187P - Ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity: First results from the CRAFT trial

Background

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.

Editorial acknowledgement

Legal entity responsible for the study

German Cancer Research Center, Heidelberg, Germany.

Funding

The trial is supported by the NCT Proof-of-Concept Clinical Trial Program and the NCT Molecular Precision Oncology Program. Study drugs are provided free of charge by Roche Pharma AG.

Disclosure

C.E. Heilig: Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, PharmaMar, Roche. A. Desuki: Financial Interests, Personal, Advisory Board: Roche, BMS, Novartis, MSD. B.D. Baier: Financial Interests, Personal, Advisory Role: Lilly. K. Steindorf: Financial Interests, Personal, Invited Speaker: Adviva, Audi Health Insurance, Murgpark Fitness, Pierre Fabre, Takeda; Financial Interests, Personal, Expert Testimony: Swiss Group for Clinical Research. C. Heining: Financial Interests, Personal and Institutional, Research Funding: Boehringer Ingelheim ; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis. P. Horak: Financial Interests, Personal, Advisory Board: Platomics; Financial Interests, Personal, Other, Honoraria: Platomics, Roche, Trillium. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Personal and Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Pfizer, AbbVie, Astellas; Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz, Pfizer. All other authors have declared no conflicts of interest.