Trastuzumab deruxtecan (T-DXd) has claimed a large share of the HER2-positive breast cancer landscape, even finding room among tumors previously thought to be HER2-negative. The DESTINY series of trials are international studies investigating T-DXd as a potential treatment option for eligible patients with certain cancers, including breast, gastric, lung, and other cancer types. Among these trials, there are two in particular that cause clinicians to wonder which approach demonstrates the optimal use of T-DXd in patients with breast cancer.DESTINY-Breast051 tested T-DXd in the adjuvant setting in patients with residual disease after neoadjuvant therapy, and DESTINY-Breast112 examined its benefit in the neoadjuvant setting.
This was the topic of a spirited debate at the 43rd Annual Miami Breast Cancer Conference, sponsored by Physicians Education Resource, between two breast cancer experts with opposing views: Paolo Tarantino, MD, an advanced fellow in the Breast Oncology Center at Dana-Farber Cancer Institute and Harvard Medical School, and Giuseppe Curigliano, MD, PhD, Full Professor of Medical Oncology, University of Milano, and Chief of the Clinical Division of Early Drug Development at the European Institute of Oncology in Italy.
Neoadjuvant T-DXd Is Preferred
Neoadjuvant therapy allows for the eradication of local, regional, and micrometastatic disease; the identification of tumors that are highly sensitive to systemic treatment and thus the avoidance of adjuvant cytotoxic therapy; and the shrinking of locoregional disease to enable more limited surgery and perhaps a more conservative radiotherapy approach, Dr. Tarantino pointed out.
Paolo Tarantino, MD
Giuseppe Curigliano, MD, PhD
“At ESMO last year, with DESTINY-Breast11 we saw the best regimen for achieving these things,” he said. DESTINY-Breast11 tested neoadjuvant T-DXd plus THP [paclitaxel, trastuzumab, pertuzumab] in HER2-positive patients with large (≥ cT3) or node-positive tumors, vs dose-dense doxorubicin/cyclophosphamide followed by THP (ddAC/THP). “It’s important to remember the population mostly included patients with hormone receptor–positive disease, which is very hard to shrink, yet the pathologic complete response (pCR) rate was still an ‘unprecedented’ 67% in the T-DXd/THP arm compared to 56% in the ddAC/THP arm. In hormone receptor–negative disease, it was 83%, equally unprecedented in this very high-risk scenario,” he said.
“Despite enrolling a high-risk population, DESTINY-Breast11 demonstrated the highest pCR rate across the randomized controlled trials [of neoadjuvant therapy in HER2-positive patients],” he noted, maintaining that T-DXd has proven itself to be the most effective neoadjuvant approach, leaving little faith in any of the alternatives. “I realize this is provocative, and TCHP [taxane/carboplatin/pertuzumab/pertuzumab] is recommended in the NCCN guidelines, but it’s not looking so solid anymore. At least two randomized trials (NeoCARHP3 and HELEN0064) have shown that carboplatin does not improve pCR and therefore adds little but toxicity,” he argued. “Also, THP alone may not be enough, as it doesn’t achieve the pCR rate of T-DXd plus THP, and without event-free survival results from trials, we aren’t sure we are curing patients or if [their disease] will eventually recur. Even after a pCR, patients with high-risk disease have up to a 15% risk of recurrence, so we don’t want to undertreat them.”
Benefit was observed in all subgroups. The absolute increase of nearly 26% in the HER2 3+ subset was particularly striking, “despite an intensive regimen of anthracycline/taxanes,” he added. Event-free survival was not a primary endpoint, but the “very promising” hazard ratio of 0.56 was worth noting, he said, as prevention of recurrence is very important.
Serious adverse events were halved with T-DXd/THP compared with standard cytotoxic chemotherapy, and quality of life was better for most time points. As he noted, “T-DXd is felt to be a lighter approach.” The short duration of neoadjuvant treatment also lessens the risk for interstitial lung disease (ILD), he added. ILD typically develops after 5 to 6 months of treatment, a time frame that is not reached after only four cycles. This was reflected in DESTINY-Breast11, in that only about 4% of patients on T-DXd/THP developed ILD compared to 10% in DESTINY-Breast05.
Finally and most importantly, he said, neoadjuvant use would allow more patients access to T-DXd if such access is based on trial eligibility. DESTINY-Breast11 was open to virtually any patient with stage II or III disease, the only exclusion being T2N0. In contrast, DESTINY-Breast05 included a highly selected population of stage II and III inoperable or node-positive disease following neoadjuvant therapy, reflective of only about 15% of the stage II to III population, he pointed out.
“I think we should give T-DXd to most patients—in the neoadjuvant setting—and not wait to give it to a few patients in the adjuvant setting. Four cycles of T-DXd followed by THP is the approach that gives you the highest chance of achieving a pCR, which is important for curing patients but also for sparing patients additional cytotoxic and antibody-drug conjugates in the adjuvant setting,” Dr. Tarantino said. “For the one-third of patients who unfortunately do not achieve a pCR after neoadjuvant T-DXd/THP, we have many additional strategies to optimize outcomes in the adjuvant setting.”
T-DXd Belongs Primarily in the Adjuvant Setting
“I personally disagree with Dr. Tarantino, and I will explain why,” said Dr. Curigliano. He maintained that the appropriate neoadjuvant strategy should remain dual HER2 blockade, as the results of DESTINY-Breast11 are far from mature enough—at 4.5% maturity—to change practice.
Furthermore, he questioned, “Are we going to treat patients to cure them or to shrink the tumor? DESTINY-Breast11 was not powered to demonstrate an event-free survival benefit.” In contrast, he said, DESTINY-Breast05 was a trial of 1600 patients with residual disease powered to demonstrate invasive disease–free survival and overall survival. Patients (79% hormone receptor–positive, similar to DESTINY-Breast11) were randomly assigned to 14 cycles of the standard of care, T-DM1 or T-DXd.
He pointed out the difference in the patient population: “The DESTINY-Breast05 patients are not the patients in DESTINY-Breast11—52% vs 47% with inoperable disease at presentation, and 80.7% vs 19.3% with positive nodes vs negative at the time of surgery. This is a very high-risk population. This is the real patient population that we see every day.”
Adjuvant T-DXd achieved a 53% reduction in the risk of invasive disease recurrence. “These are data we had never seen,” he emphasized. “More than 90% of patients alive after 3 years (92.4% vs 83.7%; hazard ratio = 0.47; P < .0001), and if you don’t have a relapse after 3 years, it’s very uncommon to have one later in this patient population… The majority of first invasive disease–free survival events were distant events, which would predict an overall survival benefit… All subgroups benefited, and there was a reduction in brain metastases, which is most important in this population. For distant recurrence–free survival, the hazard ratio was 0.49, reflecting an improvement of 7.8%. Follow-up was not long, but we saw 100 relapses with T-DM1 vs 52 with T-DXd.”
As for safety, he said that oncologists “know very well how to manage toxicities related to T-DXd,” including ILD. Drug-related adjudicated ILD was reported in 9.6% of patients, mostly low-grade and reversible, suggesting that the risk is manageable with appropriate monitoring and timely intervention. More than 72% of patients completed treatment, and this rate was comparable in both arms. There were fewer treatment discontinuations with T-DXd (18% vs 13%).
“So personally, I believe this is the real practice-changing trial. This should establish T-DXd as a new standard of care for high-risk patients with residual disease after neoadjuvant therapy,” Dr. Curigliano said, noting that its publication in the New England Journal of Medicine should serve as validation of its clinical impact. “For me, a 53% reduction in the risk of invasive disease recurrence and a 3-year invasive disease–free recurrence rate of 92% vs 83%, with a delta of 10%, is enough to demonstrate that this new standard of care will dramatically impact overall survival.”
“In my opinion, T-DXd in the post-neoadjuvant setting in the high-risk population should be considered the new standard of care, not the DESTINY-Breast11 approach. With DESTINY-Breast11, you can increase pCR by 10%, but you cannot demonstrate you will improve event-free survival, and [without that] you will not improve overall survival.”
DISCLOSURE: Dr. Tarantino disclosed personal relationships with Lilly, Novartis, Seagen, Roche-Genentech, Pfizer, Menarini, AstraZeneca, Daichi Sankyo, BMS, Celcuity, Blueprint, and Gilead. Dr. Curigliano had personal disclosures for AstraZeneca, BioNTech, Daichi Sankyo, Exact Sciences, Lilly, Menarini, Merck, Novartis, Pfizer, Gilead, BMS, Seagen, and Roche.
REFERENCES
1. Loibl S, Park YH, Shao Z, et al: Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med 394(9):845-857, 2026.
2. Harbeck N, Modi S, et al: Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11). Ann Oncol 37;166-179, 2026.
3. Gao H-F, Ye G-L, Lin Y, et al: Neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. January 23, 2026.
4. Chen XC, et al: De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab vs docetaxel, carboplatin, trastuzumab, and pertuzumab in patients with HER2-positive early breast cancer.. Lancet Oncol 26(1):27-36, 2025.
