 60% of cases.

Most patients were classified as HER2-low (IHC 1+ or 2+), while 153 were classified as HER2-ultralow (IHC 0 with membrane staining, or below IHC 1+).

Eligible patients had progressed on endocrine therapy, with or without targeted treatment.

The median age was between 57 and 58, and none had received chemotherapy for metastatic breast cancer.

Results

• Median Progression-Free Survival (HER2-Low Group):

  • T-DXd treatment: 13.2 months
  • Chemotherapy group: 8.1 months
  • Hazard ratio (HR): 0.62
  • Confidence interval (95% CI): 0.51-0.74
  • P value: < 0.0001

• Overall Population (Including HER2-Ultralow Patients):

  • Hazard ratio (HR): 0.63
  • Confidence interval (95% CI): 0.53-0.75
  • P value: < 0.0001

• Overall Survival:

  • Could not be assessed because complete trial data were not yet available.
  • However, trends favored T-DXd.

• Tumor Response Rates:

  • Patients treated with T-DXd: 57%
  • Patients treated with standard chemotherapy: 31%

• T-DXd's Effectiveness:

  • T-DXd demonstrated effectiveness in both HER2-low and HER2-ultralow patients.
  • Determining the lowest HER2 expression level at which metastatic breast cancer can benefit from T-DXd will be extremely important.

Serious treatment-related adverse events were more common with T-DXd. In this group, 11% developed drug-related interstitial lung disease, and three patients died from it. Five patients in the T-DXd group died from treatment-related adverse events, versus none with standard chemotherapy. Overall, 11 patients in the T-DXd group and six in the chemotherapy group died.

What Does This Mean in Practice?

DESTINY-Breast06 suggests that HER2 expression needs to be reconsidered. Even very low HER2 expression matters and may be used to improve treatment. However, T-DXd may not be the right first choice for everyone, particularly given safety concerns. With overall survival and quality-of-life data still incomplete, oncologists will need to decide case by case who should receive first-line T-DXd.

For patients with symptomatic metastatic disease who need a response to relieve symptoms and whose cancer is unlikely to respond well to chemotherapy—for example, those with a short relapse interval after adjuvant chemotherapy—first-line T-DXd makes sense to take advantage of its substantially higher response rate. For asymptomatic patients with a low disease burden, however, using well-tolerated capecitabine first and T-DXd second appears very reasonable.

Patient preferences will also matter in deciding whether T-DXd becomes a first-line option. Although the latest findings reinforce its known toxicity, capecitabine—one of the trial control arm's chemotherapy options—is preferred by many breast cancer clinicians because it is effective, taken orally, well tolerated and does not cause hair loss.

Other Trials: DESTINY-Breast07 and DESTINY Breast09

DESTINY-Breast07 was conducted by Dr. Fabrice Andre and colleagues at Université Paris-Saclay in France. It investigates safety and tolerability. They presented initial results comparing T-DXd alone (monotherapy) with T-DXd plus pertuzumab (combination treatment) in metastatic breast cancer with high HER2 protein levels (IHC 3+).

Current Standard Treatment: Based on the 2015 CLEOPATRA trial, current first-line standard treatment combines pertuzumab and trastuzumab with docetaxel. T-DXd is currently approved as second-line treatment.

Trial Details: Dr. Andre and colleagues randomized 75 patients to T-DXd alone and 50 to T-DXd plus pertuzumab. Median follow-up was 2 years.

Treatment Results:

• Progression-Free Survival:
  • T-DXd plus pertuzumab: 89% (survival without progression for 1 year)
  • T-DXd monotherapy: 80%
• Tumor Response Rates:
  • Combination treatment: 84% (complete response in 20% of patients)
  • Monotherapy: 76% (complete response in 8% of patients)

Side Effects: Adverse events were common in both groups:

• In the monotherapy group, 9% of patients developed interstitial lung disease.
• In the combination group, 14% developed interstitial lung disease. However, no treatment-related deaths occurred in this trial.

Future Trials: The next trial, DESTINY Breast09, will compare T-DXd monotherapy and combination treatment with standard treatment.

In Conclusion T-DXd is rapidly gaining importance in breast cancer and other solid tumors. DESTINY-Breast06 indicates that it may be used earlier in metastatic breast cancer treatment, allowing it to be offered as the first chemotherapy option instead of many traditional treatments. The findings support not only this particular drug but also antibody–drug conjugates as a highly effective approach to cancer treatment.