During the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, an Around the Practice program occurred hosted by CancerNetwork® and focused on about the rapidly shifting treatment landscape in HER2-positive breast cancer.
The panel was moderated by Ami Shah, MD, clinical assistant professor at the Feinberg School of Medicine at Northwestern University, and included Megan Kruse, MD, director of breast medical oncology and co-leader of the Breast Cancer Program at Cleveland Clinic, and Ruta Rao, MD, director of Coleman Foundation Comprehensive Breast Cancer Clinic, and medical director of RUSH University Cancer Center.
The panel reviewed data from 3 phase 3 trials of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu): DESTINY-Breast09 (NCT04784715) in the first-line metastatic setting, DESTINY-Breast11 (NCT05113251) in the neoadjuvant setting, and DESTINY-Breast05 (NCT04622319) in the adjuvant, post-neoadjuvant setting. They also discussed depth and durability of response, central nervous system (CNS) disease, toxicity management, including interstitial lung disease (ILD), and how T-DXd fits alongside other options such as the phase 3 PATINA regimen (NCT02947685) and tucatinib (Tukysa)-based therapy from the phase 2 HER2CLIMB trial (NCT03163310).
Shah: Can you walk us through what you took from the DESTINY-Breast09, DESTINY-Breast11, and DESTINY-Breast05 data, and how you are thinking about incorporating them into practice?
Rao: It has been an exciting year for HER2-positive breast cancer, largely because of T-DXd. DESTINY-Breast09 tested T-DXd plus pertuzumab [Perjeta] against the long-standing CLEOPATRA regimen of a taxane, trastuzumab, and pertuzumab [THP] in the first-line metastatic setting. It was designed as a 3-arm trial, with a T-DXd-alone arm still maturing, but the reported comparison of T-DXd plus pertuzumab vs THP showed a median progression-free survival (PFS) of 40.7 months vs 26.9 months, respectively, with a hazard ratio of 0.56.1 That is a statistically significant and clinically meaningful improvement for a setting that had not changed in over a decade.
DESTINY-Breast11 and DESTINY-Breast05 then asked whether that benefit could translate into cure in earlier-stage disease. DESTINY-Breast11 evaluated neoadjuvant T-DXd followed by THP against dose-dense doxorubicin and cyclophosphamide followed by THP (the standard arm) in high-risk, node-positive or T3 to T4 disease; a T-DXd monotherapy arm was stopped early for a lower pathologic complete response (pCR) rate. The T-DXd-followed-by-THP arm achieved a pCR rate of 67% vs 56% with the standard regimen, an 11% absolute improvement.2 DESTINY-Breast05 then compared 14 cycles of adjuvant T-DXd against the phase 3 KATHERINE-trial [NCT01772472] standard of trastuzumab emtansine [T-DM1; Kadcyla] in patients with residual disease after neoadjuvant therapy, and found a 3-year invasive disease-free survival rate of 92% with T-DXd vs 84% with T-DM1, with distant recurrence-free survival and brain-metastasis-free survival also favoring T-DXd, although these end points need further follow-up.3
Shah: What data presented at this year’s meeting most changed how you think about using these regimens?
Kruse: It has been a flurry of information, and I think about this year’s presentations as more of a refinement period than a paradigm shift. One presentation that stood out looked specifically at the depth and timing of response with T-DXd plus pertuzumab in DESTINY-Breast09. Partial responses tended to occur early, within the first couple of months, but complete responses took longer, around 8 months, and some patients continued to deepen their response out to 24 months. That challenges the assumption that a fixed, safety-driven course of chemotherapy, like 6 to 8 cycles of taxane in the phase 3 CLEOPATRA regimen [NCT00567190], tells us anything about how long an induction period with T-DXd should last. It also reframes how we counsel patients: stable disease is still a reasonable goal, but patients who achieve a complete response or a deep partial response and appear to have meaningfully better 24-month PFS than those with a standard partial response, which changes the conversation about long-term expectations.
On the early-stage side, an abstract on radiation pneumonitis and ILD risk with adjuvant T-DXd in DESTINY-Breast05 was reassuring. Overall ILD rates were around 14% to 15% in that curative-intent population, higher than the 4% to 5% seen with the 4 cycles used in the neoadjuvant DESTINY-Breast11 trial, but concurrent or sequential radiation did not meaningfully add to that risk. Japanese patients and those with moderate renal impairment trended toward higher ILD rates, which is consistent with prior T-DXd data and worth factoring into monitoring plans.
Shah: How does a deep or complete response change the conversation you have with patients about long-term expectations?
Rao: Historically, with the CLEOPATRA regimen, we were used to the way of doing things, giving this as an induction regimen. The DESTINY-Breast09 data on depth of response is shifting that a little. The complete responses and deep partial responses take longer to appear, around 8 months, but patients who reach that depth of response have notably better 24-month PFS than those with a standard partial response. It’s going to change how much T-DXd we give; remember, it’s given until progression in the trial.
Kruse: I still tell patients that stable disease is a good outcome, and that’s true. But I now have to think harder about what a complete response or deep partial response really means for expectations around length and quality of life. That’s a more nuanced conversation than we used to have, and for some patients, questions about work, family planning, and long-term goals become part of it.
Shah: What patient factors push you toward T-DXd plus pertuzumab up front, vs the CLEOPATRA regimen?
Kruse: My thinking has evolved substantially over the past year. Initially we tried to preselect patients we thought would do fine with THP maintenance alone. Now I start with T-DXd plus pertuzumab as my intended plan for most patients and look for reasons a person’s situation might argue against it, like significant lung comorbidities. The group I feel most strongly about is de novo metastatic disease, particularly younger patients with higher-volume disease, where the chance for a truly deep, durable response is greatest. For everyone else, it is an individualized conversation grounded in being clear about the efficacy data we have.
Shah: HER2-positive metastatic disease with CNS involvement has been one of the hardest problems in this space. How does that factor into treatment selection and monitoring?
Rao: CNS disease is a real threat in HER2-positive metastatic breast cancer, but we finally have systemic options with meaningful CNS activity. There’s no formal standard for screening asymptomatic patients for brain metastases at metastatic diagnosis, but I am screening more often than I used to, in part because the DESTINY-Breast09 data support T-DXd’s CNS efficacy. For a patient who presents with brain metastases at diagnosis, T-DXd plus pertuzumab is a clear choice.
Kruse: My practice has shifted the same way. We used to avoid looking for low-volume CNS disease because our only tools were more toxic radiation approaches. Now that T-DXd (and tyrosine kinase inhibitors like tucatinib [Tukysa]) have real intracranial activity, finding CNS disease earlier and treating it more effectively makes sense. Subtle symptoms, headaches, vision changes, or cognitive changes, deserve an MRI, and CNS involvement can tip me toward T-DXd plus pertuzumab in patients where I was otherwise on the fence.
Shah: As T-DXd moves into earlier lines and curative-intent settings, how do you balance efficacy against toxicity, particularly ILD?
Rao: In our practice, we use the high-resolution CTs. These are what our radiologists have recommended that we use. They’re the best way to detect ILD. It’s important to remember that you may not see ILD on a standard CT, the one that you’re doing for your staging workup, and so you have to be looking for it because it comes down to the fact that if you can find the ILD when it1s grade 1, meaning that there’s radiographic changes but no symptoms. This is a patient that you can manage. You can even treat with steroids. You can wait till the ILD resolves, and you can put them back on that treatment. That’s so important because if it gets to the point where it’s grade 2 and it’s symptomatic with radiographic findings, the recommendation is to stop it. We know it’s such an effective drug. We want to be making sure that we’re checking for ILD so we can manage it if we find it and continue this patient on this very effective medication. The other thing to remember when we’re doing these PET CTs, that’s not a very specific CT port exam. In addition to a PET CT, I will do the high resolution CT of the chest to look for ILD.
Kruse: Going back to the early-stage setting, we have to maintain a very close eye for these patients in a way that we haven’t needed to before. Incorporating routine CTs of the chest to look for this toxicity, especially with a curative intent population, the last thing you want to do is have a patient lose their life to a treatment-related complication, and we know that we take that risk on with any regimen we give. Sometimes we can’t do anything about it, and there may be cases with the T-DXd-containing regimens where that’s still the case, but if we can pick it up early and intervene early, the data that we were talking about from ASCO this year, looking at ILD and radiation pneumonitis, suggests that the majority of patients who develop at least grade 1 ILD and are treated per the guidelines with steroids, drug holds, dose reductions if needed, that they do recover and that they maintain normal lives and normal functioning.
That is important data to know because it means that we have an opportunity to intervene before it’s irreversible toxicity, and in the early stage setting because we still have other effective treatment strategies that we could swap out for. They’re maybe not as effective as what we’re hoping for with T-DXd, but you could switch someone to another regimen if you needed to. Having awareness of what the recommended protocols for these trials are, where we’re getting CTs of the chest potentially as soon as 6 weeks, right around the time of radiation, and then maintaining that at a 12-week cadence while patients are going through adjuvant T-DXd as per DESTINY-Breast05, it’s a newer level of monitoring. It’s one more thing for us to keep track of, but it’s important as we deploy use of the drug in the curative intent situation.
The other thing is making our colleagues aware. Our radiation oncologists are already aware of these data. The story started with T-DM1, which can have pulmonary toxicity. We don’t talk about it as much, but we were already thinking about this plus radiation in the curative intent setting. It’s worth having that conversation with your radiation oncologist because they may be seeing these patients actively while on treatment when they’re developing symptoms, perhaps when we may not be, and it’s an opportunity for everyone to be aware and just continue to communicate through the multidisciplinary team.
Shah: What are your go-to strategies for managing nausea, fatigue, and alopecia with T-DXd?
Rao: Using a 4-drug antiemetic regimen is important. You certainly don’t want someone to be nauseous or vomit and then not want to do that drug again. Olanzapine [Zyprexa] has become a drug that we’ve all become very familiar with. We also know that you can use it at low doses, even the 2.5 mg, even days 7 to 10 for some of this delayed nausea. I tell patients to take it at night because it can cause some somnolence. That is a good way to control the nausea. Fatigue is a bit more challenging. What I’ve seen in my patients is that the toxicities are predictable. It’s also important to have those discussions with patients, and if they have an important life event coming up-a graduation, a birth of a grandchild, something, and they want to be feeling good for that. I’ve also been a bit relaxed about saying, “Okay, your next cycle can be in 4 weeks instead of 3. I’m certainly not changing it routinely, but we have to accommodate the big events in their life and make sure that they’re feeling good for those.”
Kruse: I am cautious because we all know that scalp cooling comes with time consequences. It comes with financial consequences, and so you do have to be honest with patients that we don’t entirely know what could happen. If it’s important for them, it may be worth a try. For a lot of our patients, maintaining their hair is something that maintains their identity [and] their mental health. It may be important for their family, who they haven’t yet disclosed or don’t necessarily want to talk about what the intensity of their cancer diagnosis is, and work situations. A lot of people don’t want to invite the outside world into their lives in a way without them controlling the narrative. When you lose your hair, you lose control over that. It’s worth discussing. As we use these regimens more in the real-world setting, we’re going to get more data that’s going to be helpful here. As of now, it’s one of those again part of in what makes these conversations very involved. They take a lot of time because there’s a lot to cover here. It’s worth opening that conversation with a patient if it’s important to them.
Shah: What unmet needs or upcoming data are you watching most closely?
Kruse: Better biomarkers, particularly circulating tumor DNA, to help select who truly needs escalation vs who could be spared it. We are also watching the phase 2 DEMETHER trial [NCT06172127], which is testing a T-DXd induction period followed by a chemotherapy-free maintenance regimen, since that will help clarify whether shorter, time-limited T-DXd courses can preserve the durable responses we’re now seeing with continuous therapy.
Rao: Overall, patients are tolerating these treatments well on studies. We have to remember that the patients we’re seeing in clinic every day may not be the same patients who are on the trials. We know that certainly the racial diversity of who we see isn’t captured in our trials, and a lot of these trials are done internationally. A lot of this is going to be putting it into practice, and then seeing how our patient populations deal with it.
References
1. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. Published online 2025. doi:10.1056/NEJMoa2508668
2. Harbeck N, Modi S, Pusztai L, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2026;37(2):166-179. doi:10.1016/j.annonc.2025.10.019
3. Geyer CE, Sonnenblick A, Untch M, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. Published online December 10, 2025. doi:10.1056/NEJMoa2514661
