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DESTINY-Breast05 (NCT04622319), presented by Dr. Charles E. Geyer (Pittsburgh, United States of America) at the ESMO Congress 2025, is a pivotal phase 3, open-label, randomized trial evaluating trastuzumab deruxtecan (T-DXd) versus the standard-of-care trastuzumab emtansine (T-DM1) in patients with HER2-positive early breast cancer (eBC) who had residual invasive disease after neoadjuvant therapy. The study was designed to determine whether T-DXd could improve long-term outcomes for this high-risk population compared with T-DM1, the established post-neoadjuvant standard of care

Background

Patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant chemotherapy and anti-HER2 therapy face a high risk of recurrence, particularly distant relapse. T-DM1 became the standard post-neoadjuvant treatment following the KATHERINE trial, but outcomes remain suboptimal for patients with high residual disease burden. Trastuzumab deruxtecan (T-DXd), a next-generation HER2-directed antibody–drug conjugate with a potent topoisomerase I inhibitor payload, has shown marked efficacy in metastatic settings, prompting investigation into its use in the early disease setting to reduce recurrence risk.

Methods

In DESTINY-Breast05, 1,635 patients with HER2-positive eBC and residual invasive disease after neoadjuvant taxane-based chemotherapy and HER2-targeted therapy were randomized 1:1 to receive either:

• T-DXd (5.4 mg/kg) every 3 weeks,for a total of 14 cycles.
• T-DM1 (3.6 mg/kg) every 3 weeks,for a total of 14 cycles.

Eligible patients were considered high risk for recurrence, defined by clinical stages T4, N0–3, M0 or T1–3, N2–3, M0 at presentation, or residual nodal disease after neoadjuvant therapy.

The primary endpoint was invasive disease-free survival (IDFS), with disease-free survival (DFS) as a key secondary endpoint. Additional endpoints included overall survival (OS), distant recurrence-free interval, brain metastasis–free interval (BMFI), and safety.

Results

At the data cutoff of July 2, 2025, median follow-up was 29.9 months in the T-DXd arm and 29.7 months in the T-DM1 arm.

• IDFS events: 6.2% with T-DXd vs 12.5% with T-DM1
• DFS events: 6.4% vs 12.6%
• Hazard ratio (HR): 0.47 for both IDFS and DFS (95% CI: 0.34–0.66; p < 0.0001)

Similarly, the key secondary endpoint of disease-free survival (DFS) demonstrated a parallel benefit, with a hazard ratio of 0.47 (95% CI, 0.34–0.66; p < 0.0001). The 3-year DFS rate was 92.3% with T-DXd compared with 83.5% with T-DM1, corresponding to an 8.8% absolute gain.

These findings represent a 53% reduction in risk of invasive disease recurrence or death with T-DXd compared with T-DM1.

A clinically meaningful improvement in BMFI was also observed (HR 0.64; 95% CI 0.35–1.17), suggesting enhanced control of central nervous system relapse.

Safety

The overall safety profile of T-DXd was manageable and consistent with prior studies.

• Grade ≥3 TEAEs: 50.6% (T-DXd) vs 51.9% (T-DM1)
• Adjudicated interstitial lung disease (ILD): 9.6% (2 grade 5 cases) vs 1.6% (none grade 5)
• Treatment-related deaths: 0.4% (T-DXd) vs 0.6% (T-DM1)

Most ILD events were grade 1–2 and resolved with treatment modification or corticosteroids. No new safety signals were identified.

Conclusions

The DESTINY-Breast05 trial demonstrated that trastuzumab deruxtecan (T-DXd) offers a statistically significant and clinically meaningful improvement in both invasive disease-free survival (IDFS) and disease-free survival (DFS) compared with trastuzumab emtansine (T-DM1) in patients with HER2-positive early breast cancer who had residual invasive disease following neoadjuvant therapy.

These findings mark a pivotal advance in the post-neoadjuvant management of HER2-positive breast cancer. By extending the proven efficacy of T-DXd beyond the metastatic setting into early-stage, high-risk disease, the results highlight its potential to redefine the standard of care for patients who previously had limited options after incomplete response to neoadjuvant therapy. Importantly, the benefit was consistent across all major subgroups, including hormone receptor–positive and –negative disease, as well as across regions and baseline disease characteristics, underscoring the robustness of the findings.

You can read the full abstract here.

Final analysis from the phase 3 COMPETE trial (NCT03049189)¹

revealed that ¹⁷⁷-Lu-edotretide (ITM-11) vs everolimus met its primary and secondary endpoints in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).The final analysis was announced at the 2025 European Association of Nuclear Medicine Annual CongressSociety for Medical Oncology (ESMO) Congress on October 18, 2025.²¹ The results were presented by Jaume Capdevila, MD, PhD, Vall d’Hebron University Hospital.

The primary endpoint was progression-free survival (PFS), which was reached with statistically significant and clinically meaningful improvement. The median PFS was significantly longer in patients who tookadministered ITM-11 compared to those who tookadministered everolimus. The secondary endpoint of the trial was overall survival (OS), which was also identified to be higher in patients who tookwere administered ITM-11 vs everolimus.²

There was a total of 207 patients in the ITM-11 group and 102 patients in the everolimus group. , respectively. The median ages of both groups were 65 (ITM-11), and 61 (everolimus). Majority of patients in both groups were male. The majority of patients had grade 2, non-functional GEP-NETs and had received prior therapy.^1,2

What Were the Results of the COMPETE Trial?

COMPETE met its primary endpoint of PFS, which proved to be significantly longer in patients treated with ITM-11 vs everolimus. The central assessment was 23.9 vs 14.1 months (HR, 0.67; 95% CI, 0.48–0.95; P=.022).; HR .67, 95% CI [.48, .95]). The local assessment was 24.1 vs 17.6 months (P=.010; HR, 0.66; 95% CI, 0 [.48–0, .91] P =.010;).²

In the subgroup analysis of PFS by tumor origin, mPFS was found to be numerically longer in GE-NETs and P-NETs in the ITM-11 arm. In GE-NETs the mPFS was 23.9 vs 12 months (P=.090; HR 0.64, 95% CI, 0i [.38–, 1.08;] P=.090;). In P-NETs the mPFS was 24.5 vs 14.7 months (HR, 0.70, P=.114; HR .70, 95% CI, 0 [.45–, 1.09; P=.114;]).²

It was also identified that mPFS was numerically longer in grade 1 and significantly longer in grade 2 tumors in the ITM-11 arm. Grade 1 was 30 vs 23.7 months (P=.753; HR, 0.89, 95% CI, 0. [.42–, 1.8; 7]P =.753;), and grade 2 was 21.7 vs 9.2 months (P=.0003; HR 0.55l , 95% CI, 0i [.37–0, .82] P =.0003).²

In exploring PFS by prior therapy, it was identified that mPFS was numerically longer in the first line and significantly longer in the second line in the ITM-11 arm. First line data showed the mPFS was not reached in the ITM-11NR vs 18.1 months (P=.249; HR, 0.60, 95% CI, 0 [.25–, 1.45; P =.249]), and second line data showed 23.9 vs 14.1 months (P=.039; HR, 0.68; , 95% CI, 0 [.47–0,, 98] P=.039).²

Overall response rates (ORR), one of the secondary endpoints of the trial, was found to be significantly higher in the ITM-11 arm. Central assessment was 21.9% vs 4.2% (P<.0001), and local assessment was 30.5% vs 8.4% (P<.0001).²

What Adverse Events Were Reported?

Adverse events (AEs) related to the drug study were experienced by 82% of patients ITM-11 group, and 97% of patients in the everolimus group. The most common AEs reported were nausea (30% vs 10.1%), diarrhea (14.3% vs 35.4%), asthenia (25.3% vs 31.3%), and fatigue (15.7% vs 15.2%). These AEs were expected based on the known safety profile of ITM-11.²

AEs leading to premature study discontinuation wereas 1.8% vs 15.2% among both groups, respectively, dose modification or discontinuation wereas 3.7% vs 52.5%, among both groups, and the amount of patients with delayed study drug administration due to toxicity was 0.9% in the ITM-11 group, and none 0% in the everolimus group.²

Dosimetry data showed targeted tumor uptake with low exposure to healthy organs, with normal organ absorbed doses well below safety thresholds.

What Were the Patient Criteria?

Patient inclusion criteria included being 18 or older, having well-differentiated, non-functional GE-NET or functional/non-functional P-NET;, grade 1/2 unresectable or metastatic, progressive, SSRT-positive+ disease; and , being treatment-naive to first-line therapies or progressing , or progressed under prior second-line therapies.^1,2

Morphologic imagining was conducted in 3-month intervals. The PFS follow-up was done every 3 months after the first 30 days. Long-term follow-up was done every 6 months.

“With these data combining extensive dosimetry information from more than 200 patients included in a prospective trial, ITM is laying the groundwork for improved therapeutic decision-making by providing important insights into tumor uptake and treatment variability,” Emmanuel Deshayes, MD, PhD, professor in biophysics and nuclear medicine at the Montpellier Cancer Institute in France, said in a news release.² “It may offer clinically meaningful implications for optimizing individualized patient management.”

Dosimetry data from COMPETE shaped the design of ITM’s phase 3 COMPOSE (NCT04919226)⁴ trial, with ITM-11 in well-differentiated, aggressive grade 2 or grade 3 SSTR-positive+ GEP-NET tumors, as well as the upcoming phase 1 pediatric KinLET (NCT06441331) study in SSTR-positive+ tumors.

DISCLOSURES: Capdevila noted grants and/or research support from Advanced Accelerator Applications, AstraZeneca, Amgen, Bayer, Eisai, Gilead, ITM, Novartis, Pfizer, and Roche; participation as a speaker, consultant, or advisor for Advanced Acclerator Applications, Advanz Pharma, Amgen, Bayer, Eisai, Esteve, Exelixis, Hutchmed, Ipsen, ITM, Lilly, Merck Serono, Novartis, Pfizer, Roche, and Sanofi; position as advisory board member for Amgen, Bayer, Eisai, Esteve, Exelixis, Ipsen, ITM, Lilly, Novartis, and Roche; and a leadership role and chair position for the Spanish Task Force for Neuroendocrine and Endocrine Tumours Group (GETNE).

REFERENCES:

1.Capdevilla J, Amthauer H, Ansquer C, et al. Efficacy, safety and subgroup analysis of 177Lu-edotreotide vs everolimus in patients with grade 1 or grade 2 GEP-NETs: Phase 3 COMPETE trial. Presented at: 2025 ESMO Congress; October 17-20, 2025; Berlin, Germany. Abstract 1706O

2. ITM presents dosimetry data from phase 3 COMPETE trial supporting favorable efficacy and safety profile with n.c.a. 177Lu-edotreotide (ITM-11) in patients with gastroenteropancreatic neuroendocrine tumors at EANM 2025 Annual Congress. News release. ITM. October 8, 2025. Accessed October 18, 2025. https://tinyurl.com/3nuscs4m

3. Lutetium 177Lu-Edotreotide versus best standard of care in well-differentiated aggressive grade-2 and grade-3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) – COMPOSE (COMPOSE). ClinicalTrials.gov. Updated September 10, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT04919226

4. Phase I trial to determine the dose and evaluate the PK and safety of lutetium Lu 177 edotreotide therapy in pediatric participants with SSTR-positive tumors (KinLET). ClinicalTrials.gov. Updated September 19, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT06441331

Patients who cannot or choose not to have cisplatin-based chemotherapy alongside surgery to remove the bladder when diagnosed with muscle-invasive bladder cancer (MIBC) cut their risk of disease progression or death by 60% by having enfortumab vedotin (EV) and pembrolizumab alongside surgery, according to data presented Saturday.¹

Results from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895) were presented during the first Presidential Session at the 50th European Society for Medical Oncology Congress (ESMO) in Berlin, Germany.¹ They show patients receiving the antibody drug conjugate (ADC) and pembrolizumab (P) combination with surgery had superior outcomes across a range of measures than those treated with surgery alone.

Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 patients each year, with MIBC accounting for 30% of all cases of bladder cancer.

The combination of EV (Padcev; Astellas/Pfizer) and the PD-1 pembrolizumab (Keytruda; Merck) previously received full FDA approval in December 2023² for first-line treatment of patients with locally advanced or metastatic urothelial cancer based on EV-302 (NCT04223856), which will have new data on older adults presented at the congress.³

As EV-303 principal investigator Christof Vulsteke, MD, PhD, said in a press briefing ahead of the session, the results in first-line care are as transformative as those in the metastatic setting presented 2 years ago at ESMO. He predicted this regimen might become the standard of care for patients who have had grim prospects.

“What is the standard of care in this population with muscle-invasive bladder cancer?” asked Vulsteke, who is head of the Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent. “We took the patients who are not fit for chemotherapy, and this is half of all the patients with [MIBC]. In half of these patients, you cannot give upfront chemotherapy—you go straight to surgery, and you know that more than half of these patients will relapse. It will be up to 70% of patients who will relapse, and after 5 years, you will lose most of these patients.”

Pointing to widely separated curves between patients receiving the EV + P regimen with surgery and those having surgery alone, Vulsteke noted the HR of 0.40 but said, “It’s also important that… you live longer,” and that overall survival (OS) is just as impressive.

Those results showed that after 25 months, OS was 50% higher for the EV + P group compared with the surgery-only group, and that median event-free survival (EFS) was not reached for patients in EV + P group compared with 15.7 months for those in the surgery-only group.¹

Study authors said that radical surgery, called cystectomy, completed with pelvic lymph node dissection, has been the standard treatment for patients with MIBC who cannot have cisplatin. Up to half of patients with MIBC may have comorbidities that make them ineligible or have developed resistance to this backbone chemotherapy. In other cases, patients may decide the benefits are not worth the toxicity.

Cisplatin shortages in recent years have also forced physicians to treat bladder cancer patients with EV off guidelines in lieu of cisplatin—which caused some controversy. (Shortages are now considered resolved.⁴) Asked if these results combined with the prior trial have implications in light of past use for patients who were eligible for cisplatin, Vulsteke noted that precise question is being studied in an ongoing trial.

“This [trial] is in the cisplatin-ineligible population, but the same trial is running also in the eligible population, and if it wins there also, this will also replace, in my opinion, the platinum-based [chemotherapy].”

Study Methods and Results

Patients were randomized 1:1 to the EV + P combination, which called for 3 cycles of EV 1.25 mg/kg on day 1 and day 8, plus P at 200 mg on day 1 at 3-week cycles, followed by the surgery, then 6 cycles of EV plus 14 cycles of P. The control group received the surgery only. Study therapy continued until progression, unacceptable toxicity, withdrawal of consent, or completion of planned treatment.¹

The primary end point was EFS as determined by blinded independent central review. Secondary end points were OS, pathological complete response (pCR) rate, and safety.

Results were as follows¹:

• 170 patients received the EV + P regimen and 174 were in the control group; more than 80% of patients were cisplatin ineligible per the Galsky criteria
• As of June 6, 2025, median follow-up time was 25.6 months (range, 11.8-53.7), with 149 patients (87.6%) in the EV + P arm and 156 (89.7%) in the control undergoing surgery
• EV + P significantly improved EFS, with the median not reached (NR) vs 15.7 months (HR, 0.40; 95% CI, 0.28-0.57; P < .001)
• OS was NR vs 41.7 months (HR 0.50; 95% CI, 0.33-0.74; P < .001)
• pCR rate was 57.1% vs 8.6%, for an estimated difference of 48.3 percentage points (95% CI, 39.5-56.5; P < .001) vs control.
• Treatment-emergent adverse events (AEs) occurred in 100% (grade ≥ 3, 71.3%) of patients in the EV + P arm and 64.8% (grade ≥ 3, 45.9%) in the control group; the most frequent grade ≥ 3 AE of special interest was severe skin reactions, for 11.4% from P and 10.8% from EV
• The study remains ongoing to assess EFS, OS, and pCR data as they mature

“The compelling EV-303 results may establish a new efficacy benchmark in muscle-invasive bladder cancer,” said Moitreyee Chatterjee-Kishore, PhD, MBA, head of oncology development, Astellas. “For the first time, a systemic treatment approach used before and after surgery has improved survival over standard surgery in cisplatin-ineligible patients. These data underscore the transformative potential of [enfortumab vedotin] plus [pembrolizumab] as we continue to explore this combination in a broad population of patients with muscle-invasive bladder cancer.”⁵

“The ability of [enfortumab vedotin] plus [pembrolizumab] to reduce the risk of death by half in this setting is a remarkable advancement for patients who have seen limited treatment options and often face poor prognosis,” said Jeff Legos, PhD, MBA, chief oncology officer, Pfizer. “These unprecedented results suggest that the transformational efficacy of this combination in advanced bladder cancer may extend into an earlier disease setting, potentially providing a life-changing impact for patients.”⁵

Strength of ADCs in First-Line Treatment

EV is a Nectin-4 directed ADC, and the EV-303 trial is among the studies involving ADCs in first-line treatment being featured at ESMO this week. At the opening press conference on Friday, ESMO 2025 President Fabrice André, MD, PhD, and scientific co-chairs Toni Choueiri, MD, and Myriam Chalabi, MD, PhD, highlighted EV-303 as well as a pair of breast cancer trials also presented during Saturday’s Presidential Session involving trastuzumab deruxtecan, the groundbreaking treatment sold as Enhertu (AstraZeneca).

During Friday’s press conference, André explained the mechanism of ADCs and how they deliver a payload of high-dose cytotoxic agents inside the cancer cell. “What we knew before is that there is this new class of agents that has some impact on patients with metastatic cancer,” he said. “What we didn’t know so far is whether this new class of drug is having an impact on patients with early-stage cancer—that is usually at the stage where patients can relapse and ultimately die.”

That question, André said, would be answered at the ESMO 2025 Congress.

References

1. Vulsteke C, Kaimakliotis H, Danchaivijitr P, et al. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin in eligible : the phase III KEYNOTE-905 study. Presented at: 50th European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
3. Powles T, Valderama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi: 10.1056/NEJMoa2312117.
4. Reed T. Critical chemo drug no longer in shortage. Axios. July 1, 2024. Accessed October 18, 2025. https://www.axios.com/2024/07/01/critical-chemo-drug-no-longer-in-shortage-vitals
5. Padcev plus Keytruda, given before and after surgery, cuts the risk of recurrence, progression or death by 60% and the risk of death by 50% for certain patients with bladder cancer. News release. PR Newswire. Astellas and Pfizer. October 18, 2025. Accessed October 18, 2025. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-given-before-and-after-surgery-cuts-the-risk-of-recurrence-progression-or-death-by-60-and-the-risk-of-death-by-50-for-certain-patients-with-bladder-cancer-302587853