Personalized Targeted IMMUNOtherapy-based Regimens in Recurrent GASTric Adenocarcinoma (IMMUNOGAST)
Status:
Recruiting
Trial end date:
2023-10-26
Target enrollment:
Participant gender:
Summary
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.