Background Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progressionfree survival in patients with aromatase inhibitor-resistant advanced breast cancer.Methods In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0•20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.

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1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.

ObjectiveTo compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3.DesignA prospective, open, randomised multicentre trial.Setting32 general hospitals located in Wales and England.Population or Sample180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment).MethodsAfter 24 weeks of treatment, complete responders were followed up at 6‐monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. Main outcome measuresTime to histologically confirmed disease recurrence (any grade of VIN).ResultsThe median length of follow up was 18.4 months. At 18 months, more participants were VIN‐free in the cidofovir arm: 94% (95% CI 78.2–98.5) versus 71.6% (95% CI 52.0–84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95–12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96–12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+.ConclusionsLong‐term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugsTweetable abstractLong‐term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.

1005 Background: Previous results from the Phase 2 FAKTION trial (NCT01992952) showed progression free survival (PFS) in patients with aromatase inhibitor (AI) resistant ER+/HER2− advanced breast cancer was significantly longer with fulvestrant plus capivasertib vs fulvestrant plus placebo. At the time of analysis, PFS benefit associated with capivasertib was not restricted to patients with activating mutations in PIK3CA (E542K, E545K, H1047R or H1047L) or PTEN protein null. We report now mature overall survival (OS) data with enhanced biomarker analysis. Methods: For the enhanced analysis, available tissue and plasma samples were sent for targeted next generation sequencing (NGS) with Foundation One CDx and GuardantOMNI assays. ‘Pathway altered’ (PA) was defined as any activating mutation in PIK3CA (exons 1,4,7,9,20) or AKT1 (E17K only) or inactivating alterations in PTEN. For samples not tested by targeted NGS, previously reported digital droplet PCR (ddPCR) results for PIK3CA were used, in addition to tissue AKT1 ddPCR analysis performed after the initial publication. Concordance between mutations identified by ddPCR and subsequent NGS was 97%. Results: In January 2022, 108 OS events were reported (77% maturity) in the intention to treat (ITT) population. The median OS was 29.3 vs 23.4 months (mo) in the capivasertib (n = 69) vs placebo (n = 71) arms respectively (HR 0.66, 95% CI 0.45–0.97; p = 0.035). In the enhanced biomarker analysis, 76 participants were classified as PA compared to 59 in the original analysis. In the PA group, OS was 39.0 vs 20.0 mo in the capivasertib vs placebo arms respectively (HR 0.46, 95% CI: 0.27–0.79; p = 0.005). Within the pathway non-altered (PNA) group, median OS was 26.0 vs 25.2 mo in the capivasertib vs placebo arms respectively (HR 0.86, 95% CI: 0.49–1.52; p = 0.60). In the updated PFS analysis, the advantage in the ITT population persisted with capivasertib vs placebo (median 10.3 vs 4.8 mo, HR 0.56, 95% CI: 0.38–0.81; p = 0.002). PFS analysis against the updated biomarker subgroups shows a significant improvement in PFS in the PA group: 12.8 vs 4.6 mo in the capivasertib vs placebo arms respectively (HR 0.44, 95% CI: 0.26–0.72; p = 0.001). In the PNA group, median PFS was 7.7 vs 4.9 mo in the capivasertib vs placebo arms respectively (HR 0.70, 95% CI: 0.40–1.25; p = 0.23). Conclusions: Updated analysis of the FAKTION trial data show a significant improvement in OS in the ITT population. Enhanced subgroup analysis suggests that the benefit of capivasertib in both PFS and OS may be predominantly in patients with PIK3CA/AKT1/PTEN pathway altered tumours, but further elucidation will be forthcoming from the ongoing Phase 3 CAPItello-291 study in which participants with PA and PNA tumours have been recruited. Clinical trial information: NCT01992952.