For patients with advanced/metastatic gastric adenocarcinomas in progression after a first line chemotherapy comprising platinum and fluoropyrimidine, the reported second line treatments are : 1) paclitaxel combined with ramucirumab (overall response rate (ORR) = 25%; median progression free survival (PFS) = 2.9 months; median overall survival (OS)= 5.9 months), or paclitaxel alone (ORR = 14%, median PFS = 2.9 months; median OS= 5.9 months); 2) docetaxel (ORR = 7%, median OS = 5.2 months) or 3) irinotecan (ORR = 0%, median OS= 4.0 months). These numbers demonstrate the poor prognosis of this disease, and the unmet medical need for innovative therapeutic strategies. Cancer Genome Atlas (TCGA) mapped a genomic landscape of gastric adenocarcinomas, and identified 4 sub-types: * Tumor positive for Epstein-Barr virus (EBV) (8%), which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, ErbB2, PD-L1 and PD-L2; * Microsatellite instable tumors (MSI-high) (22%), which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins (PIK3CA, ErbB2, ErbB3, and EGFR); * Genomically stable tumors (20%), which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; * Tumors with chromosomal instability (50%), which show marked aneuploidy and focal amplification of receptor tyrosine kinases and VEGFA. Most of diffuse-type gastric adenocarcinomas were classified in genomically stable tumors. This subgroup of cancers, accounting for about 20 to 30% of gastric adenocarcinomas, is associated with particularly poor prognosis and resistance to chemotherapy. A proteomic landscape of diffuse-type gastric adenocarcinomas was recently reported. Pembrolizumab, an anti-PDL1 drug granted with an accelerated approval by FDA in September 2017, exhibited promising activity in gastric adenocarcinoma patients previously treated with 1 or 2 lines of chemotherapy (ORR=11.6%, median PFS = 2.0 months, median OS= 5.6 months), especially in those with PDL1 positive tumors (ORR=22.7%). The tumor response was particularly high in patients with MSI-high tumor (ORR=57.1%). However the preliminary outcomes of the phase III KEYNOTE-061 trial (NCT02370498) recently released in the press suggest that pembrolizumab was not superior to paclitaxel in 592 patients with advanced gastric or gastroesophageal junction adenocarcinoma whose disease progressed after first-line treatment with platinum and fluoropyrimidine doublet therapy (the hazard ratio (HR) for OS was 0.82 (95% confidence interval = 0.66-1.03; one sided P = .042) (http://www.ascopost.com/News/58377). These outcomes suggest that, although being very promising, immunotherapy should be combined to other agents for being fully effective in gastric adenocarcinomas patients. We propose a strategy based on molecular features to select the drugs that will be associated with atezolizumab, an anti-PDL1 drug, in patients with pre-treated advanced gastric adenocarcinomas: * Patients with tumors positive for EBV or microsatellite instable tumors (30%) will be treated with atezolizumab and ipatasertib. * Patients with genomically stable tumors (20%) will be treated with atezolizumab combined with bevacizumab. * Patients with tumors with chromosomal instability (50%) will be treated with atezolizumab combined with bevacizumab. Expected outcomes: IMMUNOGAST trial will provide data about the clinical feasibility of biomolecular characterization of gastric adenocarcinomas for routine treatment adjustment. Moreover it should generate information about the relevance of adjusting combined immunotherapies based on molecular subtypes, in terms of clinical efficacy. Finally, translational research project outcomes should provide important data about relationships between efficacy and tumor immune gene spatial expression, along with tumor and circulating mutational burden. These outcomes may help identify the best candidates for tested combinations in the future.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Atezolizumab IV (1200 mg on day 1 of each 21-day cycle) and Ipatasertib PO (400 mg per day continuously, starting on cycle 1 day 1). Treatment given until disease progression or unacceptable toxicity.
Atezolizumab IV (1200 mg on day 1 of each 21-day cycle) and Bevacizumab IV (15 mg/kg on day 1 of each 21-day cycle). Treatment given until disease progression or unacceptable toxicity.
Dijon - Centre Georges-Francois Leclerc
Dijon, France
NOT_YET_RECRUITINGHcl - Hopital Edouard Herriot
Lyon, France
NOT_YET_RECRUITINGAphm - Hopital La Timone
Marseille, France
NOT_YET_RECRUITINGAphp - Hopital Saint-Louis
Paris, France
NOT_YET_RECRUITINGAphp - Hopital Pitie Salpetriere
Paris, France
NOT_YET_RECRUITINGBordeaux - Hopital Haut-Leveque
Pessac, France
NOT_YET_RECRUITINGHcl - Centre Hospitalier Lyon Sud
Pierre-Bénite, France
RECRUITINGHcl - Centre Hospitalier Lyon Sud
Pierre-Bénite, France
NOT_YET_RECRUITINGToulouse - Iuct Rangueil-Larrey
Toulouse, France
NOT_YET_RECRUITINGObjective response rate
Objective response rate, using iRECIST, defined as the percentage of patients experiencing a complete response or a partial response, as their best tumor responses during the whole treatment period
Time frame: Through the expected duration of the treatment, an average of 27 weeks and a maximum of 2 years (estimated)
Overall survival
The overall survival (OS) will be measured from the date of inclusion to the date of death or to the end of the study or in a complementary study (to collect vital status and date of death, every 3 months for 5 years for patients alive at the end of the study).
Time frame: From the date of inclusion (Day -28 to Day 0) to the date of death or to the end of the study or in a complementary study (to collect vital status and date of death, every 3 months for 5 years for patients alive at the end of the study
Progression-free survival
The progression-free survival (PFS) will be evaluated according to iRECIST criteria.
Time frame: From the date of inclusion (Day -28 to Day 0) to the date of disease progression, or death or to the end of the study up to 52.5 months
Safety, treatment-related adverse events
Treatment-related adverse events are defined as the nature, number and grade of adverse events observed throughout the study and assessed using NCI-CTCAE v.5.0 criteria.
Time frame: 100 days after the last experimental treatment
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.