T-DXd Plus Pertuzumab Sets New Treatment and Research Standards in HER2+ Breast Cancer

As fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) emerges as a highly effective new first-line standard of care for patients with HER2-positive metastatic breast cancer, researchers are now investigating innovative induction and maintenance therapy strategies to balance survival outcomes with the need to manage long-term toxicities and maintain patient quality of life (QOL), according to Milana V. Dolezal, MD, MSci.

“It’s an exciting time; we have a lot of changes in the first-line setting,” Dolezal said in an interview with OncLive®.

In the interview, Dolezal discussed how the phase 3 CLEOPATRA trial [NCT00567190] paved the way for the ensuing HER2-positive breast cancer research, highlighted data from the phase 3 DESTINY-Breast09 trial (NCT04784715), and where the future may be headed.

Dolezal is a clinical associate professor of medicine – oncology at Stanford Medicine in California.

OncLive: What key points about the DESTINY-Breast09 trial are important to note?

Dolezal: The CLEOPATRA trial regimen, that Egyptian queen, had a long reign for many years. The median follow-up of that trial was 99.9 months, and this was with the addition of pertuzumab to trastuzumab [Herceptin] and docetaxel [THP].¹ There was a median overall survival in that study of [approximately 57.1] months, which is that gold standard.

Then, the paradigm changed most recently with DESTINY-Breast09 that challenged that CLEOPATRA reign with the antibody-drug conjugate T-DXd in HER2-positive disease. [DESTINY-Breast09 had] an interesting patient population; approximately half of the patients on that trial had metastatic disease, approximately half of them were treated in Asia, and approximately one-third of them had a PI3K mutation. That’s relevant because in the CLEOPATRA survival curves, there was a drop off at the beginning, and Sandra Swain, MD [of Georgetown University in Washington, DC], et al, did some additional analyses to show that those types of PI3K mutation patients were the ones [who affected those survival curves] as opposed to the tails of those curves, [which represented] the patients who were the long responders.

DESTINY-Breast09 investigated T-DXd plus pertuzumab vs T-DXd plus a pertuzumab placebo, or that CLEOPATRA regimen of THP. There was an improvement in the primary end point of progression-free survival [PFS] from 26.9 months [(95% CI, 21.8-not estimable [NE]) in the control arm] to 40.7 months [(95% CI, 36.5-NE) in the T-DXd/pertuzumab arm], with a delta of 13.8 months.² It’s important to note that T-DXd was continued indefinitely. That’s something we should talk a lot about. The PFS breakdown in terms of hormone receptor (HR)–positive vs –negative disease in that HER2-positive metastatic first-line setting is similar in terms of an approximately 40-month median, so there were no differences in terms of HR-positive or triple-positive disease.

The other thing that’s important to note is when you look at the breakdown in that first-line setting with T-DXd by PI3K mutation status, it didn’t matter whether patients had PI3K-mutated disease vs PI3K wild-type disease. There was still a meaningful change in PFS [with T-DXd] in both those patient populations. That formed the basis for [the 2025 FDA approval of T-DXd plus pertuzumab for the treatment of patients with HER2-positive breast cancer]. The overall response rate was 87% [95% CI, 83%-90%], and the complete response (CR) rate was nearly doubled [with T-DXd plus pertuzumab].

How might the DESTINY-Breast09 findings continue to affect clinical practice?

We’re accustomed to doing an induction type of strategy with that CLEOPATRA THP [regimen]: 6 to 8 cycles, de-bulk, and then move on to trastuzumab/pertuzumab alone. Patients get their hair back, they can take their kids to school, they can show up to soccer games with hair, all those QOL things that are important. But when [they continue] T-DXd indefinitely, they are not necessarily regaining that QOL, so other induction strategies are being talked about now.

There was a presentation by Yeon Hee Park, MD, PhD, [of Samsung Medical Center in Seoul, South Korea], at the 2026 ASCO Annual Meeting that evaluated patients [who had] a CR or a deep partial response (PR). The median duration of response for the deep PR population was 39.2 months [95% CI, 35.3-NC].³ These patients needed to receive at least 16 cycles, so approximately 11 months, of T-DXd therapy. That’s relevant when you start talking about how long you’re going to keep them on this drug.

What questions remain regarding optimal therapy duration for HER2-positive breast cancer that future research might answer?

There are other strategies like that from the DEMETHER study [NCT06172127], which is investigating T-DXd for this induction phase for 6 cycles.⁴ This is a phase 2 single-arm [trial with] 165 patients, [where induction therapy is] followed by maintenance with circulating tumor DNA monitoring, which is an emerging technology that might help us in terms of understanding prognostic factors.

There is another [planned] trial called DB-guide, which is a different phase 2 trial in the triple-positive setting of T-DXd plus pertuzumab up front. This is an industry trial designed by Daiichi Sankyo and AstraZeneca, where T-DXd plus pertuzumab is [received for] 18 to 24 cycles, [looking at] longer response [outcomes beyond] the 6 induction cycles. The longer the patients are receiving a drug, the more money the industry potentially makes on it. But what happens afterward is that maintenance phase; those patients transition to receive trastuzumab plus pertuzumab and palbociclib, so sort of the phase 3 PATINA [(NCT02947685) trial design], but later on, after 18 or 24 cycles of T-DXd induction. The primary end point there is PFS, so it’ll be interesting to see what happens. There are still a lot of unknowns there.

It’s also important to point out, when we talk about durations of T-DXd in the first-line setting, whether it’s an induction strategy or even a year [of therapy], approximately 45% of patients aren’t able to maintain T-DXd. That’s important in terms of that second-line setting as well, because that means that patients are experiencing adverse effects. In DESTINY-Breast09, approximately 20% of patients could not continue to receive the study treatment with T-DXd and pertuzumab due to AEs, treatment discontinuations, dose reductions, etc. That QOL issue is important to understand.

References

1. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0
2. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. Accessed June 27, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
3. Park YH, Tolaney SM, Manich CS, et al. A DESTINY-Breast09 analysis of treatment duration and clinical outcomes by best response to trastuzumab deruxtecan (T-DXd) + pertuzumab (P). J Clin Oncol. 2026;44(suppl 16):1021. doi:10.1200/JCO.2026.44.16_suppl.1021
4. Cortés J, García-Mosquera JJ, Antonarelli G, et al. DEMETHER: a single-arm phase II trial to evaluate the efficacy & safety of subcutaneous pertuzumab & trastuzumab maintenance after induction treatment w/ trastuzumab deruxtecan (T-DXd) for previously untreated HER2-positive advanced breast cancer. Clin Cancer Res. 2025;31(suppl 12):P5-03-11. doi:10.1158/1557-3265.SABCS24-P5-03-11