ESMO Congress 2026

Palbociclib is an oral small-molecule CDK4/6 inhibitor whose position in hormone receptor-positive advanced breast cancer has been established by multiple phase III trials: in the first-line setting, PALOMA-2 showed in 666 postmenopausal patients with ER+/HER2− disease and no prior treatment for advanced disease that palbociclib plus letrozole achieved a median PFS of 24.8 months versus 14.5 months with placebo plus letrozole ^[1], building on the earlier randomized phase 2 PALOMA-1/TRIO-18 ^[2]; after progression on endocrine therapy, PALOMA-3 showed fulvestrant plus palbociclib improved PFS over fulvestrant plus placebo (median 9.2 months in the palbociclib arm) ^[4], with the final analysis confirming the benefit and including biomarker analyses ^[3], and the overall survival analysis showing median OS of 34.9 vs 28.0 months with a hazard ratio for death of 0.81 ^[5]; a review also summarized that selective CDK4/6 inhibitors deliver substantial PFS improvement with a well-tolerated profile in ER-positive advanced breast cancer ^[6].

At this meeting two palbociclib-related readouts were presented, with the main line being GEICAM's retrospective translational analysis of the phase II FLIPPER (GEICAM/2014-12) trial, presented as a poster by Dr. Federico Rojo. FLIPPER itself had demonstrated the benefit of fulvestrant plus palbociclib as first-line treatment in postmenopausal HR+/HER2− metastatic breast cancer; the new analysis used liquid biopsy to evaluate the prognostic and predictive value of ctDNA and thymidine kinase activity (TKa), including 903 serial plasma samples from 187 (99%) patients. Detection of ≥2 ctDNA mutations or elevated TKa levels, both before treatment initiation and at week 12, were independently associated with early progression and worse survival: ≥2 mutations correlated more closely with worse prognosis in patients treated with fulvestrant, whereas elevated TKa indicated worse prognosis in those receiving fulvestrant plus palbociclib. Integrating both biomarkers identified a high-risk subgroup representing 7% of analyzed patients, with PFS roughly two times shorter and probability of early progression more than six times higher; molecular follow-up also revealed increases in ESR1 and TP53 mutations at progression. The other readout is the VIKTORIA-1 Study 2 update: in PIK3CA-mutant HR+/HER2− advanced breast cancer, gedatolisib + fulvestrant + palbociclib maintained its PFS benefit over alpelisib + fulvestrant, at 9.8 vs 5.6 months (HR 0.52), with benefit observed both with and without visceral metastases (HR 0.38 and 0.46, respectively); the median PFS reported at ASCO26 was 11.1 months.

In terms of the step beyond existing knowledge, PALOMA-3 had emphasized the need to identify patients most suitable for adding palbociclib after endocrine resistance ^[3]; the FLIPPER translational analysis moves the biomarker question forward to the first-line setting and shows that integrating two circulating biomarkers can quantify a clearly ultra-high-risk subgroup, while the dynamic evolution of ESR1 and TP53 during treatment offers clues for research on resistance mechanisms and subsequent therapeutic strategies. VIKTORIA-1 Study 2 is an exploratory comparison of different PI3K pathway inhibition regimens in the PIK3CA-mutant population, with palbociclib appearing as a component of the triplet regimen.

Regarding limitations: FLIPPER is a retrospective analysis with the high-risk subgroup accounting for only 7%, and the biomarker combination still requires prospective validation; in VIKTORIA-1 Study 2, the contribution of palbociclib remains unclear, and IV administration continues to be a practical limitation.