CE / CME
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: October 19, 2023
Expiration: October 18, 2024
DESTINY-Breast03: T-DXd vs T-DM1 in Previously Treated HER2-Positive MBC
What are the options for HER2-positive MBC following progression on first-line trastuzumab-based therapy? Quite clearly, the standard of care now is T-DXd following the head-to-head comparison of T-DXd vs trastuzumab emtansine (or T-DM1) in the phase III DESTINY-Breast03 study.50 The patients included in this trial had progressed on a taxane plus trastuzumab with or without pertuzumab as their first-line therapy (N = 524). The primary endpoint of the study was PFS by BICR. Secondary endpoints were OS, ORR, duration of response, and PFS by the investigator.
DESTINY-Breast03: Updated PFS (Primary Endpoint)
Regarding the primary endpoint of PFS by BICR, this trial showed a remarkable and clinically significant improvement in median PFS with T-DXd vs T-DM1 (28.8 vs 6.8 months; P <.0001).51
DESTINY-Breast03: Updated OS (Key Secondary Endpoint)
The trial also showed an improvement in OS.51 Although median OS has not yet been reached in either arm, the hazard ratio of 0.64 favoring the T-DXd arm vs T-DM1 was statistically significant (P = .0037). So, clearly, T-DXd has been established as the standard of care in the second-line setting in patients with HER2-positive disease.
DESTINY-Breast04: T-DXd vs Chemotherapy for Previously Treated HER2-Low ABC
HER2 low is not HER2 positive. HER2 positive is defined as IHC 3+ or FISH positive, whereas HER2 low is IHC 1+, or IHC 2+ and FISH negative.5 However, T-DXd is also a great option for our patients with HER2-low disease, and it is approved by the FDA in the second-line and later settings based on data from the phase III DESTINY-Breast04 trial. In DESTINY-Breast04, T-DXd was compared with single-agent chemotherapy in patients with unresectable or metastatic HER2-low disease and 1-2 previous lines of chemotherapy or recurrence ≤6 months after adjuvant chemotherapy. The primary endpoint of the study was PFS in HR-positive disease by BICR.52
DESTINY-Breast04: PFS
When looking at the PFS data, we see that regardless of whether we look at patients with HR-positive disease on the left or all-comers on the right, we see approximately a doubling of PFS with use of T-DXd compared with single-agent chemotherapy (P <.001).52
DESTINY-Breast04: OS
We also see an improvement in OS with T-DXd vs chemotherapy of more than 6 months, both in the HR-positive population and in all-comers.52 These data underscore the point that T-DXd is a very important agent for use in the second-line setting and beyond for patients with HER2-low MBC.
T-DXd: Safety Profile
T-DXd is not without toxicity.52 Nausea of any grade can be expected in 73% of patients (grade 3 in 5%), so patients should be advised about the use of olanzapine every night at bedtime for as long as the nausea persists.53 Neutropenia is much less with T-DXd vs chemotherapy (33% vs 51%), including rates of grade 3 neutropenia (14% vs 41%, respectively). Some patients can experience alopecia (38%), but scalp cooling can help.
Administration Considerations for T-DXd and Sacituzumab Govitecan in Breast Cancer
When using highly emetogenic therapy such as T-DXd and sacituzumab govitecan, we treat prophylactically with antiemetic regimens including 5-HT3 receptor antagonists or NK1 receptor antagonists in combination with dexamethasone.47,53 As I mentioned previously, with T-DXd, a minority of patients can develop low-grade, chronic nausea, so you do want to consider olanzapine 2.5 mg at bedtime for those individuals.
In terms of the dosing schedule, T-DXd is administered once every 3 weeks, and sacituzumab govitecan is given on Days 1 and 8 of every 21-day cycle. Regarding dose reductions, T-DXd is first reduced from 5.4 to 4.4 mg/kg, then down to 3.2 mg/kg, and then you should permanently discontinue therapy. With sacituzumab govitecan, you start with 10 mg/kg, go down to 7.5 mg/kg, then to 5 mg/kg, and then you should permanently discontinue therapy.
Managing ILD/Pneumonitis With T-DXd
ILD is a consideration with T-DXd. In DESTINY-Breast04, 3 patient deaths in the T-DXd arm were attributed to ILD/pneumonitis. For this reason, we want to obtain noncontrast chest CTs every 6-9 weeks.52 The protocol specified every 6 weeks, but I do chest CTs every 9 weeks. If you find asymptomatic grade 1 ILD on chest CT, you hold T-DXd until ILD/pneumonitis resolves to grade 0, then restart at starting dose if resolved in <28 days. If it takes longer for ILD to resolve, then you may need to reduce the dose 1 dose level.53 If patients develop any cough or shortness of breath and the chest CT shows ILD, you have to permanently stop the T‑DXd given the high risk for developing higher-grade disease and potential death. Thus, we can only continue T‑DXd if we catch it when it is asymptomatic, which is why I do routine surveillance to look for very early ILD, so I can treat it with steroids and resume the treatment at a reduced dose.
In an asymptomatic patient, stop the T-DXd, treat with steroids, repeat the chest CT to document resolution, and then resume the T-DXd at a lower dose.53,54 If patients develop any symptoms, we stop treatment, we give steroids (eg, 1 mg/kg of prednisone), and we do not restart. One also should get a pulmonologist consultation. If patents are very symptomatic and have grade 3 ILD, they have to be admitted to the hospital and receive IV corticosteroids, and you have to get the pulmonary consultation as soon as possible
Tucatinib + Trastuzumab and Capecitabine in Patients With MBC and CNS Progression (HER2CLIMB)
The phase II HER2CLIMB trial evaluated the combination of tucatinib with trastuzumab and capecitabine vs placebo with trastuzumab and capecitabine in patients with HER2‑positive MBC who had received previous trastuzumab and pertuzumab and T‑DM1 (N = 612).55 This was a remarkable trial allowing patients with brain metastases, including patients who had untreated brain metastases that did not need immediate local therapy. The primary endpoint of the study was PFS by RECIST version 1.1 by BICR among the first 480 randomized patients. Key secondary endpoints included OS in patients with brain metastases.
HERCLIMB: OS in All Patients With Brain Metastases
In patients we brain metastases, we clearly see an advantage in OS for adding tucatinib vs placebo to trastuzumab and capecitabine (median OS: 21.6 vs 12.5; P = .00078; hazard ratio: 0.600), including a 2-year OS (48.5% vs 25.1%). Thus, clearly, the combination has clinically meaningful activity in patients with active brain metastases and is a preferred treatment in this setting.
Intracranial Overall Response and Duration of Response in Patients With Active Brain Metastases
When we look at the objective measures of intracranial overall response, here again we see evidence of response in the brain with the addition of tucatinib to trastuzumab and capecitabine, with a response rate approaching 50% compared with 20% with trastuzumab and capecitabine alone. Duration of response was 8.6 months (95% CI: 5.5-10.3) vs 3.0 months (95% CI: 3.0-10.3) in the experimental arm vs the control arm, respectively.
HERCLIMB: Safety
Regarding safety, both tucatinib and capecitabine can be associated with diarrhea. It was not surprising that the triplet regimen was associated with approximately 30% higher incidence of diarrhea (81% vs 53%). In other words, 4 of 5 patients had diarrhea. Other common AEs included fatigue (70%), palmar–plantar erythrodysesthesia syndrome (61%), and nausea and anemia (61% each). The incidence of serious AEs was 4% vs 3.3%, respectively.
Intracranial Efficacy Outcomes With Neratinib + T-DM1 in HER2-Positive MBC and Brain Metastases (TBCRC 022)
I also would like to briefly mention new data from the TBCRC 022 study, which evaluated the combination of T-DM1 with neratinib specifically for patients with HER2-positive MBC with brain metastases.56 Full-dose T-DM1 was combined with neratinib 160 mg orally once daily in 3 different cohorts: cohort 4A, which consisted of patients with untreated brain metastases; cohort 4B, which included patients with progressive brain metastases but no prior T-DM1; and cohort 4C, which consisted of patients with progressive brain metastases and prior T-DM1. The primary endpoint was response per the Response Assessment in Neuro-Oncology Criteria.
TBCRC 022: CNS Response
Central nervous system (CNS) responses were quite encouraging. In this table, you can see comparable response rates in the brain of approximately 30% for all 3 cohorts evaluating T-DXd/neratinib.56 If we add in stable disease lasting ≥6 months, the CBR rate was 50% in patients with untreated disease and approximately 33% in patients who had prior brain irradiation with or without prior T-DM1. This regimen is a nice option for patients.
TBCRC 022: Change From Baseline in CNS Response and 12-Month OS Rates
In terms of CNS response rates, you can see the waterfall plots here, which show a pretty impressive level of activity when combining these 2 agents in the metastatic setting.56 The percentage of patients alive at 1 year, shown on the bottom right, was >80% in each cohort.
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