Enhertu (fam-trastuzumab deruxtecan-nxki)

P1/2, N=22, Active, not recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Recruiting --> Active, not recruiting

These data support T-DXd as a broadly efficacious treatment for patients with HR+, HER2-low/-ultralow mBC after ≥1 ET, regardless of TTP on prior first-line ET + CDK4/6i, endocrine resistance, or disease burden.

Patients receiving chemotherapy following ET had limited benefit from available treatments, highlighting unmet treatment needs in this population.

P2, N=37, Recruiting, The First Affiliated Hospital with Nanjing Medical University

Given the single-intervention design in DESTINY-Lung02, two external comparator arms (ECAs) were created using docetaxel from INTEREST and VITAL, to connect T-DXd to a broader evidence network...Notably better PFS improvements were observed on T-DXd across all comparisons, with hazard ratios (HRs) [95% CrI] varying from 0.15 [0.09, 0.26] versus pemetrexed to 0.33 [0.20, 0.56] versus paclitaxel + bevacizumab...This ITC suggested that T-DXd was associated with a consistent and meaningful benefit in terms of PFS and favorable OS relative to relevant comparators. For HER2m metastatic NSCLC adults, this review supports that T-DXd may be the best treatment option in the second-line or later settings.

The value of HER2-targeted treatments in patients with HER2+ mCRC has been evidenced by clinical trials and meta-analyses, with strong evidence from MOUNTAINEER and DESTINY-CRC01 which supports the use of tucatinib + trastuzumab or trastuzumab deruxtecan, respectively, among this patient population. Strong evidence and clinical guidelines support the value of HER2-targeted treatment among patients with HER2+ mCRC. There is a need for increased awareness and earlier uptake of HER2 testing among patients with mCRC to broaden treatment options and optimise outcomes for this patient population.

These findings highlight the importance of early ILD detection and management so patients can receive, and potentially benefit from, subsequent anti-HER2 targeted therapies. ILD recurrence/exacerbation during subsequent therapies was low in patients who experienced ILD with T-DXd.

P3, N=608, Completed, Daiichi Sankyo | Active, not recruiting --> Completed

Key 2025 findings (50 clinical trials) include: (1) confirmation of overall survival benefit with adjuvant CDK4/6 inhibitors in HR+/HER2- early breast cancer (monarchE: HR = 0.842, p = 0.0273); (2) establishment of trastuzumab deruxtecan (T-DXd) as a new standard in high-risk HER2+ early disease (DESTINY-Breast05: IDFS HR = 0.47) and first-line metastatic settings (DESTINY-Breast09: PFS HR = 0.58); (3) validation of TROP2-directed ADCs as first-line therapy for metastatic triple-negative breast cancer (ASCENT-03: PFS HR = 0.62; BEGONIA: ORR 79%); (4) paradigm shift to proactive, liquid biopsy-guided therapy switching (SERENA-6: PFS HR = 0.44); (5) updated efficacy and safety of the oral SERD imlunestrant from the EMBER-3 trial, supporting its role in ESR1-mutated advanced breast cancer and in combination with abemaciclib; (6) confirmation of long-term survival benefit for neoadjuvant carboplatin in early TNBC and new positive adjuvant data; (7) pivotal advances in HER2+ metastatic disease sequencing with tucatinib and T-DXd; (8) evidence supporting optimized adjuvant endocrine therapy in HER2+/HR+ early disease; and (9) emergence of novel agents with improved therapeutic indices, including PROTAC degraders, oral SERDs, and mutant-selective PI3K inhibitors. Unifying themes include biomarker-driven personalization, strategic treatment sequencing, management of unique toxicities, and emphasis on patient-reported outcomes. Future challenges include optimizing treatment integration, managing financial toxicity, and ensuring equitable global access.

In the largest real-world cohort reported to date, T-DXd demonstrated robust systemic and intracranial activity in HER2-mutant NSCLC, including treatment-naïve patients and those with active brain metastases who were largely excluded from prior studies. Toxicity was consistent with previous reports, with ILD remaining the main safety concern. These findings support integration of HER2-targeted therapies into evolving treatment algorithms.

The target population for these recommendations is patients with unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. Results from testing for actionable biomarkers should be available as soon as possible to inform treatment decision making. Immunotherapy with doublet chemotherapy is recommended for patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal adenocarcinoma or squamous cell carcinoma and PD-L1 expression ≥1; patients with higher PD-L1 expression are more likely to benefit from immunotherapy. Zolbetuximab is recommended for patients with gastroesophageal adenocarcinoma, PD-L1 <1, and positive CLDN18.2 expression. Patients with dual PD-L1 and CLDN18.2 positivity should engage in shared decision making, considering the factors outlined in the guideline. Doublet chemotherapy alone is recommended for patients who are not positive for actionable biomarkers or are not considered candidates for targeted therapy or immunotherapy. For patients with pMMR/MSS HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinoma, trastuzumab and doublet chemotherapy is recommended; for patients with PD-L1 expression ≥1, the addition of pembrolizumab is recommended. Immunotherapy alone or with doublet chemotherapy is recommended for patients with mismatch repair deficient/microsatellite instability-high gastroesophageal cancer. Second-line therapy options include ramucirumab with paclitaxel, trastuzumab deruxtecan for HER2-positive gastric/GEJ adenocarcinoma, and immunotherapy for PD-L1 ≥1 esophageal squamous cell carcinoma after first-line combination chemotherapy without immunotherapy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Key recommendations included: mandatory biopsy at metastasis with ER/PgR/HER2 retesting, HER2-low assessment, and molecular profiling (BRCA, PIK3CA, AKT1/PTEN, ESR1, plus PD-L1 testing in mTNBC); for HR+/HER2- mBC, first-line endocrine therapy plus CDK4/6 inhibitor, followed by targeted agents, chemotherapy, or antibody-drug conjugates based on progression and visceral crisis; for mTNBC, first-line immune checkpoint inhibitor plus chemotherapy in PD-L1-positive, PARP inhibitors in BRCA-positive patients, and sacituzumab-govitecan or trastuzumab-deruxtecan later; systematic toxicity monitoring; and integrated supportive and palliative care. Sixty-one oncologists completed the survey, with >90% overall agreement, suggesting broad acceptance of recommendations as Romania's national standard for mBC care.