Medical oncologist Shanu Modi is studying next-generation targeted therapies for breast cancer.
On August 5, 2022, the FDA approved the first targeted therapy for patients with HER2-low breast cancer that has spread to other parts of the body and is unable to be surgically removed. The drug, trastuzumab deruxtecan (T-DXd), was approved based on a clinical trial led by Memorial Sloan Kettering Cancer Center (MSK) breast medical oncologist Shanu Modi, who presented the findings at this year’s American Society of Clinical Oncology (ASCO) meeting.
“The results of this trial are practice-changing and redefine how a large population of patients with metastatic disease will be treated,” Dr. Modi says. “Although this trial focused on patients with breast cancer, we believe that these results could also have implications for the future treatment of people with other types of cancer that express HER2 at low levels.”
Until now, HER2 targeted therapy has not been successful in treating cancer that is HER2-low. Targeted therapy works by precisely identifying and attacking certain types of cancer cells, without killing normal cells, therefore resulting in fewer side effects.
In the first trial of its kind, patients were given T-DXd (also known as Enhertu®), which targets a protein called HER2. The results showed that those who received T-DXd did significantly better than those who received standard chemotherapy. The targeted drug held their cancer in check nearly twice as long and increased their survival by about 35%.
The findings from this international, multicenter trial, called DESTINY-Breast04, were also published June 5, 2022, in The New England Journal of Medicine (NEJM).
Expanding Access to a Powerful Drug
Trastuzumab (Herceptin®) was the first targeted therapy developed to treat HER2-positive patients. “HER2-positive,” which accounts for 15% to 20% of all breast cancers, means there is a high level of the HER2 protein on the surface of cancer cells, driving tumor growth. Trastuzumab is a lifesaving drug that works by binding to HER2 and blocking tumor growth.
Unfortunately, many patients who initially respond to trastuzumab eventually develop resistance to the drug. In recent years, scientists have developed new drugs that target HER2 cancers more effectively. One of these drugs is T-DXd, which was originally approved by the U.S. Food and Drug Administration in 2019 for treating patients with HER2-positive, metastatic breast cancer who have stopped responding to other HER2 drugs. That approval was based on a study also published in NEJM; Dr. Modi was the first author.
Trastuzumab directly blocks growth signals sent out by HER2, but T-DXd works in a different way. With this drug, the trastuzumab is attached to a payload of chemotherapy, which it delivers to the site of the tumor. Because T-DXd is so much more powerful than standard trastuzumab, Dr. Modi and her colleagues hypothesized that it could be effective against tumors with low (but not absent) levels of HER2. More than 60% of tumors that traditionally have been labeled HER2-negative actually have some HER2 — the group that was considered “HER2-low” in this study.
Making Targeted Therapy Available to More People with Breast Cancer
Significantly Improved Survival
The phase 3 DESTINY-Breast04 trial enrolled 557 patients with metastatic breast cancer whose tumors were HER2-low. About two-thirds were assigned to the T-DXd group, and one-third received standard chemotherapy.
At the ASCO meeting, Dr. Modi reported that T-DXd nearly doubled progression-free survival (the time it takes for tumors to start growing again), from 5.4 months to 10.1 months. Patients in the T-DXd group also lived longer — an average of 23.9 months compared with 17.5 months for those in the chemotherapy group.
T-DXd does have side effects. The common ones are nausea and lowered blood counts, and these can be managed with medication. However, a small number of people who receive the drug have a severe response: a condition called interstitial lung disease, which means their lungs developed inflammation and, in some cases, scarring, leading to difficulty breathing. This risk has been noted from the very first studies of the drug. In the DESTINY-Breast04 trial, it occurred in about 12% of patients who received T-DXd.
Dr. Modi expects that the findings from this trial will lead to even more uses for T-DXd. “Given the robust efficacy for the drug in this trial, there’s a lot of excitement about moving it to an earlier-stage setting for high-risk patients, where we hope to cure more patients with breast cancer and prevent more recurrences,” she says.
Patients with other types of cancer that are HER2-low are also likely to benefit. Subsets of stomach (gastric), lung, colorectal, and other cancers are known to express HER2 as well, and T-DXd is already approved for a subset of patients with advanced gastric cancer and is under testing for its benefits in other tumor types to treat people who have HER2-expressing or HER2-altered tumors. “This drug has the potential to significantly improve treatment outcomes for a large population of patients with cancer,” Dr. Modi says.
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