ESMO Congress 2026

PIK3CA is one of the most well-grounded targetable pathways in oncology. In the comprehensive molecular portrait study of breast cancer, only three genes—TP53, PIK3CA and GATA3—were mutated at >10% incidence across all breast cancers, with PIK3CA mutations enriched in the luminal A subtype^[1]; PIK3CA is a frequently mutated gene in endometrial carcinoma^[4], EBV-positive gastric cancers display recurrent PIK3CA mutations^[3], and HPV-associated head and neck squamous cell carcinomas are dominated by helical domain mutations of PIK3CA^[5]. This cross-tumor-type evidence underpins the biological rationale for the PIK3CA-pathway-targeting asset class, and explains why the PIK3CA-mutant population in HR+/HER2− breast cancer has long been a central setting for targeted combinations after endocrine therapy.

At ESMO 2026, Celcuity presented updated results from the PIK3CA MT cohort of the Phase 3 VIKTORIA-1 study in patients with HR+/HER2− advanced breast cancer previously treated with CDK4/6 inhibitors. Live posts indicate that gedatolisib-based regimens (gedatolisib+palbociclib+fulvestrant and gedatolisib+fulvestrant) improved PFS versus alpelisib+fulvestrant, with treatment discontinuations due to adverse events of 4–5% vs 19%; another Japanese-language post added that the addition of gedatolisib provided benefit almost regardless of PIK3CA pathway mutation status. Specific PFS values and hazard ratios were not disclosed in the posts.

Relative to prior knowledge, the step forward in this readout is that in the post-CDK4/6i population—where new options are urgently needed—gedatolisib regimens not only extended PFS versus alpelisib+fulvestrant but also reduced AE-related discontinuation from 19% to 4–5%, sending a clear signal on tolerability; the observation that benefit appears almost independent of PIK3CA pathway mutations suggests the benefiting population may be broader than PIK3CA mutation itself. Notably, another post in the same discussion argued that CDK4 inhibitors will likely enter routine breast cancer care, and that 2nd-line endocrine therapy faces a choice between biomarker-guided treatment based on ESR1, PIK3CA/AKT1/PTEN alterations and direct CDK4 inhibition, with the latter's advantage being that no CDx is required. This view aligns directionally with the gedatolisib signal of not strictly depending on PIK3CA pathway mutations, both pointing to the need to reassess biomarker strategies.

On limitations: the live posts did not provide specific PFS numbers, hazard ratios, or follow-up maturity, and OS data were not disclosed; whether the comparison against alpelisib+fulvestrant was a randomized head-to-head design, and the sample size and testing definitions underlying the 'independent of pathway mutations' conclusion, remain to be confirmed with full data.