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Armando Orlandi: Historic PROTAC Milestone and Pivotal Phase 3 Results on ASCO25 Day 2

Armando Orlandi/photos.asco.org

Jun 1, 2025, 09:36

Armando Orlandi: Historic PROTAC Milestone and Pivotal Phase 3 Results on ASCO25 Day 2

Armando Orlandi, Medical Director at the Agostino Gemelli University Hospital Foundation IRCCS, shared a post on LinkedIn:

“ASCO25 Day 2: Historic PROTAC Milestone & Pivotal Phase 3 Results.

May 31st marked a historic milestone in oncology with the first-ever PROTAC technology reaching Phase 3, alongside practice-changing results:

HISTORIC BREAKTHROUGH – FIRST PROTAC IN PHASE 3:

VERITAC-2: Vepdegestrant represents a revolutionary moment- the first Proteolysis Targeting Chimera (PROTAC) to demonstrate efficacy in a Phase 3 trial.

This novel protein degradation approach achieved superior outcomes over fulvestrant in ESR1-mutated ER+/HER2- advanced breast cancer (5.0 vs 2.1 months PFS; HR 0.57, P<0.0001). This validates an entirely new therapeutic modality, moving beyond traditional inhibition to targeted protein degradation.

PRACTICE-CHANGING PHASE 3 RESULTS:

ASCENT-04: Sacituzumab govitecan + pembrolizumab established a new first-line standard for PD-L1+ advanced TNBC, significantly outperforming chemotherapy + pembrolizumab (11.2 vs 7.8 months PFS; HR 0.65, P=0.0009; DOR 16.5 vs 9.2 months).

COMPELLING TARGETED EVIDENCE:

DESTINY-Breast06 biomarkers:

Remarkable T-DXd efficacy in BRCA1/2-mutated patients (21.4 vs 5.6 months PFS)- though small subgroup (n=36), this 4-fold improvement suggests profound activity in homologous recombination deficiency.

INAVO120: Inavolisib combination showed exceptional OS benefit in PIK3CA-mutated disease (34.0 vs 27.0 months; P=0.019).

MA.40/FINER: Confirmed AKT pathway targeting post-CDK4/6 progression (5.32 vs 1.94 months PFS; HR 0.61, P=0.0007).

PATIENT EXPERIENCE IMPROVEMENTS:

EMBER-3 PRO: Oral imlunestrant improved quality of life vs injection therapy.

DHP107: Oral paclitaxel non-inferior with reduced neuropathy.

Today’s data represents both technological evolution (first PROTAC success) and therapeutic revolution. The vepdegestrant breakthrough validates protein degradation as a viable therapeutic approach, while ASCENT-04’s impressive PFS improvement (11.2 vs 7.8 months) establishes “immediate” practice change in PD-L1+ TNBC.

The striking T-DXd activity in BRCA-mutated patients, despite limited numbers, warrants dedicated investigation in this molecularly defined population.”

Historic PROTAC Milestone

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