[Vic-]trastuzumab duocarmazine extends PFS in HER2-positive breast cancer
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Patients with pretreated locally advanced or metastatic HER2-positive breast cancer had significantly longer PFS after treatment with [vic-]trastuzumab duocarmazine vs. physician’s choice of treatment, according to study results.
[Vic-]trastuzumab duocarmazine (SYD985, Byondis) is an HER2-targeting antibody-drug conjugate (ADC) that consists of the monoclonal antibody trastuzumab (Herceptin, Genentech) bound to a linker drug that contains duocarmycin.
![[Vic-]trastuzumab duocarmazine vs. physician’s choice of treatment study results.](/~/media/slack-news/hemonc/misc/infographics/hot-infographics/2021/09-september/hot0921saura-manich_esmo_ig_web.jpg?w=800)
“The drug-to-antibody ratio ranges from 2.4 to 2.8,” Cristina Saura Manich, MD, PhD, head of the breast cancer unit of the medical oncology service at Vall d’Hebron University Hospital in Barcelona, Spain, said before presenting the results during the virtual ESMO Congress 2021.
The agent received FDA fast track designation in 2018 based on phase 1 data among heavily pretreated HER2-positive patients with metastatic breast cancer.
The randomized phase 3 SYD985.002/TULIP trial included 437 patients with HER2-positive locally advanced or metastatic breast cancer who received prior treatment for metastatic disease with two or more therapies or ado-trastuzumab emtansine (Kadcyla, Genentech), also called T-DM1. Researchers randomly assigned 291 patients to 1.2 mg/kg [vic-]trastuzumab duocarmazine via IV every 21 days and 146 patients to physician’s choice of treatment, which included lapatinib (Tykerb, Novartis) and capecitabine, or trastuzumab (Herceptin, Genentech) with capecitabine, vinorelbine or eribulin. Treatment continued until disease progression or unacceptable toxicity.
The investigators stratified patients based on region, number of previous treatment lines for locally advanced or metastatic disease (1-2 vs. 2) or whether they received prior treatment with pertuzumab (Perjeta, Genentech).
The [vic-]trastuzumab duocarmazine and physician’s choice treatment groups had similar baseline characteristics, including median age (56 years vs. 58 years), percentage of white patients (69.4% vs. 65.1%) and median number of prior treatments for metastatic breast cancer (4 vs. 5). Most patients in each group had received prior systemic anti-HER2 treatment for metastatic breast cancer with trastuzumab (89.3% vs. 86.3%), T-DM1 (87.6% vs. 87.7%) and pertuzumab (60.8% vs. 57.5%). Some also had received new emerging therapies such as tucatinib (Tukysa, Seagen) or tucatinib/placebo (3.1% vs. 6.8%), margetuximab (Margenza, MacroGenics; 2.1% vs. 0) and fam-trastuzumab deruxtecan (Enhertu, AstraZeneca, Daiichi Sankyo; 2.1% vs. 1.4%).
Centrally assessed PFS served as the primary endpoint. Secondary endpoints included investigator-assessed PFS, OS, overall response rate and health-related quality of life.
Results showed median PFS by central review of 7 months in the [vic-]trastuzumab duocarmazine group and 4.9 months in the physician’s choice group (HR = 0.64; 95% CI, 0.49-0.84). The PFS benefit was consistent across patient subgroups, Saura Manich said.
The [vic-]trastuzumab duocarmazine group also had significantly longer investigator-assessed median PFS (6.9 months vs. 4.6 months; HR = 0.6; 95% CI, 0.47-0.77). The difference in median OS at the first interim OS analysis was not statistically significant (20.4 months vs. 16.3 months; HR = 0.83; 95% CI, 0.62-1.09). Further OS analysis will be performed when the data are more mature, Saura Manich said.
ORR was 27.8% with [vic-]trastuzumab duocarmazine vs. 29.5% with physician’s choice of therapy, but the study-treatment group had a higher percentage of patients with measurable disease at baseline and reduction in target lesion measurements (70.2% vs. 58.2%) and higher clinical benefit rate (38.5% vs. 32.2%).
The treatment groups had similar rates of treatment-related adverse events (96.5% vs. 96.4%), including grade 3 or higher events (52.8% vs. 48.2%).
More than three-quarters (78.1%) of patients in the [vic-]trastuzumab duocarmazine group experienced eye toxicity — including conjunctivitis (38.2% any grade; 5.6% grade 3) and keratitis (38.2% any grade; 12.2% grade 3) — compared with 29.2% of patients in the physician’s choice group. Eye toxicity led to dose modifications for 22.9% of patients in the study-treatment group and discontinuation of the treatment for 20.8% of patients.
Interstitial lung disease/pneumonitis occurred among 7.6% of patients who received [vic-]trastuzumab duocarmazine, and 2.4% of cases were grade 3 or higher. This led to dose modifications for 2.1% of patients and treatment discontinuation for 5.2%.
“These toxicities have to be carefully monitored and treated appropriately,” Saura Manich said.
Six deaths were reported in the study-treatment group, including four related to treatment (respiratory failure, pneumonia and two cases of pneumonitis). Researchers observed no significant differences in health-related quality of life between the groups.
“SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive breast cancer,” Saura Manich said.
Discussant Barbara Pistilli, MD, medical oncologist in the breast cancer unit at Gustave Roussy Cancer Campus in France, noted the increasing number of ADCs that have received FDA approval.
“I like to think that in the next 10 years we will be able to define the best combination strategies of ADCs that can lead to improvement in ADC delivery in the tumor tissue, but also to improve the immuno-response to the ADC, to improve the target expression and internalization and the payload activity,” she said. “We can even imagine combining different ADCs eventually in concomitant or alternating schedules. All this to overcome the resistance to the [ADCs] and expand their therapeutic index.
“Finally, I think we can move in the direction to have platforms of more personalized ADCs that can be created on the basis of specific tumor characteristics in terms of receptor target expression, endosomal proteins and biomarkers of payload activity, in order to have the most treatable ADC for each patient,” Pistilli said. “That means to have a lot of flowers in our treatment landscape.”
Perspective
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Antibody-drug conjugates such as T-DM1, trastuzumab deruxtecan and sacituzumab govitecan (Trodelvy, Immunomedics) have made incremental progress in treating both HER2-overexpressing and triple-negative breast cancers. A newer drug-antibody conjugate is [vic-]trastuzumab duocarmazine. This molecule was evaluated in the TULIP trial among over 400 heavily pretreated women with HER2-overexpressing breast cancers who were randomly assigned to [vic-]trastuzumab duocamazine or physician's choice.
Researchers observed statistically significant improvement in PFS with [vic-]trastuzumab duocamazine, and trial met its primary endpoint. Also, there were no differences in ORR and health-related quality of life.
[Vic-]trastuzumab duocamazine is not devoid of toxicity, with conjunctivitis, keratosis and diarrhea occurring in about one-third of women. As observed with trastuzumab deruxtecan, [vic-]trastuzumab duocamazine causes interstitial pneumonitis in about 5% of recipients.
The HER space is fertile ground for drug discovery and FDA approvals. The optimal sequencing of HER2-overexpressing antibody conjugates is not known and use of them prior to T-DM1 would not increase the efficacy.
Icahn School of Medicine at Mount Sinai
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Saura Manich C, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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