Armando Orlandi, Medical Director at the Agostino Gemelli University Hospital Foundation IRCCS, shared on LinkedIn:
“ESMO 2026, Madrid: the Answers!
Before Madrid I asked 5 clinical questions on breast cancer. The data answered.
Hormone receptor-positive (HR+) early disease: a survival gain?
- NATALEE (LBA25): Yes. Overall survival (OS) hazard ratio (HR) 0.81, +2.1% at 6 years: the study’s statistical design could not have delivered a stronger OS signal (nominal p, positive direction). The invasive disease-free survival gap keeps widening (+5.3%), off ribociclib for nearly 3 years,
- B-42 (LBA24): after 16 years, extended letrozole lowers distant recurrence (9.7% to 6.9%) with no OS gain. A choice for the individual patient,
- lidERA (538RO): giredestrant preserves quality of life, with less side-effect bother than standard endocrine therapy,
- JCOG1204A1 (542RO): circulating tumour DNA (ctDNA) detects relapse nearly 7 months early (HR 60). Whether acting on it changes survival is still unanswered.
Antibody-drug conjugates (ADCs) in curative HER2-low?
TALENT (LBA23): Not yet. Residual cancer burden 0/1 in only 16-17%, true pathological complete response 3-9%. HER2 levels fall on trastuzumab deruxtecan (T-DXd), TROP2 stays stable.
After the CDK4/6 inhibitor: progression-free survival (PFS) ≠ OS
- KEYNOTE-B49 (LBA51): PFS HR 0.74, OS HR 1.04,
- FINER (LBA14): OS HR 0.97, even if AKT-altered,
- postMONARCH (1RO): OS 32.1 vs 24.6 months, not significant.
New options: atirmociclib (FOURLIGHT-1, PFS HR 0.60, phase II); gedatolisib (VIKTORIA-1, active in liver metastases, no hyperglycaemia); giredestrant + everolimus (evERA, benefit across ESR1 variants and TP53/RB1-mutated tumours).
After an ADC, which ADC?
- SWITCH (4RO): a first prospective hint. New target, same topoisomerase-I payload: objective response rate 0-8%, with responses seen only after a payload switch. Small cohorts of heavily pretreated patients, but the data suggest that resistance may follow the payload more than the antigen,
Further ADC data:
- PANKU-Breast01 (LBA50): iza-bren, PFS 8.2 vs 4.0 months (HR 0.41),
- OptiTROP-Breast01 (4639RO): final OS 14.7 vs 9.9 months (HR 0.60); 30-month OS doubled (27% vs 13%).
Brain metastases
- DESTINY-Breast09 (LBA49), HER2+: Yes. Central nervous system PFS HR 0.26, intracranial response 52% vs 27%, 35% complete!
- TROPION-Breast02 (LBA96), triple-negative: PFS HR 0.37, early intracranial signal. Exploratory, small numbers, but clear!
What changes from Wednesday?
NATALEE update confirms the role of adjuvant ribociclib across the broad eligible population.
T-DXd + pertuzumab will have to be our first-line start in HER2+ metastatic disease (hopefully soon in Italy too), all the more in light of the new intracranial efficacy data: doubts about maintenance cannot undermine this first-line choice. The rest: hypotheses, many promising.
The thread holds: sequence matters as much as the drug. And the payload is part of the sequence.”
You can also read: What Changes in Breast Oncology After ESMO 2026? The Trials, Treatment Shifts, and Unanswered Questions Shaping Clinical Practice.
