Sep 20, 2021

Source: Saura Manich C, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021. Disclosures: Byondis funded this study. Saura Manich reports consultant/advisory board roles with or travel grants from AstraZeneca, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, Puma Biotechnology, Sanofi-Aventis, Seagen and Zymeworks. Please see the abstract for all researchers’ relevant financial disclosures. Pistilli reports personal fees from AstraZeneca, Myriad, Pfizer and Pierre Fabre and nonfinancial support from AstraZeneca, Daiichi Sankyo, Merus, Puma Biotechnology. ADD TOPIC TO EMAIL ALERTS Receive an email when new articles are posted on Please provide your email address to receive an email when new articles are posted on . Subscribe ADDED TO EMAIL ALERTS Back to Healio We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com . Back to Healio 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. Data derived from Saura Manich C, et al. Abstract LBA15. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021. “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. Cristina Saura Manich 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