Abstract
The treatment of advanced gastrointestinal (GI) cancers has become increasingly molecularly driven. Molecular profiling for HER2 and PD-L1 status is standard for metastatic gastroesophageal (GEJ) cancers to predict benefits from trastuzumab (HER2-targeted therapy) and pembrolizumab (anti-PD-1 therapy), while extended RAS and BRAF testing is standard in metastatic colorectal cancer to predict benefits from epidermal growth factor receptor (EGFR)-targeted therapies. Mismatch repair (MMR) or microsatellite instability (MSI) testing is standard for all advanced GI cancers to predict benefits from pembrolizumab and in metastatic colorectal cancer, nivolumab with or without ipilimumab. Here we review recent seminal trials that have further advanced targeted therapies in these cancers including Poly (adenosine diphosphate–ribose) polymerases (PARP) inhibition in pancreas cancer, BRAF inhibition in colon cancer, and isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) inhibition in biliary tract cancer. Targeted therapies in GI malignancies constitute an integral component of the treatment paradigm in these advanced cancers and have widely established the need for standard molecular profiling to identify candidates.
Highlights
Molecular studies, generation sequencing, has become more affordable and efficient in the modern era of oncology
The prevalence of deficient mismatch repair (dMMR) in GI malignancies according to a comprehensive review by Lorenzi et al was 13% for Stage 1–2 cancers, and 10%
While clinical practice will likely continue to favor chemotherapy as the first line choice in microsatellite stable gastric cancer populations, this study provided that first-line pembrolizumab may be favorable in microsatellite instability (MSI)-H high populations. [12]
Summary
Generation sequencing, has become more affordable and efficient in the modern era of oncology. P = 0.0046) and objective response rate (ORR) was 47% vs 35% (OR 1.70) [25] These results established trastuzumab and chemotherapy as first-line therapy in patients with HER2 positive metastatic gastric or GEJ adenocarcinoma. The BEACON trial, a Phase III trial involving 665 patients with BRAF V600E-mutated metastatic CRC who had progressed after one to two prior lines of therapy found that there was a median OS benefit to triplet therapy with encorafenib, binimetinib and cetuximab compared to investigator’s choice chemotherapy plus cetuximab. A notable limitation of this study was the use of placebo as the control arm because discontinuation of all treatment after 4 months of chemotherapy is not the standard of care for PDAC when patients are still receiving benefits from therapy Despite these limitations, the data from this trial led to the FDA approval of olaparib on.
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