Recent Progress in the Biomarker Landscape for Gastrointestinal Malignancies

TOP - July 2021 Vol 14, No 4 - Sarlis Says
Nicholas Sarlis, MD, PhD, FACP
Chief Science Officer, The Lynx Group, LLC

Sarlis Says

Gastrointestinal (GI) malignancies account for 26% of the global cancer incidence and 35% of all cancer-related deaths.1 There is an urgent need for new therapeutic options for patients with advanced disease beyond the standard, highly burdensome combinatorial approach of polychemotherapy, radiotherapy, and surgery.1 Recent advances in tumor molecular profiling are transforming the therapeutic landscape for patients with GI cancers, allowing for prognostication and predictive risk assessment, as well as more individualized regimens that can extend survival while minimizing the side effects that have long been associated with existing “legacy” treatment options.

In the near future, we can expect that treatment plans for an increasing number of GI cancers will be dictated by novel biomarkers, with the choice of therapy fine-tuned for very specific populations. In fact, this is such a significant leap forward, the American Society of Clinical Oncology (ASCO) has named “molecular profiling driving progress in GI cancer” one of the most notable advances of 2021.1

Targeting HER2-Positive Tumors

Approximately 25% of GI cancers overexpress the HER2 protein.1 As a result, the monoclonal antibody trastuzumab (Herceptin) combined with chemotherapy is currently the standard first-line targeted treatment for patients with this type of cancer.1

Building on the paradigm of using targeted agents along with chemotherapy in colorectal cancer (CRC)—including treatments that mitigate the hyperactivity of signaling pathways dependent on the epidermal growth factor receptor (EGFR) in RAS wild-type tumors and the vascular endothelial growth factor receptor—we are now seeing encouraging results with trastuzumab deruxtecan (Enhertu), a novel antibody−drug conjugate that interrupts DNA replication in cancer cells,1 in the treatment of HER2-positive GI cancers, which, in the case of CRC, comprises approximately 2% to 5% of all diagnoses.2

In the phase 2 DESTINY-CRC01 clinical trial, which included patients with metastatic CRC whose disease had progressed after ≥2 treatment regimens, nearly half (45.3%) of those treated with trastuzumab deruxtecan experienced an objective response.2 Trastuzumab deruxtecan is currently being studied in DESTINY-CRC02, a phase 2 follow-up trial enrolling patients with locally advanced, unresectable, or metastatic CRC who have experienced disease progression following treatment with standard-of-care chemotherapy.3

Moreover, based on the positive results of the phase 2 DESTINY-Gastric01 trial,4 trastuzumab deruxtecan was recently approved by the FDA for the treatment of patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a previous trastuzumab-based regimen. Of note, approximately 20% of gastric or GEJ adenocarcinomas are classified as HER2-positive at the time of diagnosis.

But, what about the approximately 80% and 90% of patients with gastric cancer and CRC, respectively, whose tumors are HER2-negative or whose HER2 tumoral expression status is unknown? This past year has offered a wealth of exciting news for them as well. Let’s consider a few additional recent advances.

Modulating the PD-1/PD-L1 Pathway

A rich molecular pathway for immunotherapy options in GI cancer is the PD-1/PD-L1 pathway, whereby the associated biomarker (ie, PD-L1) has a prevalence of tumor expression of approximately 60% in advanced gastric cancers. In this tumor type, PD-L1–positive expression, as per a combined positive score (CPS) >10 as assessed with the companion diagnostic (CDx) PD-L1 immunohistochemistry (IHC) 22C3 pharmDx (Agilent/Dako) assay, has been shown to positively correlate with overall survival.5 This association was discovered in a subanalysis of 3 clinical trials of pembrolizumab (Keytruda), namely, KEYNOTE-059 (post-hoc), KEYNOTE-061 (post-hoc), and KEYNOTE-062 (primary).5 Agents targeting the PD-1/PD-L1 pathway, including the anti–PD-1 monoclonal antibodies pembrolizumab, nivolumab (Opdivo), and tislelizumab (BGB-A317), have all demonstrated significant antitumor activity in patients with advanced gastric and GEJ cancer.

Pembrolizumab is among the preferred second-line treatment options for patients with mismatch repair-deficient (dMMR) gastric cancer.5 Although the survival benefit seen with pembrolizumab in earlier studies of metastatic gastric and GEJ cancer was established in microsatellite instability-high (MSI-H) tumors or tumors with PD-L1 expression CPS ≥10, the FDA recently approved this agent for the treatment of patients with locally advanced unresectable or metastatic esophageal and GEJ cancer, regardless of PD-L1 expression status and tumor histology, based on results from the phase 3 KEYNOTE-590 clinical trial.5,6 Of note, pembrolizumab is also approved for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR CRC based on results from the phase 3 KEYNOTE‑177 study. Final results from this study were presented at the virtual 2021 ASCO Gastrointestinal Cancers Symposium.7

In addition, the FDA recently approved the PD-1 inhibitor nivolumab in combination with chemotherapy for advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, based on results from the phase 3 CheckMate-649 study; this was an accelerated approval based on overall response rate and duration of response data. It is interesting to note that although the main efficacy outcome measures were assessed and reported in patients with PD-L1 expression CPS ≥5 (assessed using the CDx PD-L1 IHC 28-8 pharmDx [Agilent/Dako] assay), the FDA-approved label is broader and essentially includes all patients irrespective of tumoral CPS value.8 The initial results from this study were presented at the virtual European Society for Medical Oncology Virtual Congress 2020.9

Targeting Claudin 18.2

The tight junction molecule claudin 18.2 (CLDN18.2) is selectively expressed in healthy and malignant gastric epithelial tissue, and it is a tantalizing target for novel therapies, particularly because it appears to be overexpressed in approximately 40% of advanced gastric cancers with significantly higher expression in cancer cells than in normal tissue.10,11 In the recently published final report from the phase 2 FAST clinical trial, treatment with zolbetuximab (IMAB362), an investigational monoclonal antibody that specifically binds to CLDN18.2, appeared to produce significant improvements in progression-free survival and overall survival when added to the combination of epirubicin, oxaliplatin, and capecitabine compared with the combination alone.10 As a result of these promising findings, zolbetuximab is currently being studied in 2 ongoing large, randomized, pivotal phase 3 studies in metastatic gastric cancer and GEJ cancer (SPOTLIGHT and GLOW, respectively). The companion diagnostic that is concomitantly being developed uses a Roche Ventana Medical Systems platform with the antibody clone 43-14A and defines CLDN18.2 tumor tissue positivity at a threshold of ≥75% of tumor tissue staining 2+/3+ on IHC.

Targeting RTK Fusions

CRCs associated with receptor tyrosine kinase (RTK) fusions are rare, but these oncogenic fusions offer promising therapeutic targeting opportunities. An article by investigators at the Dana-Farber Cancer Institute, Boston, MA, published in March 2021, identified 12 of these fusions, which occurred exclusively in BRAF and RAS wild-type tumors.12 RTK fusions appear to predict resistance to EGFR-directed therapy, although further investigation is needed to confirm these findings. The researchers described 2 patients with fusion-associated cancer who benefited from therapeutic targeting of their translocations. The first patient, with a tumor expressing a CAD-ALK fusion construct, responded sequentially to the ALK inhibitors crizotinib (Xalkori) and alectinib (Alecensa), whereas the second patient, whose tumor bore a GOPC-ROS1 fusion, responded to the ROS1 inhibitor entrectinib (Rozlytrek).12

Targeting CEACAM7

With a 5-year survival rate of <5%, pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at a late stage and is resistant to conventional therapies.13 Chimeric antigen receptor (CAR) T-cell therapy, which has been shown to be effective in B-cell malignancies, has thus far proven elusive in solid tumors due to the following: (1) there is a lack of differentiation in CAR T-cell target antigen expression between malignant and normal cells; (2) CAR T-cells only recognize extracellular epitopes; and (3) there is a need for these antigens to be expressed in high density in a given tumor to be optimally targeted by CAR T-cells. Thus, it is not surprising that trials of CAR T-cells targeting antigens, such as HER2 and mesothelin, in patients with PDAC have shown limited efficacy to date.

However, earlier this year, investigators from the United Kingdom and Canada reported on CEACAM7, a member of the carcinoembryonic antigen family of genes with expression restricted to the colon and pancreas, which may open up PDAC to the option of applying CAR T-cell therapy with potentially clinically meaningful effectiveness. They found that CEACAM7 is expressed in high density in a large subset of PDAC tumors, but only at a low to undetectable level in all normal tissues tested. The investigators developed a CAR T-cell therapy that could specifically and effectively target these CEACAM7-expressing PDAC cells in patient-derived xenograft tumors, thus offering a promising new therapeutic avenue for patients with PDAC, with a potentially higher margin of safety than previous CAR T-cell targets being developed in this and other GI malignancies.13


These examples of recent fundamental advances in clinical and translational research are solidifying the paradigm whereby treatment choice in these GI malignancies will continue to be driven by biomarker-selected strategies. Moving forward, we must continue to focus on optimizing new blood- and tissue-based biomarkers that predict response and resistance to immunotherapies, targeted therapies, and other multimodality treatments. The technologies used for biomarker detection, including various CDx that are inextricably linked to the regulatory approval and clinical use of novel agents, are diverse, ranging from next-generation sequencing in tumor tissue or circulating tumor DNA to MSI-H/dMMR assays, and from IHC to tumor mutational burden quantification. Although there is obvious need for further harmonization and enhanced applicability, we are moving closer to true personalized medicine in GI cancers and doing so at a rapid pace.


  1. Smith SM, Wachter K, Burris III, HA, et al. Clinical cancer advances 2021: ASCO’s report on progress against cancer. J Clin Oncol. 2021;39:1165-1184.
  2. Siena S, Di Bartolomeo M, Raghav K, et al; for the DESTINY-CRC01 Investigators. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2021 May 4. Epub ahead of print.
  3. Daiichi-Sankyo. DESTINY-CRC02 phase 2 trial of ENHERTU initiated in patients with HER2 overexpressing advanced colorectal cancer. April 6, 2021. Press release. Accessed May 17, 2021.
  4. Shitara K, Bang Y-J, Iwasa S, et al; for the DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382:2419-2430.
  5. Wainberg ZA, Fuchs CS, Tabernero J, et al. Efficacy of pembrolizumab monotherapy for advanced gastric/gastroesophageal junction cancer with programmed death ligand 1 combined positive score ≥10. Clin Cancer Res. 2021;27:1923-1931.
  6. Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(suppl_4):S1192-S1193.
  7. Shiu K-K, Andre T, Kim TW, et al. KEYNOTE-177: phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. J Clin Oncol. 2021;39(3_suppl):Abstract 6.
  8. US Food and Drug Administration. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. April 16, 2021. Press release. Accessed May 17, 2021.
  9. Moehler M, Shitara K, Garrido M, et al. Nivolumab plus chemotherapy vs chemo as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. ESMO Virtual Congress 2020. Abstract LBA6_PR. Presented September 21, 2020.
  10. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32:609-619.
  11. Moran D, Maurus D, Rodhe C, Arozullah A. Prevalence of CLDN18.2, HER2 and PD-L1 in gastric cancer samples. Ann Oncol. 2018;29:viii32.
  12. Singh H, Li YY, Spurr LF, et al. Molecular characterization and therapeutic targeting of colorectal cancers harboring receptor tyrosine kinase fusions. Clin Cancer Res. 2021;27:1695-1705.
  13. Raj D, Nikolaidi M, Garces I, et al. CEACAM7 is an effective target for CAR T-cell therapy of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2021;27:1538-1552.
Last modified: August 3, 2021