Erika Hamilton, MD, on Metastatic Breast Cancer: Safety Follow-up Data on T-DXd vs T-DM1
2022 ASCO Annual Meeting
Erika Hamilton, MD, of Sarah Cannon Research Institute at Tennessee Oncology, discusses phase III data from the DESTINY-Breast03 study, which reinforced the consistent safety profile of fam-trastuzumab deruxtecan-nxki (T-DXd) vs ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable and/or metastatic breast cancer. The findings also support T-DXd’s risk benefit over that of T-DM1 (Abstract 1000).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
As we know, trastuzumab deruxtecan was previously approved based on the results of DESTINY-Breast01; however, DESTINY-Breast03 brought trastuzumab deruxtecan up into the earlier line setting. This was a study of trastuzumab deruxtecan versus T-DM1, and what was presented was a safety update. So now the median duration of follow up remained at 6.9 months in the T-DM1 arm but has lengthened to 16.1 months in the trastuzumab deruxtecan arm.
What we saw in the safety update with further follow up was that grade 3 treatment-emergent adverse events really were quite consistent between the arms, 53% for T-DXd and about 50% for T-DM1. We also looked at adverse events that led to discontinuation, and that was a bit higher with trastuzumab deruxtecan, specifically 14.8% of patients compared to 7.3% of patients. If we look at why that is, it was really driven by ILD pneumonitis for trastuzumab deruxtecan, with about 8% of patients discontinuing due to ILD pneumonitis.
The most common reason for discontinuation with T-DM1 was thrombocytopenia. When we look at tolerability across the board, there were a few adverse events that were a little bit more frequent with trastuzumab deruxtecan: nausea, vomiting, and alopecia or hair loss. The nausea and vomiting events really in general were quite mild, grade 1 or grade 2. Interestingly, they happened right away in the early treatment cycles and then really stabilized over time and became consistent. So this emphasizes making sure that we're using good supportive care antiemetics for our patients.
There was a new variable we looked at, and it's something called exposure-adjusted incidence rates and exposure-adjusted incidence rates are standardized measure of risk per patient year used to describe safety in long-term studies where the follow-up between the arms may differ. When we looked at exposure-adjusted incidence rates, across the board these were actually lower with trastuzumab deruxtecan compared to T-DM1 with one exception, and that exception was treatment-emergent adverse events leading to discontinuation that was again driven by that about 8% of patients that discontinued due to ILD pneumonitis.
We also saw that time to either a dose reduction or a dose hold was longer for trastuzumab deruxtecan than it was with T-DM1, really again emphasizing that patients on the trastuzumab deruxtecan arm in general were tolerating therapy quite well and weren't experiencing side effects where they were needing to dose reduce.
Finally, when we looked at interstitial lung disease pneumonitis, which was a safety event we've been closely following due to the fact that there were fatal cases in the initial study with DESTINY-Breast01, even with this updated follow up, there are no grade 4 or grade 5 cases of ILD pneumonitis. In addition, grade 3 rates of ILD pneumonitis with trastuzumab deruxtecan remains at less than 1%, 0.8% to be specific. So this really reassured us as we're moving trastuzumab deruxtecan up into earlier lines, initially third line and beyond from DESTINY-Breast01, now in the so-called second line setting based on DESTINY-Breast03, and this really encompasses patients that have either progressed on a taxane or trastuzumab in the metastatic setting or relapsed within six months of neoadjuvant or adjuvant HER2 directed therapy.
There are trials ongoing looking at trastuzumab deruxtecan in even earlier lines, in first lines, in a so-called KATHERINE type indication for patients that may not have a pathologic complete response as well as even neoadjuvant. So very reassuring that we're no longer seeing any severe cases of ILD or pneumonitis, and that our patients really are tolerating trastuzumab deruxtecan well.
Georgina V. Long, MD, PhD, of the Melanoma Institute Australia, The University of Sydney, discusses phase III findings from the KEYNOTE-716 study. The trial showed that compared with placebo, adjuvant pembrolizumab significantly improved distant metastasis–free survival in patients with resected stage IIB and IIC melanoma. The findings also suggest a continued reduction in the risk of recurrence and a favorable benefit-risk profile (Abstract LBA9500).
Sumanta K. Pal, MD, of City of Hope National Medical Center, discusses findings from the COSMIC-021 study, which showed that cabozantinib plus atezolizumab demonstrated encouraging clinical activity with manageable toxicity in patients with inoperable locally advanced or metastatic urothelial carcinoma. The combination was administered as first-line therapy in cisplatin-based chemotherapy–eligible and –ineligible patients and as second- or later-line treatment in those who received prior immune checkpoint inhibitors (Abstract 4504).
Thomas Powles, MD, PhD, of Barts Health NHS Trust, Queen Mary University of London, and Jonathan E. Rosenberg, MD, of Memorial Sloan Kettering Cancer Center, discuss the 24-month findings from the phase III EV-301 trial, which suggest that enfortumab vedotin-ejfv continues to show a significant and consistent survival advantage over standard chemotherapy in patients with previously treated advanced urothelial carcinoma (Abstract 4516).
Courtney D. DiNardo, MD, MSCE, of The University of Texas MD Anderson Cancer Center, and Jorge E. Cortes, MD, of Georgia Cancer Center at Augusta University, discuss phase III results from the ASCEMBL trial, which showed that after more than 2 years of follow-up, asciminib continued to yield superior efficacy and better safety and tolerability vs bosutinib in patients with chronic myeloid leukemia (CML) in chronic phase. These results continue to support the use of this kinase inhibitor as a new CML therapy, says Dr. Cortes, with the potential to transform the standard of care (Abstract 7004).
Nabil F. Saba, MD, of Winship Cancer Institute of Emory University, discusses new data from a trial of pembrolizumab and cabozantinib in patients with recurrent metastatic head and neck squamous cell carcinoma. The study met its primary endpoint of overall response rate. The regimen was well tolerated and exhibited encouraging clinical activity in this patient population (Abstract 6008).