Gastrointestinal Malignancies: Actionable Takeaways from the 2023 Precision Oncology Summit

Basic Science in Gastrointestinal Precision Oncology

Basic studies of GI cancers investigate how the process by which these tumors start, grow, and then spread to other organ sites, and how to noninvasively measure that growth, through modalities such as cellular genomics, molecular spatial analysis, and cell free molecular analysis. GI cancers are characterized by genetic diversity. Initiating and cooperative drivers lead to increased cellular heterogeneity with eventual formation of cancer cells. Many cancer driver mutations and chromosomal rearrangements can be identified via whole genome analysis. Single cell analysis can also identify genetic and genomic alterations.

Citing an example of a digestive tract cancer and its corresponding molecular and cellular changes, a cascade of histopathologic changes due to an inciting infectious organism can lead to chronic gastritis, followed by atrophic gastritis, followed by intestinal metaplasia and finally gastric cancer. Early cancer cells have characteristic features that can be identified using new experimental methods such as spatial gene expression, prior to the development of an invasive malignancy, representing an earlier time point. The tumor microenvironment promotes growth and metastatic spread and has characteristic features that can be detected via single cell and spatial molecular analysis.¹ Finally, tumor growth and molecular changes can be monitored from the blood, as methylation sequencing in colorectal cancer for example can provide a means for longitudinal tracking of metastatic colon cancer.²

Translational Science Considerations in GI Malignancies

Progress has stalled in reducing mortality from GI malignancies as compared to other solid malignancies, and there is an urgent need for new FDA-approved drugs in this sphere.³

Translational efforts are key to bringing successful therapeutic options to the GI oncology clinic. One example is the exploration of KRAS G12C inhibitors in colorectal cancers (CRC). Those targeted therapies are FDA-approved for non-small cell lung cancer but have shown limited efficacy in CRC due to high levels of RTK signaling by CRC tumors which confer resistance.⁴ Translational studies, however, demonstrate the potential of cetuximab combinations in improving clinical efficacy, via reversal of this resistance mechanism.⁵

A phase 1/2 study of adagrasib and cetuximab reveals an improvement in median PFS of 6.9 months vs 5.6 months with adagrasib alone.⁶ Interim results of a phase 1 trial of GDC-6036, a next generation G12C inhibitor, in combination with cetuximab has shown a confirmed ORR of 62%, as presented by Desai et al. in the 2023 American Association for Cancer Research annual meeting.

In conclusion, progress in GI oncology relies on further translational research that can pave the way towards enhancing our current therapeutic options.

Precision Oncology in Biliary Tract Malignancies

Biliary tract malignancies are notable for their anatomic and genomic heterogeneity, and potential for targeted therapies against mutated oncogenes. Approximately one third of patients with intrahepatic cholangiocarcinoma (ICC) have targetable mutations such as FGFR2 fusions and rearrangements, IDH1 mutations and BRAF V600E mutations.

While detection of FGFR2 fusions can be difficult, they are present in about 10% of patients with ICC. Pemigatinib, an ATP-competitive FGFR inhibitor was approved here in the US in 2020 after demonstrating ORR of 35.5% and a median PFS of 6.9 months.⁷ Futibatinib, a covalent inhibitor, received accelerated approval in the US in 2022, with a median PFS of 9 months, and median OS of 21.7 months in the second line setting for FGFR2-rearranged cholangiocarcinoma.⁸

IDH1 mutations occur in approximately 13% of ICC.⁹ Ivosidenib, a selective oral inhibitor of mutant IDH1, was approved in 2021 after the ClarIDHy trial demonstrated an improvement in median PFS of 2.7 vs 1.4 months, median OS 10.3 vs 7.5 months and ORR of 2% vs 0% as compared to placebo.¹⁰ Finally, 5-7% of patients with ICC harbor a BRAF V600E mutation and the combination of Dabrafenib with Trametinib can be utilized in this setting with promising response rates.

Future directions in the field will center around antibodies paving the way to precision enrollment in CAR T trials. Zolbetuximab is a monoclonal antibody targeting Claudin18.2, a protein expressed in the tight junction of gastric mucosa cells, and its addition to chemotherapy results in improved PFS and OS in gastric malignancies expressing Claudin 18.2.

Claudin 18.2 CAR shows early promise in gastric/GEJ malignancies, with ORR of 57.1% and 6-month OS of 81.2%¹¹ On-target and off-tumor toxicity is a major limitation to the implementation of engineered T cells targeting solid tumors, since almost all potential CAR T cell targets are also expressed on healthy tissue. Therefore, new cellular designs which build circuits for cell-cell recognition and signal integration are necessary to allow for customized sense/response programs.¹² These efforts will eventually move from bench to bedside and revolutionize our current care paradigm.

Conflict of Interest

Hanlee Ji, MD, reports travel support from Oxford Nanopore and research support from 10X Genomics.

Funding Information

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Ethical Statements

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Acknowledgement

The authors thank Drs. Chris Chen, Eric Collisson and George A. Fisher Jr for their engaging sessions during the Precision Oncology Summit meeting, which are highlighted in this manuscript.

Author Contributions

• All authors: conception and design

• All authors: data collection and assembly

• IA: data analysis, manuscript writing

All authors have approved this manuscript.