Barbara Pistilli, MD
Barbara Pistilli, MD, of the Breast Cancer Group at Gustave Roussy Cancer Center, Villejuif, France, said the results of the TULIP trial, showing the progression-free survival benefit for vic-trastuzumab duocarmazine (SYD985), help to establish antibody-drug conjugates as key components of the breast cancer treatment landscape.1 “It’s likely that optimal sequencing of HER2 therapy will change in the coming months. The question now is how to integrate the results of the TULIP trial into this changing framework,” she said.
“Both T-DXd (fam-trastuzumab deruxtecan-nxki) and SYD985 showed substantial activity after treatment with T-DM1 (ado-trastuzumab emtansine),” said Dr. Pistilli. Based on strong preclinical and phase I data, trastuzumab duocarmazine was granted Fast Track designation in January 2018.
“Now, a randomized phase III trial of 437 patients has clearly demonstrated a clinically meaningful and statistically significant improvement in progression-free survival, 7 months vs 4.9 for standard therapy, with SYD985. More importantly, more than 87% of patients had received prior treatment with T-DM1, so the drug is active in this specific population,” she commented.
As for T-DXd, in the DESTINY-Breast01 trial, where all patients had prior T-DM1, the median progression-free survival was 19.4 months.2 And, in DESTINY-Breast03, with patients previously treated with trastuzumab and a taxane, and also reported at this year’s ESMO Congress,3 the median progression-free survival was not reached with T-DXd and was 6.8 months with T-DM1—a risk reduction of 74% (P = 7.8 × 10–22).
When Should Trastuzumab Duocarmazine Be Used?
According to Dr. Pistilli, the question now is: when should we use trastuzumab duocarmazine? “Is there a chance the drug is active after T-DXd? We don’t have clinical data yet,” she added.
When to use this novel agent largely depends on the mechanisms of resistance of trastuzumab duocarmazine. These mechanisms are not yet understood, but there are hypotheses that it could be effective in this setting. “Of course, we have to keep in mind cross-toxicities,” she added. Both drugs can cause interstitial lung disease, despite having different payloads and linkers.
It becomes important to identify patients who will be more sensitive upfront to one or the other, and especially the 10% to 20% who are not sensitive to T-DXd and might derive an immediate benefit from trastuzumab duocarmazine. To address this issue, one needs to consider “that antibody-drug conjugates are very complex drugs, not just vehicles for chemotherapy delivery,” reminded Dr. Pistilli. “There is a complex interplay of different components, and the target is more than immunohistochemistry expression…. One antibody-drug conjugate does not fit all.”
Dr. Pistilli predicted the use of sophisticated technologies to help identify more granular biomarkers of response and resistance. These markers may involve aspects of the signaling pathways and even the nontumor cells within the microenvironment, she continued.
In all malignancies, the number of antibody-drug conjugates has doubled in just 1 year, including the approval of three in breast cancer. The next decade will probably find these agents being used in combination, sequentially or in alternating schedules, to enhance drug delivery and immune response as well as to overcome resistance, she indicated.
Finally, Dr. Pistilli predicted the field will move toward platforms of more personalized antibody-drug conjugates, designed upon biomarker analysis of biopsies for multiple receptor targets, endosomal proteins, and biomarkers of payload activity. The aim will be to create the most suitable antibody-drug conjugate for each patient.
DISCLOSURE: Dr. Pistilli has received personal fees from AstraZeneca, Myriad, Pfizer, and Pierre Fabre.
REFERENCES
1. Saura Manich C, O’Shaughnessy J, Aftimos PG, et al: Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. ESMO Congress 2021. Abstract LBA15. Presented September 19, 2021.
2. Modi S, Saura C, Yamashita T, et al: Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract PD3-06. Presented December 8, 2020.
3. Cortés J, Kim S, Chung W, et al: Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: Results of the randomized phase III DESTINY-Breast03 study. ESMO Congress 2021. Abstract LBA1. Presented September 18, 2021.
