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TAKTIC trial explores investigational AKT-blockade triplet therapy in endocrine-refractory HR+/HER2– metastatic breast cancer

Preliminary, hypothesis-generating findings on feasibility, adverse-event profile, and potential biomarker directions for an investigational, non-approved combination.

  • Seth A Wander, MD PhD; Maxwell R Lloyd, MD; Jennifer C Keenan, BS; Elizabeth C Scott, BA; Andrzej Niemierko, PhD; Laura M Spring, MD; et al.

  • May 1, 2026

  • The Lancet Oncology
  • The Lancet Oncology, Volume 27, Issue 5, Pages 580–591
  • 10.1016/S1470-2045(26)00059-8

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Evidence before this study

A formal literature search was not performed, but relevant results from the SOLAR-1 trial on aleplisib with fulvestrant for patients with PIK3CAmut metastatic breast cancer and preclinical evidence suggest that AKT1 alterations might mediate resistance to CDK4/6 inhibition. Before our TAKTIC trial, the first-in-class PI3K inhibitor alpelisib was approved in combination with fulvestrant based on the SOLAR-1 trial. Several AKT inhibitors were in active clinical development at the time of study initiation, but none had been approved for this patient population. The feasibility of using AKT inhibition after progression on CDK4/6 inhibitor-based therapy and the potential of triplet therapy incorporating an antioestrogen, a CDK4/6 inhibitor, and an AKT inhibitor were undefined.

Added value of this study

To our knowledge, these data are among the first to investigate the adverse event profile of triplet regimens incorporating AKT blockade in this treatment-refractory population and include preliminary hypothesis-generating findings, which aim to define genomic and molecular predictors of response after fulvestrant, palbociclib, and ipatasertib.

Implications of all the available evidence

Our data, along with previous and concurrent trials, show the feasibility of triplet therapy (including AKT blockade), provide new insights into potential clinical activity, and aid in the identification of genomic features, which should improve future biomarker-driven efforts to improve precision therapeutics for patients with endocrine-refractory HR+/HER2– metastatic breast cancer.

Source: The Lancet Oncology

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