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Ref Type abstract
PMID
Authors C.E. Heilig,M. Singh,M-V. Teleanu,A. Desuki,T. Kindler,M. Bitzer,B.D. Baier,V. Kunzmann,N. von Bubnoff,H. Süsse,L. Heiligenthal,K. Steindorf,A. Benner,S. Kreutzfeldt,C. Heining,P. Horak,D. Hübschmann,H. Glimm,S. Fröhling,R.F. Schlenk
Title 187P Ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity: First results from the CRAFT trial
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 34 Suppl_2 2023 S256-S257
URL https://www.annalsofoncology.org/article/S0923-7534(23)03748-1/fulltext
Abstract Text CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) is an open-label, 7-arm, cross-entity phase 2 trial investigating the efficacy of combinations of molecularly targeted agents and PD-L1 inhibition with atezolizumab in cancers with targetable molecular alterations (PMID: 34808524). We report the interim efficacy analysis of ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity. Methods Adult patients with locally advanced/metastatic cancer refractory to ≥1 medical treatment and selected molecular tumor characteristics (arm 1: BRAF V600E/K mutations; arm 2: ERBB2 amplification/overexpression, activating ERBB2 mutations; arm 3: ALK rearrangements/ALK mutations; arm 4: aberrations predicting increased PI3K-AKT pathway activity; arm 5: activating PIK3CA mutations; arm 6: aberrations predicting increased RAF-MEK-ERK pathway activity; arm 7: alterations predicting anti-PD-L1/anti PD-1 sensitivity) were eligible. Main exclusion criteria were hematologic/primary brain cancers. In arm 4, ipatasertib 400 mg q.d. was given in a 21-days-on/7-days-off schedule, and atezolizumab was administered every 3 weeks. Statistics are based for each arm on a Simon’s optimal 2-stage design with 14 patients accrued in stage 1 and 11 additional patients if ≥4 patients achieve the primary endpoint, i.e., disease control (complete/partial remission [PR] or stable disease [SD]) at day 110. Results Until 04/2023, 51 patients were registered, and 28 were treated. Thirteen patients with various cancers and PI3K-AKT-activating alterations (PTEN deletion/loss-of-function mutation: n=8; activating PIK3CA mutation: n=2; activating AKT1 mutation: n=3) were enrolled in arm 4. One patient with breast cancer and a homozygous AKT1 E17K and one patient with prostate cancer and PTEN loss achieved a PR and SD, respectively. None of the remaining 11 patients reached the endpoint. Toxicity was mainly gastrointestinal and manageable. Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5). Clinical trial identification NCT04551521, EudraCT 019-003192-18.

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