The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) proved to be superior to the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1), significantly improving progression-free survival and overall survival, in women with unresectable or metastatic HER2-positive breast cancer as second-line therapy, according to updated results of the phase III DESTINY-Breast03 trial, which were presented at the 2022 San Antonio Breast Cancer Symposium.1
The updated analysis found that T-DXd significantly reduced the risk of death by 36% compared with T-DM1, and median progression-free survival was approximately four times longer with T-DXd vs T-DM1. Even though the treatment duration was much longer with T-DXd, the safety profile was manageable and comparable to that of T-DM1.
These findings solidly place T-DXd as the second-line standard of care in patients with HER2-positive metastatic breast cancer. T-DM1 is an alternative second-line option.— Sara A. Hurvitz, MD
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“Updated results [of DESTINY-Breast03] continue to demonstrate a clinically meaningful and statistically significant improvement in overall survival and progression-free survival with T-DXd over T-DM1 in patients with HER2-positive metastatic breast cancer previously treated with pertuzumab and a taxane,” said lead author Sara A. Hurvitz, MD, of David Geffen School of Medicine, University of California, Los Angeles, and Jonsson Comprehensive Cancer Center. “With a longer duration of therapy, T-DXd continued to have a manageable and tolerable safety profile.”
She concluded: “These findings solidly place T-DXd as the second-line standard of care in patients with HER2-positive metastatic breast cancer. T-DM1 is an alternative second-line option.”
The CLEOPATRA trial established the combination of trastuzumab, pertuzumab, and a taxane as standard-of-care first-line therapy for HER2-positive metastatic breast cancer.2 The EMILIA trial established T-DM1 as the second-line standard of care in this setting.3 More recently, the DESTINY-Breast03 trial found that T-DXd is the preferred second-line option, based on its safety and superior efficacy to T-DM1.4
The interim analysis of DESTINY-Breast03 found that the risk of disease progression or death was reduced by 72% in patients randomly assigned to receive T-DXd vs T-DM1. Median progression-free survival was not reached with T-DXd vs 6.8 months with T-DM1 (P < .001). At the 2022 San Antonio meeting, Dr. Hurvitz provided updated results of DESTINY-Breast03 that further support T-DXd as standard second-line therapy.
DESTINY-Breast03 was a randomized, open-label, multicenter phase III study that enrolled 524 patients with unresectable or metastatic HER2-positive breast cancer who previously received standard-of-care treatment and experienced disease recurrence within 6 months of therapy. Patients were randomly assigned 1:1 to receive T-DXd or T-DM1.
At baseline, there were high rates of participants from Asia: about 51% in the T-DXd arm and 67% in the T-DM1 arm. The median number of prior lines of therapy was two. About 60% had received prior trastuzumab.
The primary endpoint was progression-free survival, and a key secondary endpoint was overall survival. In the prespecified interim analysis, median overall survival was not reached for either arm, but the survival curves separated early favoring T-DXd, which showed a 32% reduction in deaths.
In the updated analysis presented by Dr. Hurvitz, median progression-free survival was 28.8 months with T-DXd vs 6.8 months with T-DM1 (P < .000001). At 12 months, the rate of progression-free survival was 75.2% vs 33.9%, respectively. At 24 months, the corresponding rates were 53.7% and 26.4%. “The rate of progression-free survival was four times higher with T-DXd,” Dr. Hurvitz emphasized.
The updated survival analysis showed a 36% improvement with T-DXd over T-DM1, which was also statistically significant (P = .0037). The 12-month survival rates were 94.1% with T-DXd and 86% with T-DM1. The corresponding 24-month survival rates were 77.4% and 69.9%.
“Overall survival was improved with T-DXd regardless of the subgroup, including those with baseline brain metastasis and hormonal status,” she noted.
Confirmed objective response rates according to blinded independent central review were 78.5% and 35%, respectively. Complete response rate was 21.1% vs 9.5%, respectively.
“The majority of patients saw a reduction in tumor size,” she noted. “The median duration of response was just over 3 years with T-DXd vs just under 2 years with T-DM1 [36.8 months vs 23.8 months, respectively].” The median duration of treatment was 18.2 months for T-DXd vs 6.9 months for T-DM1.
It is interesting that the rates of [interstitial lung disease] did increase across time, but the lack of deaths and lack of grade 4 events in this trial are notable.— Sara A. Hurvitz, MD
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The most common treatment-emergent adverse events with T-DXd were nausea (77%) vomiting (51.8%), and alopecia (39.7%). With T-DM1, the most common such events were decreased platelet count (43.7%), increased aspartate aminotransferase (41.4%), and nausea (30.3%).
Interstitial lung disease or pneumonitis is a life-threatening side effect of particular concern with T-DXd. The rate of any-grade interstitial lung disease/pneumonitis was 15.2% for T-DXd–treated patients vs 3.1% for those who received T-DM1. There were no grade 4 or 5 interstitial lung disease or pneumonitis events and no new grade 2 events since the interim analysis. “The additional events were all grade 1,” Dr. Hurvitz said.
“It is interesting that the rates of [interstitial lung disease] did increase across time, but the lack of deaths and lack of grade 4 events in this trial are notable. I think we are becoming better at managing [interstitial lung disease]/pneumonitis. We look at lung scans and when there are infiltrates in an asymptomatic patient, we withhold treatment. Also, we withhold treatment in any patient with symptomatic [interstitial lung disease]. With grade 2 [interstitial lung disease], there is a hard stop, and we can’t retreat, although ongoing studies are looking at whether we can retreat and under what circumstances,” Dr. Hurvitz commented. “Oncologists should follow [computed tomography] scans closely in patients receiving T-DXd, because [interstitial lung disease]/pneumonitis can develop for up to a year. Only with close monitoring will we get the results that we got here.”
Additional questions to be addressed include the benefit of T-DXd in the first-line setting. Also, the action of this drug in patients with brain metastasis is another area of study.
“This trial hints at activity of T-DXd in patients with brain metastases. Studies in the neoadjuvant setting will give us insights into the activity in situ of T-DXd,” Dr. Hurvitz said.
DISCLOSURE: Study sponsors were Daiichi Sankyo and AstraZeneca. Dr. Hurvitz has received institutional research support from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Daiichi Sankyo, CytomX, Dantari, Dignitana, G1 Therapeutics, Genentech/Roche, Gilead Sciences, GSK, Immunomedics, Eli Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Phoenix Molecular Designs, Orinove, Pieris, Puma Biotechnology, Radius, Samumed, Sanofi, Seagen, and Zymeworks.
1. Hurvitz S, Hegg R, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results of the randomized, phase 3 study DESTINY-Breast03. 2022 San Antonio Breast Cancer Symposium. Abstract GS2-02. Presented December 7, 2022.
2. Swain S, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.
3. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.
4. Cortes J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 386:1143-1154, 2022.