The potential shift of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) into the frontline setting of HER2-positive advanced or metastatic breast cancer may reopen a previously filled clinical need for effective later line therapies in the event of disease progression, according to Naoto T. Ueno, MD, PhD, FACP.
“As we change the order of the previously established treatment, how we sequence [these therapies] needs to be addressed,” Ueno said in an interview with OncLive®. “That’s where complications can come in because we generally focus on the new type of treatment, but we don’t spend a lot of time on trying to work on the [place of the] previous treatment.”
Ueno is the interim program coleader and a full member of the Cancer Biology Program in the Department of Translational and Clinical Research, as well as the director of the University of Hawai’i Cancer Center in Honolulu. He is also a professor (researcher) at the University of Hawai’i Cancer Center, University of Hawai’i at Mānoa, and a professor in the Department of Medicine at the John A. Burns School of Medicine at the University of Hawai’i at Mānoa.
How Should I Sequence ADCs for Advanced or Metastatic Disease?
In December 2019, T-DXd earned its first indication in the HER2-positive space, netting an FDA approval for the treatment of patients with unresectable or metastatic HER2-positive breast cancer following at least 2 prior anti–HER2-based regimens in the metastatic setting.1 Based on compelling new data from the phase 3 DESTINY-Breast09 trial (NCT04784715), T-DXd in combination with pertuzumab (Perjeta)could also soon become a treatment option in the frontline setting for patients with HER2-positive advanced or metastatic breast cancer, Ueno said.
Findings from DESTINY-Breast09 demonstrated that patients who received T-DXd plus pertuzumab (n = 383) achieved a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) per blinded independent central review compared with 26.9 months (95% CI, 21.8-NC) among patients treated with standard of care (SOC) paclitaxel or docetaxel plus trastuzumab (Herceptin) and pertuzumab (THP; n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).2 The 24-month PFS rates were 70.1% (95% CI, 64.8%-74.8%) and 52.1% (95% CI, 46.4%-57.5%). Notably, the PFS benefit with T-DXd was consistently observed across prespecified patient subgroups.
“The current DESTINY-Breast09 data [have the potential to] bring T-DXd upfront,” Ueno said. “We have to remember that all of these trials are moving ADCs upfront, but [it doesn’t necessarily] mean that one treatment is more effective than another.”
In light of the new data from DESTINY-Breast09, ado-trastuzumab emtansine (T-DM1; Kadcyla) could represent a viable option in the second-line and later settings if T-DXd is established as the SOC in the frontline, according to Ueno. The agent also has a role in patients who are candidates for adjuvant treatment, holding an FDA approval in this setting for patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.4
Although there are currently no solid clinical trial data to confirm the benefit of T-DM1 after T-DXd, this treatment sequence is being evaluated in a prospective observational study in Korea (NCT06928818).5 The study is currently recruiting patients and the estimated primary completion is in September 2028.
“As [new data] come in, we need to continue to think about how we bring back older treatments,” Ueno said. “These are not bad treatments; how we can bring more treatment options to patients is something that we have to think about.”
Where Can I Go to Get Practical Advice Regarding Breast Cancer Management?
At the upcoming 2nd Annual Hawaii Cancer Conference, hosted by Physicians’ Education Resource®, LLC, which Ueno will be cochairing alongside David R. Gandara, MD, Hope S. Rugo, MD, FASCO, and Nicolas Villanueva, MD, investigators will engage in case-based panel discussions to further address treatment sequencing considerations in HER2-positive breast cancer and other clinical questions in breast cancer such as the role of minimal residual disease testing, optimal treatment approaches for patients with early-stage and metastatic triple-negative breast cancer, and which patients with HER2-positvie early breast cancer may require neoadjuvant and adjuvant therapy.6 The conference will also include a lung cancer component that will cover care aspects for patients with early-stage, locally advanced, and metastatic disease.
“Instead of a group of community physicians sitting in an audience and listening to experts speak about a subject in a lecture, in this meeting there are no lectures,” Gandara explained in an interview with OncLive. “The expert [will present] a case, and there [will be] a panel representing the specialties that are involved in [such a] case. We [can] ask the panel and the audience via audience response device [questions such as], what test would you order based on this? What treatment would you give? How would you manage [a potential adverse effect]?”
Gandara is the chief medical officer of the International Society of Liquid Biopsy, the codirector for the Center for Experimental Therapeutics in Cancer, and the senior advisor to the director at the University of California Davis Comprehensive Cancer Center in Sacramento. He is also an adjunct clinical professor in the Translational and Clinical Research Program at the University of Hawai’i Cancer Center in Honolulu.
The panel discussions will be moderated by expert investigators in breast and lung cancers from academic centers in the mainland US and will allow those from Hawai’i and other areas who practice in the community to bring the best practices back to their clinics. The Hawai’i Cancer Conference will take place from January 24 to 25, 2026, at the ‘Alohilani Resort Waikiki Beach in Honolulu.
“A key point is that the faculty in all of the case-based panels are [mostly] local community physicians,” Gandara explained. “We bring [approximately] 8 individuals from the mainland, [including] a surgeon, a radiation oncologist, and a medical oncologist, and the rest are faculty that practice in Honolulu, and we also have a group from a community hospital in Louisiana. It makes for a fantastic interactive experience; [attendees] get to hear their local [colleagues] give opinions rather than listening to a lecture and they get to vote on [what should be done in each situation].”
References
- FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. December 20, 2019. Accessed September 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer
- Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008
- Enhertu plus pertuzumab granted breakthrough therapy designation in the U.S. as first-line therapy for patients with HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. July 17, 2025. Accessed September 16, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202507/20250717_E.pdf
- FDA approves ado-trastuzumab emtansine for early breast cancer. FDA. Updated May 6, 2019. Accessed September 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer
- Trastuzumab emtansine(T-DM1) after trastuzumab deruxtecan(T-DXd) in HER2-positive breast cancer in Korea. ClinicalTrials.gov. Updated April 17, 2025. Accessed September 17, 2025. https://clinicaltrials.gov/study/NCT06928818
- 2nd Annual Hawaii Cancer Conference. Physicians’ Education Resource, LLC. Accessed September 16, 2025. https://www.gotoper.com/courses/annual-hawaii-cancer-conference?sessionFields=%5B%5B%22profession%22%2C%22Physician%22%5D%5D