The Most Important Development in Oncology in 2022: Enhertu for HER2-Low Breast Cancer

The most notable study at the ASCO 2022 Congress came from the field of breast cancer.

HER2 is a receptor expressed at high or low levels on the surface of breast cancer cells, providing information about the course of the disease and serving as a target for targeted drugs. After 2000, breast cancers began to be classified according to HER2 positivity.

When a pathologist examines breast cancer tissue under a microscope, the tumor’s HER2 status is determined with special immunohistochemical (İHK) stains. Under our now-conventional approach, İHK staining is interpreted as follows:

• 0 HER2 “negative”
• 1+ HER2 status “low positive” = “negative”,
• 2+ HER2 status “equivocal positive,” in which case HER2 must be assessed with a FISH test for confirmation. The tumor’s final HER2 status is determined according to whether FISH is positive or negative. 
• 3+ HER2 status is considered “positive.”

This new study enrolled breast cancer patients with a “low positive” HER2 result (İHK 1+, İHK 2+ / FISH negative). Patients whose tumors are HER2-low account for 50% of all breast cancer patients, making this a very important development.

Patients with HER2-low breast cancer, previously considered untreatable with HER2-targeted therapies, benefited significantly from the “anti-HER2 antibody-drug conjugate” trastuzumab-deruxtecan (Enhertu). In hormone receptor-positive (HR+) and HER2-low patients, compared with chemotherapy, the duration for which disease is controlled on treatment, known as progression-free survival doubled.

Presented concurrently with the ASCO 2022 Congress in NEJM, the results of this clinical study, called DESTINY-Breast04, clearly appear set to change practice in oncology. The study demonstrates the benefits of this antibody-drug conjugate in an entirely new patient group that has traditionally been very difficult to treat. This development has raised a new question about how HER2 status should now be classified.

This conjugate drug contains the anti-HER2 antibody “trastuzumab” and the topoisomerase I inhibitor “deruxtecan,” which interferes with DNA copying.

The drug Enhertu, containing trastuzumab-deruxtecan, had received FDA approval

• in 2019 for advanced HER2-positive breast cancer previously treated with at least 2 lines of anti-HER2 regimens,
• in 2021 for previously treated advanced HER2-positive gastric cancer, and
• in May 2022 for advanced HER2-positive breast cancer previously treated with one line of anti-HER2 therapy.

Dr. Shanu Modi, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, received a standing ovation after presenting DESTINY-Breast04 at ASCO 2022. According to Dr. Modi, 60% of breast cancer patients can be classified as HER2-low using conventional methods.

In 2022, Annals of Oncology published a study in which:

• 40% of triple-negative breast cancers were classified as HER2-low,
• 45-55% of moderately hormone-positive breast cancers were HER2-low, and
• >60% of highly hormone-positive breast cancers were classified as HER2-low.

Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies (such as Herceptin and Perjeta) had failed in this patient group, Dr. Modi emphasized the structure of the drug conjugate, including its high drug load and use of a topoisomerase inhibitor rarely used against breast cancer.

When released from the antibody, the drug retains the ability to cross cell membranes and enter the tumor microenvironment. This bystander effect may allow the chemotherapy drug to reach neighboring cells that do not highly express HER2 on their surfaces. Dr. Modi said, "We know HER2 expression within a tumor is very heterogeneous. I think that is why we are seeing efficacy for a targeted drug conjugate for the first time".

Study Details

The phase-III DESTINY-Breast04 study in Asia, Europe, and North America evaluated hormone receptor (HR)-negative or positive, HER2-low, previously treated with one or two lines of therapy, unresectable and/or metastatic breast cancer in 557 patients.

Patients were randomly assigned in a 2:1 ratio to one of two arms to receive trastuzumab deruxtecan or several standard chemotherapy drugs chosen by their physician.

The planned primary endpoint was progression-free survival in the hormone receptor-positive group. Secondary endpoints were progression-free survival in all patients and overall survival in the hormone receptor-positive group and in all patients.

Of the 557 patients, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease.

After a median follow-up of 18.4 months,

• Compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in the risk of progression and a 36% reduction in death.
• The group also had longer progression-free survival (10.1 versus 5.4 months) and overall survival (23.9 versus 17.5 months).

Although side effects were similar between the two groups (52.6% with trastuzumab deruxtecan and 67.4% with chemotherapy), lung toxicity occurred in 12% of the trastuzumab deruxtecan group and resulted in 3 deaths (0.8%). Prior trastuzumab exposure has been associated with interstitial lung disease/pneumonia, and an earlier meta-analysis found a 2.4% incidence and a 0.2% death rate.

Additional studies are ongoing to determine the minimum HER2 expression threshold required to benefit from trastuzumab deruxtecan treatment.