Publication
Article
Peer Reviewed
The tumor-agnostic FDA approval of T-DXd for HER2-positive unresectable or metastatic solid malignancies exemplifies the importance of understanding the risks associated with targeted therapy and the need for proactive monitoring strategies.
Precision medicine has revolutionized cancer treatment by targeting shared genetic markers and shifting oncology care away from traditional cancer type–specific approaches. The targeted therapy fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd; Daiichi Sankyo, Inc) received FDA approval on April 5, 2024, for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] score of 3+) solid tumors, expanding its former treatment landscape beyond metastatic breast, colorectal, gastric, and non–small cell lung cancers. The recognition of HER2 as a therapeutic target across various tumors has evolved since 2015, supported by clinical trials such as DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. These trials demonstrated the efficacy of T-DXd across multiple tumor types, especially in cohorts with HER2 IHC 3+ expression. However, treatment with T-DXd can lead to unique and potentially fatal adverse events such as interstitial lung disease, highlighting the importance of patient monitoring and management strategies such as baseline assessments and regular imaging to detect complications early. Despite the potential risks, T-DXd offers an effective treatment option for patients with refractory solid tumors. As more therapies receive site-agnostic FDA approvals, understanding the risks associated with targeted therapy becomes crucial for proactive management and optimizing treatment outcomes.
Cancer cells present diverse treatment challenges. Image Credit: © atar - stock.adobe.com
Since systemic cancer treatments were discovered in the 1940s, they have been targeted toward specific cancer types.1 However, precision medicine has transformed the cancer landscape over the past 2 decades by identifying shared genetic and molecular markers (eg, genes, proteins, receptor expression) across tumor types. On April 5, 2024, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd; Daiichi Sankyo, Inc) for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] score of 3+) solid tumors, making it the latest treatment to enter the space of site-agnostic approvals.2 As of this writing, 8 other FDA oncology approvals (larotrectinib [Vitrakvi; Bayer HealthCare Inc], entrectinib [Rozlytrek; Genentech, Inc], repotrectinib [Augtyro; Bristol Myers Squibb]; pembrolizumab [Keytruda; Merck Sharp & Dohme LLC], dostarlimab-gxly [Jemperli; GSK PLC], dabrafenib [Tafinlar; Novartis Pharmaceuticals Corporation], trametinib [Mekinist; Novartis Pharmaceuticals Corporation], and selpercatinib [Retevmo; Eli Lilly and Company]) share the site-agnostic space,2 the first of which was pembrolizumab in 2017.
This latest T-DXd approval expands the agent’s treatment landscape, which was previously limited to certain populations with HER2-positive breast cancer,
HER2-positive gastric or gastroesophageal junction adenocarcinoma, HER2-low breast cancer, or non–small cell lung cancer (NSCLC) with an activating ERBB2 (also known as HER2) mutation.3 However, because treatment with T-DXd can lead to unique and potentially life-threatening adverse events (AEs) such as interstitial lung disease (ILD),3 this site-agnostic FDA approval exemplifies the importance of understanding the risks associated with targeted therapy to proactively and effectively manage AEs and optimize treatment outcomes.
The HER2 tyrosine kinase domain is within the family of epidermal growth factor receptors and is encoded by the ERBB2 gene. HER2 and ERBB2 are often used interchangeably to describe ERBB2 mutations, which are distinct from HER2 amplification (an abnormally high number of ERBB2 gene copies) and HER2 overexpression (an abnormally high number of HER2 receptors on the surface of cancer cells).4
The introduction of HER2-directed therapies into the breast cancer treatment landscape significantly reduced relapse rates for patients with early breast cancer and improved survival rates for those diagnosed with advanced or metastatic disease.5 The recognition of HER2 as a therapeutic target across tumor sites dates to 2015. A study analyzing HER2 expression across nearly 38,000 patient samples found HER2 overexpression and/or HER2 amplification in bladder carcinomas; extrahepatic cholangiocarcinoma; and gallbladder, cervical, uterine, and testicular cancers.6 Several clinical trials since have demonstrated the clinical efficacy of HER2-directed therapies, including those used as the basis for T-DXd’s site-agnostic approval: DESTINY-PanTumor02 basket trial, DESTINY-Lung01 (NSCLC), and DESTINY-CRC02 (metastatic colorectal cancer).
The open-label phase 2 DESTINY-PanTumor02 study (NCT04482309) evaluated treatment with T-DXd (5.4 mg/kg every 3 weeks) in 7 tumor cohorts: endometrial (n = 40), cervical (n = 40), ovarian (n = 40), bladder (n = 41), biliary tract (n = 41), pancreatic (n = 25), and other (n = 40). The most common cancer in the other tumor cohort was salivary gland cancer (n = 19), followed by cancer types with a maximum of 3 individuals per group. The study enrolled patients with HER2-expressing (IHC 3+/2+) local or metastatic disease after at least 1 prior systemic treatment or those without alternative treatment options. Participants had a median of 2 prior lines of therapy, and investigators followed participants for a median of 12.8 months. The primary end point was objective response rate (ORR).7
The overall ORR was 37.1% (n = 99; 95% CI, 31.3%-43.2%), with some degree of response noted in all tumor cohorts.7 The median duration of response (DOR) was 11.3 months (95% CI, 9.6-17.8), the median progression-free survival (PFS) was 6.9 months (95% CI, 5.6-8.0), and the median overall survival (OS) was 13.4 months (95% CI, 11.9-15.5).7 Participants with HER2IHC 3+ expression experienced the greatest benefit from treatment (Figure),7 which may have influenced the FDA’s decision to require IHC 3+ expression for the latest T-DXd indication. The response rates among gynecologic malignancies (ovarian, 63.6%; cervical, 75.0%; and endometrial, 84.6%) were particularly impressive and practice changing given the historically low response rates and higher mortality rates with later lines of treatment in this patient population.7,8 Of note, only 2 patients with pancreatic cancer had IHC 3+ expression, and neither responded to treatment with T-DXd.7 Overall, T-DXd demonstrated efficacy and durable responses across numerous tumor types in DESTINY-PanTumor02, with the most robust responses observed in the biliary tract, bladder, ovarian, cervical, and endometrial tumor cohorts with HER2 IHC 3+ expression.7 The safety profile of T-DXd was consistent with its known profile (including ILD).7
DESTINY-Lung01 (NCT03505710) was a multicenter, 2-cohort, phase 2 study of T-DXd (6.4 mg/kg every 3 weeks) in patients with unresectable or metastatic, HER2-mutated, nonsquamous NSCLC refractory to standard therapy. The trial’s primary end point was ORR. Patients were largely pretreated (median, 2 prior lines of systemic therapy), with 90% of patients having received any previous cancer therapy. Patients with ALK, BRAF, ROS1,or EGFR mutations who had received previous therapy targeted for those alterations could be enrolled in the trial, but the investigators did not report participants with these gene alterations by percentage.9
Among the 91 participants followed for a median of 13.1 months, the ORR was 55% (95% CI, 44%-65%).9 The median DOR was 9.3 months (95% CI, 5.7-14.7), the median PFS was 8.2 months (95% CI, 6.0-11.9), and the median OS was 17.8 months (95% CI, 13.8-22.1).9 Considering the median historical OS of 12.3 months in a heterogeneous population of patients with NSCLC receiving paclitaxel, carboplatin, and bevacizumab (Avastin),10 T-DXd provides a novel promising treatment option for patients with HER2-expressing tumors.
Due to the high rate of drug-related ILD/pneumonitis (27.5%) in the DESTINY-Lung01 trial,11 the dose-optimization phase 2 DESTINY-Lung02 trial (NCT04644237) evaluated a 5.4 mg/kg dose (n = 102) with a 6.4 mg/kg dose (n = 50) via a 2:1 random assignment of patients with HER2-mutated metastatic NSCLC who were previously treated with a platinum-containing therapy. The trial had a primary end point of ORR and demonstrated comparable efficacy between the 2 doses.12 The ORR was 49.0% and 56.0% for the 5.4 mg/kg and 6.4 mg/kg doses, respectively, with rates of ILD/pneumonitis halved in the lower-dose group (12.9% vs 28.0%).12 Results from the DESTINY-Lung02 trial established the justification for the recommended T-DXd dose of 5.4 mg/kg every 3 weeks.12
The multicenter, phase 2 DESTINY-CRC02 study (NCT04744831) is assessing the efficacy of T-DXd (5.4 and 6.4 mg/kg) in patients with metastatic colorectal cancer and centrally confirmed HER2 expression. Participants were heavily pretreated, with a median of 3 lines of prior therapy in the 5.4 mg/kg arm and 4 lines in the 6.4 mg/kg arm, and the majority of patients in both arms (78.0% and 85.0%%, respectively) had HER2 IHC 3+ expression. Confirmed ORR, the primary end point, was 37.8% (95% CI, 27.3%-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6%-43.9%) in the 6.4 mg/kg arm, with only partial responses (PRs) in both arms. The median DOR was 5.5 months (95% CI, 4.2-8.1) and 5.5 months (95% CI, 3.7 to not evaluable) in the 5.4 mg/kg and 6.4 mg/kg arms, respectively, and the median PFS was 5.8 months (95% CI, 4.6-7.0) and 5.5 months (95% CI, 4.2-7.0), respectively. Safety favored the lower dose and was consistent with T-DXd’s known safety profile.13
The results of this trial may challenge other treatment options for patients with heavily pretreated metastatic colorectal cancer, considering the historically low median PFS of 2.0 months for both regorafenib (Stivarga; Bayer HealthCare Inc) and trifluridine-tipiracil (Lonsurf; Taiho Oncology, Inc) in earlier trials.14,15 The OS benefit will be important to identify as DESTINY-CRC02 data mature, but in the interim, this trial demonstrates a significant advance for patients with heavily pretreated metastatic colorectal cancer.13
Because of T-DXd’s mechanism of action as an antibody-drug conjugate with a topoisomerase 1 inhibitor payload, treatment with T-DXd is associated with unique AEs such as ILD, not otherwise seen with typical HER2-directed therapies, as well as other significant AEs, including nausea and vomiting, cytopenias, and cardiotoxicity, that require close monitoring and management. For example, as T-DXd has been studied and ultimately approved for 5 indications,3 we have become more knowledgeable about its pulmonary toxicity.
In a pooled analysis of 9 T-DXd monotherapy studies that evaluated ILD/pneumonitis risk in 1150 heavily pretreated patients across multiple tumor types, including HER2-positive breast cancer, Powell et al found that the overall incidence of drug-related ILD/pneumonitis was 15.4%, with a median time to onset of 5.4 months and an overall rate of fatal events of 2.2%.18
In the DESTINY-PanTumor02 trial, 10.5% (n = 28/267) of patients developed ILD (Table), and 3 of these patients died, with rates of ILD and ILD-related deaths consistent with prior trials. The most common drug-related AEs in DESTINY-PanTumor02 across all 7 tumor cohorts were nausea (55.1%), anemia (27.7%), diarrhea (25.8%), vomiting (24.7%), fatigue (24.7%), and neutropenia (18.7%). Notably, this trial showed different rates of AEs across the 7 tumor cohorts.7
As previously mentioned, the 6.4 mg/kg dose in the DESTINY-Lung02 trial was associated with a greater drug-related risk of ILD compared with the 5.4 mg/kg dose (28.0% vs 12.9%, respectively). DESTINY-Lung02 trial investigators theorized that the higher ILD rate in the 6.4-mg/kg arm vs trials of other types of cancers treated with that same dose may be due to existing lung damage caused by smoking, surgery, or radiation in patients with NSCLC. In addition, the difficulty distinguishing among respiratory symptoms and imaging lung abnormalities due to the disease itself vs ILD in patients with NSCLC may also lead to higher rates of ILD diagnosis.12
Not unique to T-DXd is the risk of cardiotoxicity, specifically left ventricular dysfunction, due to its trastuzumab component. Based on pooled safety information from 9 T-DXd trials, the rate of left ventricular ejection fraction (LVEF) decline was 3.8% at the 5.4 mg/kg dose in patients with HER2-positive and HER2-low metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors, with 0.6% being grade 3.3
Because T-DXd has proven to be effective across multiple cancer types but is associated with significant AEs, it is vital to monitor patients on T-DXd to avoid irreversible complications such as cardiomyopathy due to LVEF decline and pulmonary fibrosis secondary to ILD. Prior to initiation of therapy, patients require a baseline ejection fraction study as well as consideration for a high-resolution CT (HRCT) scan of the chest and a baseline reading of oxygen saturation levels.19,20 Consideration for T-DXd candidacy should take into account clinical trial exclusion criteria for ejection fraction minimums (eg, 50% in the DESTINY-PanTumor02 trial) and additional risk factors for the development of ILD, such as prior chest radiation, moderate to severe renal impairment, and a preexisting chronic lung condition that required recent
corticosteroid use.20
Patients identified as candidates for T-DXd treatment should be educated on signs and symptoms of ILD, such as worsening cough (especially dry cough), shortness of breath and dyspnea upon exertion, and fever. Suspected ILD may require radiographic imaging and a pulmonology consultation.20
Expert consensus recommendations include taking a multidisciplinary approach with oncologists, pharmacists, and radiologists to monitoring and managing ILD. Monitoring recommendations include HRCT scans of the chest every 6 to 9 weeks for patients with respiratory symptoms and at least every 12 weeks for asymptomatic individuals. More frequent HRCT scans may be warranted in patients with Japanese ancestry, lower oxygen saturation levels, or renal impairment.20
Strategies to minimize the risk and impact of T-DXd–related ILD are more easily remembered with the 5 “S” rules, as follows21:
In addition, due to T-DXd’s high emetic risk, patients should receive appropriate prophylaxis and antinausea medications for breakthrough nausea as well as psychosocial and nutritional support as necessary. Risk of neutropenia has been universally observed with T-DXd but may be dose dependent. For example, rates of grade 3 or 4 neutropenia were observed in 51% of patients receiving the 6.4 mg/kg dose of T-DXd for gastric cancer vs 16% of patients with metastatic breast cancer or NSCLC receiving the 5.4 mg/kg dose.3
Thomas Bokinz, PharmD, is a postgraduate year 1 pharmacy resident at Stony Brook University Hospital in New York.
Britny R. Brown, PharmD, BCOP, is a clinical associate professor at the University of Rhode Island College of Pharmacy in Kingston and a clinical oncology pharmacist at Yale New Haven Health Smilow Cancer Center-Westerly.
T-DXd provides patients with metastatic, refractory solid tumors an additional effective treatment option. Given the recent positive results from the phase 3 DESTINY-Breast06 trial (NCT04494425) of T-DXd in HER2-low, hormone receptor–positive, metastatic breast cancer, it is anticipated that T-DXd use will be expanded to this patient population.22 Future studies will elucidate the safety and efficacy of T-DXd in other settings, such as for earlier-stage treatment of patients with HER2-positive breast cancer and in patients with HER2-positive breast cancer and active brain metastases.23,24 To overcome treatment resistance, combination therapies are of particular interest, with phase 1 trials underway of T-DXd in combination with other types of medications, such as immunotherapy and PARP inhibitors.25
As more targeted therapies emerge with site-agnostic FDA approvals, it is imperative that we familiarize ourselves with the risks of these treatments to proactively and effectively mitigate negative safety outcomes and maximize treatment effects.
