March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
Trastuzumab deruxtecan (brand name: Enhertu) is a Food and Drug Administration (FDA) approved drug for certain stage four breast cancer patients whose tumors are classified as HER2- low. Previous therapies targeting cancer tumors with HER2 (Human Epidermal Growth Factor 2)-low proteins, such as trastuzumab (brand name: Herceptin), have largely failed to benefit the HER2-low population, representing a large fraction of the diagnosed breast cancers. The benefit of Enhertu for this population, as demonstrated in the DESTINY-Breast04 trial, is so significant that it has already been incorporated into the National Comprehensive Cancer Network (NCCN) Guidelines for the treatment of HER2-low tumors, which have failed at least one prior line of chemotherapy, or HER2-positive tumors which have become immune to the traditional hormone therapies.
Enhertu is not exactly a new drug. It has heretofore been used to treat HER2-positive breast cancers with great success. “This drug has been around for a few years, and it’s very effective in the HER2-positive population,” Dr. Julie Gralow, MD, FACP, FASCO, the chief medical office and the executive vice president of the American Society of Clinical Oncology, tells SurvivorNet. “Now, however, we have a whole, huge group [HER2-low] of patients who have the potential for benefit, who we never even thought of giving HER2 targeted therapy to.” Dr. Gralow tells us this represents yet another leap in using tumor characteristics to inform an individualized, targeted treatment for each patient, which usually begets improved patient outcomes.
Dr. Sylvia Adams, director of the Breast Cancer Center at Perlmutter Cancer Center and an international leader in triple-negative breast cancer immunotherapy trials, echoes this enthusiasm: “Classically, [breast cancers were] either [HER2] negative or positive… [However, almost 60% of these] tumors that were officially classified as HER2-negative are HER2-low, meaning that the target is found in relatively low concentrations [on these cells].” She continues, “However, it is enough that [Enhertu] deliver the chemotherapeutic that it carries!”
HER2 Status and Treatment Options for Patients:
Breast cancer is an exceedingly common diagnosis with a projected 290,000 new cases in the United States in 2022. Yet its treatment is extremely nuanced, particularly in the metastatic setting when cancer has spread outside the breast. There has been a trend in oncology toward customizing treatment for each patient based on the pathologic and genomic characteristics of their tumors. HER2 is one such characteristic. HER2 are receptors on the surface of cancer cells, not unlike hormone receptors, such as those for estrogen (ER) and progesterone (PR).
The HER2 status of a tumor is usually assessed via two laboratory assays, fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). FISH tests divide tumors into 3 categories: no, low, or high HER2 amplification. The latter separates the HER2 status numerically, with 0 representing no HER2 expression and 4+ representing maximal expression. 1+, 2+, 3+ describe those tumors with intermediate HER2 expression. Traditional classification groups IHC 3+ and 4+ as HER2-positive, and others as HER2-negative. HER2-low is a nascent designation, encompassing tumors that her IHC 1+ or 2+ and FISH negative. This population was historically lumped together as HER2-negative.
This new HER2 group, previously HER2-negative, has been traditionally treated with hormone therapy or chemotherapies with modest success. However, the DESTINY-Breast04 Phase III trial, which used Enhertu as the investigational treatment for this group, may have changed the treatment approach for the better.
“[Classically, the subtypes of breast cancer were] estrogen-sensitive tumors, which are about 70% of breast cancers. And then, we have HER2-[positive] tumors, which represent about 15-20% [of the cases]. Then, [there are the] triple negative tumors, which lack estrogen and HER2 receptors. But because of this new therapy on the market, we have an additional relevant group of women… that have low HER2 receptors on the tumors and can benefit from this treatment,” summarizes Dr. Adams.
How Does Enhertu Work?
Enhertu is a HER2-directed antibody tethered to a chemotherapy drug. The antibody selectively binds to the HER2 proteins on the surface of breast cancer cells and infuses highly potent chemotherapy directly into those cancer cells. This selectivity allows for the sparing of normal cells and the consequent side effects.
This mechanism is separate from the way more established drugs like Herceptin operate. Herceptin targets the same HER2 receptors, thereby preventing them from binding to substances that may promote cancer cell growth. The distinct modus operandi of Enhertu is the reason that has succeeded in treating HER2-low patients while Herceptin failed to do so.
What Did The Trial Show?
DESTINY-Breast04 was a phase III randomized trial, representing the highest level of scientific evidence available in medicine. 557 patients with unresectable or metastatic breast cancer who were also HER2-low were selected for the trial. The HER2 classification was based on the results of combined FISH and IHC testing, with those testing negative for the former and 1+ or 2+ for the latter categorized as HER2-low. These patients were spread across a wide variety of ages, hormone receptor statuses (ER and PR), and races including White, Asian, African American, and Hispanic and Latino. All in all, this translates to a trial whose results can veritably be used to inform the clinical decision-making process for the general population.
The results from this trial were game-changing. Across all the patients, those who received Enhertu had progression-free survival (PFS) of 9.9 months as compared to the group who received traditional chemotherapy, whose PFS was 5.1 months. PFS represents the time a patient is alive without a worsening of their disease. Overall survival (OS), the ultimate measure of a treatment’s efficacy, is defined as the length of time patients are alive after their initial diagnosis of cancer. In the DESTINY-Breast04 trial, the OS for the Enhertu and the chemotherapy treatment groups was 23.4 months and 16.8 months respectively, a very impressive difference.
Like All Drugs, It Carries Side Effects:
Enhertu is not without its side effects. Its side-effect profile in this trial was like that reported in the study which used the drug for HER2-positive metastatic breast cancer. The most reported side effect was interstitial lung disease (ILD), which was noted in 12% of the patients, with most of these cases being mild to moderate and reasonably treatable. There were, however, 3 deaths attributed to ILD caused by Enhertu. This is a reminder that despite all the amazing benefits of such drugs, they are not without risk. A discussion of such risks should be part of a comprehensive discussion between physicians and patients considering Enhertu for their treatment. In the words of Dr. Gralow, “the antibody-drug conjugates carry real toxicities and are not benign treatments.”