Posted: Thursday, September 3, 2020
“Unprecedented” is rarely used to characterize the results of oncology therapies, but it has been used by many to describe the results with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in breast cancer. A HER2-directed antibody and topoisomerase inhibitor conjugate, T-DXd demonstrated a 61% response rate in a population of patients with pretreated HER2-positive, unresectable and/or metastatic breast cancer.1
Rarely does a drug appear to provide benefit to all patients, especially in the third-line setting of metastatic disease, but nearly every patient treated with T-DXd had clinical benefit in the multicenter, phase II DESTINY-01 trial. According to Shanu Modi, MD, lead author of the study published in The New England Journal of Medicine, however, the duration of response was even more impressive than the response rate.
“A progression-free survival of 16 months in a population with a median of six prior lines has not been previously reported,” commented Dr. Modi, a medical oncologist specializing in breast cancer at Memorial Sloan Kettering Cancer Center (MSK), New York. “For most patients starting a new therapy in this setting, the duration of benefit is typically short, at 3 to 6 months, but T-DXd can work for some patients for a long time, which also indirectly suggests the therapy is generally well tolerated if patients can stay on it for this long.”
“It is exciting to find an agent that works so well in patients who have otherwise run out of effective options,” Dr. Modi added.
Mechanism of Action
As Dr. Modi explained, like trastuzumab emtansine (T-DM1),2 T-DXd is a HER2-directed antibody-drug conjugate with a backbone of trastuzumab, the monoclonal antibody that targets HER2. However, T-DXd has a much higher ratio of cytotoxic drug to antibody than T-DM1, rendering it more potent against cancer cells.
“The small-molecule deruxtecan is a topoisomerase I inhibitor attached to the antibody by a cleavable linker, and it is manyfold more potent than other topo-1 inhibitors used in the clinic,” Dr. Modi told JNCCN 360. “It also has a membrane permeability potential, so it can pass through cell membranes and enter neighboring cells that are not heterogeneously HER2-positive. It’s a great way of delivering a potent chemotherapy payload to the cells of interest (ie, the cancer cells) while generally sparing significant toxicity to the rest of the body.”
Given its potency and potential for cell permeability, T-DXd is active even in cancers that have low levels of HER2 expression. “This phenomenon is known as the ‘bystander effect’ and may explain why this drug works even for what have been traditionally referred to as HER2-negative breast cancers, where other HER2-targeted therapies have failed to show a benefit,” Dr. Modi said.
Administration of T-DXd
According to Dr. Modi, T-DXd is relatively easy to administer. The recommended dosage is 5.4 mg/kg, which is given as an intravenous (IV) infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.3 “The 3-week schedule is convenient for many patients and is another advantage compared with many of our weekly IV options for patients in this setting,” said Dr. Modi. “We had some patients traveling long distances to be able to get this treatment.”
The 3-week schedule is convenient for many patients and is another advantage compared with many of our weekly IV options for patients in this setting.The first infusion should be administered over 90 minutes, but subsequent infusions can be given over approximately 30 minutes. Although the label indicates permanent discontinuation in the case of severe infusion reactions, Kelly Kindy, APN/CNP, a nurse practitioner in the Division of Hematology/Oncology at Northwestern Medicine, Chicago, told JNCCN 360 she has never observed any infusion reactions.
Before IV infusion of T-DXd, Ms. Kindy and colleagues also administer two IV agents to prevent nausea and emesis: the 5-HT3 antagonist palonosetron and the corticosteroid dexamethasone. In addition, the oral antiemetic prochlorperazine is prescribed to patients to take at home as needed in the event of nausea. Dr. Modi and colleagues are following a similar protocol at MSK.
“There is no mandated premedication in the label, but the most common side effect is nausea,” said Dr. Modi. “It is typically grade 1 or 2 level nausea, so it is manageable. However, at our institution, we have decided to start all patients on antinausea medication preemptively rather than wait until a patient reports nausea.”
According to Ms. Kindy, this premedication strategy is working. “A couple of patients have experienced an acute onset of nausea within the first 1 or 2 days, but we are not seeing a lot of delayed nausea and, thankfully, no vomiting,” she said.
One of several highly active, HER2-targeted agents to be approved in the past year,4 T-DXd is specifically indicated for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting. As Ms. Kindy explained, patients treated with T-DXd in the clinic comprise a heterogeneous population.
“The age of patients can range from 30 years to more than 80 years,” she said. “Although some patients are generally healthy, others have multiple comorbidities, such as diabetes and hypertension.”
For patients who have had metastatic disease for a long time, continued Ms. Kindy, the biggest issue seems to be the cumulative toxicity from chemotherapy, which can present as fatigue, weakness, neuropathy, or persistent gastrointestinal issues. Providers should consider previous treatment-related toxicities and the potential for next-line therapy to exacerbate these side effects.
In addition to nausea, significant hair loss occurs in approximately half of patients treated with T-DXd. Patients are informed about this possibility, said Dr. Modi, who noted that alopecia is one of the differentiating side effects between T-DM1 and T-DXd.
In addition to nausea, significant hair loss occurs in approximately half of patients treated with T-DXd.
Providers should also be careful to monitor patients for cardiotoxicity, a known side effect of HER2 antibodies. According to Dr. Modi, however, because patients receiving T-DXd are in the third-line setting of HER2-targeted drugs, they usually have already passed the cardiac stress test. “These patients have already received trastuzumab and pertuzumab and T-DM1, so they don’t seem to be susceptible to the cardiac toxicity of HER2-targeted therapy,” she explained. “We did not see any safety signal with respect to cardiotoxicity on this trial.”
Nevertheless, routine echocardiography should be part of surveillance to monitor heart function. Even if patients have experienced heart damage from prior HER2 agents, T-DXd may still be an option because cardiotoxicity is typically reversible, said Ms. Kindy.
As Dr. Modi explained, many of the other side effects associated with T-DXd are familiar to oncologists who are accustomed to prescribing chemotherapy. They include decreased blood cell counts and neutropenia, although blood cell counts typically fall within a safe and acceptable range. In the case of severe neutropenia, which is rare, dose reduction is recommended. Growth factor support, such as with filgrastim and pegfilgrastim, was also used in the clinical trial to maintain counts when appropriate, Dr. Modi reported.
Although neutropenia is typically treatable, Ms. Kindy noted that patients with decreased white blood cell counts should follow strict neutropenic precautions, especially given the current added risk of the COVID-19 pandemic. “Patients are probably doing this already, but we make a point to educate them about frequent hand washing and avoiding contact with any sick friends or family,” said Ms. Kindy. “In the setting of the COVID-19 pandemic, they should be wearing their masks in public and maintaining social distancing, too.”
Interstitial Lung Disease
Although the majority of side effects associated with T-DXd are expected with its drug class and are manageable, one less common but important side effect has drawn attention for its potential severity: lung toxicity. Of the 14% of patients who experienced lung toxicity on the DESTINY-Breast01 trial, the majority experienced grade 1 or 2 adverse events, but four patients had fatal lung toxicity. Approval of T-DXd by the U.S. Food and Drug Administration came with a boxed warning for interstitial lung disease.
“Interstitial lung disease is rare [with T-DXd], but it’s potentially very serious, so this has received a lot of attention,” said Dr. Modi. “Compared with other HER2-targeted agents, where we typically do not see this rate of grade 5 events, this is an important risk associated with T-DXd.”
Interstitial lung disease is rare [with T-DXd], but it’s potentially very serious.
According to Dr. Modi, the key to safe delivery of T-DXd is for both physicians and patients to be aware of the risk. In addition, patients should promptly report any new lung symptoms, including shortness of breath, fever, cough, and profound fatigue.
“Patients need to be encouraged to inform their physicians about these symptoms, and then the care team needs to take appropriate action when these new symptoms appear or when there is worsening of baseline respiratory symptoms,” said Dr. Modi. “It’s a challenge, however, because for some patients, these symptoms may be related to their disease as well.”
If symptoms do occur, treatment with T-DXd should be held until a high-resolution computed tomography scan of the chest and oxygen saturation levels can clarify the cause. Pulmonologists should be involved early, and steroids should be initiated promptly if there are concerning signs on imaging suggestive of drug toxicity. Some patients will require bronchoscopy potentially to differentiate the etiology of these findings, Dr. Modi advised.
“If you can confidently attribute the findings to an alternate diagnosis such as infection or pneumonia (ie, not drug toxicity), once patients recover, treatment with T-DXd may be resumed,” she continued. “However, if the symptoms are due to lung toxicity, you should stop treatment with T-DXd.” For true interstitial lung disease (grade 2 and higher) that occurred during the clinical trial, “treatment was stopped, and no attempts to re-challenge with T-DXd were made,” she explained.
As Dr. Modi reported, confirmatory phase III, randomized trials are well underway. DESTINY-Breast02 will randomly assign patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with TDM-1 either to T-DXd or physician’s choice (capecitabine plus lapatinib or capecitabine plus trastuzumab; NCT03523585).
DESTINY-Breast03 is a head-to-head comparison of T-DXd and TDM-1 in an earlier-line setting of HER2-positive, metastatic disease previously treated with trastuzumab and a taxane (NCT03529110). There are also ongoing, phase III studies testing T-DXd in patients with HER2 low–expressing breast cancer.5
Finally, said Dr. Modi, the activity of T-DXd is not necessarily limited to metastatic breast cancer. There are data in gastric cancer,6 colorectal cancer,7 and many other tumor types.8
“I think we are eventually going to see this drug available for a variety of patients,” Dr. Modi concluded. Until then, Ms. Kindy had some straightforward advice for breast cancer teams with little or no clinical experience with T-DXd: “Don’t hesitate to use this drug.”
“I know sometimes we may worry about how our patients are going to respond to new agents, but I’m optimistic about this drug because of its efficacy and how well it is tolerated,” said Ms. Kindy. She noted that all of her patients who have started therapy with T-DXd have demonstrated stable-to-improved disease on their first set of scans. “To have another antibody-drug conjugate with somewhat minimal side effects is wonderful.”
Shanu Modi, MD, has served as an advisor or consultant for AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, MacroGenics, and Seattle Genetics; has served as a speaker or a member of a speakers bureau for AstraZeneca, Daiichi Sankyo, and Genentech; and has received grants for clinical research from Daiichi Sankyo, Genentech, Novartis, and Seattle Genetics.
Kelly Kindy, APN/CNP, reported no relevant financial relationships.
- Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020;382:610–621.
- von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019;380:617–628.
- Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use. Prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf. Accessed August 17, 2020.
- Lin NU, Murthy RK, Anders CK, et al: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). ASCO20 Virtual Scientific Program. Abstract 1005.
- A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Trial of DS-8201A, an Anti-HER2-Antibody Drug Conjugate, Versus Treatment of Physician’s Choice for HER2 Low, Unresectable and/or Metastatic Breast Cancer Subjects. Available at https://www.mskcc.org/cancer-care/clinical-trials/19-100. Accessed August 17, 2020.
- Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020;382:2419–2430.
- Siena S, Di Bartolomeo M, Raghav KPS, et al: A phase II, multicenter, open-label study of trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC01. ASCO20 Virtual Scientific Program. Abstract 4000.
- Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung 01. ASCO20 Virtual Scientific Program. Abstract 9504.