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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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN inact mut Advanced Solid Tumor no benefit Atezolizumab + Ipatasertib Phase II Actionable In a Phase II trial (CRAFT), treatment with Ipatasertib (GDC-0068) plus Tecentriq (atezolizumab) demonstrated safety but limited clinical benefit in advanced solid tumor patients harboring PI3K-AKT pathway mutations (n=13), including PTEN deletion/inactivating mutations or activating mutations in PIK3CA or AKT1, with a partial response in a breast cancer patient with AKT1 E17K and stable disease in a prostate cancer patient with PTEN loss (Ann Oncol (2023) 34 (suppl_2): S256-S257;NCT04551521). detail...
PIK3CA act mut Advanced Solid Tumor no benefit Atezolizumab + Ipatasertib Phase II Actionable In a Phase II trial (CRAFT), treatment with Ipatasertib (GDC-0068) plus Tecentriq (atezolizumab) demonstrated safety but limited clinical benefit in advanced solid tumor patients harboring PI3K-AKT pathway mutations (n=13), including PTEN deletion/inactivating mutations or activating mutations in PIK3CA or AKT1, with a partial response in a breast cancer patient with AKT1 E17K and stable disease in a prostate cancer patient with PTEN loss (Ann Oncol (2023) 34 (suppl_2): S256-S257;NCT04551521). detail...
PTEN del Advanced Solid Tumor no benefit Atezolizumab + Ipatasertib Phase II Actionable In a Phase II trial (CRAFT), treatment with Ipatasertib (GDC-0068) plus Tecentriq (atezolizumab) demonstrated safety but limited clinical benefit in advanced solid tumor patients harboring PI3K-AKT pathway mutations (n=13), including PTEN deletion/inactivating mutations or activating mutations in PIK3CA or AKT1, with a partial response in a breast cancer patient with AKT1 E17K and stable disease in a prostate cancer patient with PTEN loss (Ann Oncol (2023) 34 (suppl_2): S256-S257;NCT04551521). detail...