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Biomarker Testing and Novel Targeted Agents in the Management of Gastrointestinal Cancers: Experts Address FAQs

John L. Marshall, MD

Chief, Division of Hematology/Oncology
Department of Medicine
Georgetown University Hospital
Washington, DC

John L. Marshall, MD: consultant/advisor/speaker: Bayer, Merck, Pfizer, Taiho, Caris; salary: Indivumed.

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Michael J. Pishvaian, MD, PhD

Associate Professor
Sidney Kimmel Cancer Center
Johns Hopkins University
Clinical Research, GI and Phase I Oncology in the National Capital Region
Johns Hopkins at Sibley Memorial Cancer Center
Washington, DC

Michael J. Pishvaian, MD, PhD: consultant/advisor/speaker: AstraZeneca, Merck, Novartis, Pfizer; researcher: Arcus Bio, Ideaya, Merck, Novartis, Pfizer, Repare Tx, Seattle Genetics, Takeda, Tesaro, Tizonia; ownership/intellectual property: AbbVie, Perthera.

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Manish Shah, MD

Bartlett Family Professor of Gastrointestinal Oncology
Solid Tumor Services
Director, Gastrointestinal Oncology Program
Weill Cornell Medical College
 New York, New York

Manish A. Shah, MD: researcher: Bristol-Myers Squibb, Merck.

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Released: August 22, 2022

Key Takeaways

  • HER2 testing should be performed for patients with metastatic gastric and colorectal cancer, as several HER2-targeted agents are effective for patients with HER2-positive disease.
  • NTRK fusion testing can identify rare but actionable alterations and should be a standard part of initial molecular profiling in advanced gastrointestinal cancers to guide treatment choices with TRK inhibitors.
  • Exciting recent data have suggested the potential of PD-1 inhibition to be highly efficacious for patients with locally advanced microsatellite instability–high/mismatch repair deficient rectal cancer.

In this commentary adapted from a discussion among John L. Marshall, MD; Michael J. Pishvaian, MD, PhD; and Manish A. Shah, MD, the experts address important clinical questions about how to integrate biomarker testing into treatment strategies for patients with gastrointestinal cancers.

What barriers to biomarker testing exist in gastrointestinal cancers?

Michael J. Pishvaian, MD, PhD:
Multiple barriers can prevent optimal biomarker testing in gastrointestinal cancers. These can include increasingly complicated biomarker panels and the cost of next-generation sequencing. Although a biopsy often is required for optimal determination of biomarker status, access to biopsies can be challenging, and sample size may be insufficient for testing.

John L. Marshall, MD:
While liquid biopsies can be useful, they are often less informative than tissue-based testing.

How will new data on neoadjuvant PD-1 inhibition for microsatellite instability (MSI)–high rectal cancer impact clinical practice?

John L. Marshall, MD:
At the 2022 American Society of Clinical Oncology Annual Meeting, Cercek and colleagues presented results from a phase II study of curative-intent therapy with the PD-1 antibody dostarlimab for patients with stage II/III mismatch repair (MMR) deficient rectal cancer. Patients received single-agent dostarlimab 500 mg IV every 3 weeks for 9 cycles; those patients who achieved a complete clinical response underwent a nonoperative surveillance period, and those who had residual disease received chemoradiotherapy (CRT) and, potentially, surgery.

Initial results showed that, of the 14 patients who completed dostarlimab treatment, all achieved a complete clinical response after dostarlimab, and no patient required CRT or surgery, with no recurrences to date. These are remarkable results for initial therapy in locally advanced rectal cancer. Historically, the standard of care for these patients has been CRT followed by surgery. This trial was essentially designed to answer the question of whether a complete response with dostarlimab can indicate patients with rectal cancer who do not need CRT or surgery and can be observed instead. It will be important to follow patients long enough to gain a definitive answer, and I expect that the eventual real-world experience will be slightly less impressive than these provocative early data.

What tests should be used to determine if a patient with gastrointestinal cancer has an NTRK fusion? What TRK-targeted agents are available?

John L. Marshall, MD:
NTRK gene fusions generally occur in fewer than 5% of gastrointestinal cancers. Both larotrectinib and entrectinib are TRK inhibitors currently approved for adult and pediatric patients with solid tumors and an NTRK gene fusion without an acquired resistance mutation who have metastatic disease or are not candidates for surgery and have either progressive disease or no satisfactory treatment options.

To be eligible to receive one of these agents, an NTRK gene fusion must be detected by an FDA-approved companion diagnostic test. NTRK testing should be part of physicians’ standard initial molecular profiling for patients with metastatic gastrointestinal cancer. It is important to determine the presence of this alteration as early as possible. Originally, rare fusions such as NTRK were detected with immunohistochemistry, but this is an imperfect approach, as it cannot detect the position of a fusion partner. Today, many clinics use next-generation DNA sequencing to detect the 3 potential NTRK gene fusions. Even more accurate results can be obtained with RNA sequencing to detect these fusions. Response rates with the approved TRK inhibitors are very impressive, and although it is rare to find an NTRK fusion, it can be like finding a golden ticket for your patient.

Even when patients have an NTRK fusion and receive larotrectinib or entrectinib, there is a possibility that second-line therapy (and later lines of therapy) will be needed. Patients with NTRK fusions also should be tested for resistance mutations after progression on a TRK inhibitor.

Repotrectinib and selitrectinib are second-generation investigational TRK inhibitors. In a phase I study in NTRK fusion–positive solid tumors, among patients who had progressed or were intolerant to ≥1 prior TRK inhibitor, selitrectinib treatment resulted in a 34% overall response rate (ORR). Repotrectinib was evaluated in the phase I/II TRIDENT-1 study, which enrolled patients with NTRK-positive solid tumors. In the subgroup of patients with previous TRK tyrosine kinase inhibitor therapy, ORR with this therapy was 43%.

How should patients with HER2-positive metastatic colorectal cancer (CRC) be managed?

John L. Marshall, MD:
It is very important to test patients with metastatic CRC for HER2 amplifications. This is important because, if they have a HER2-positive cancer, they should not receive an EGFR inhibitor, which is a standard of care in CRC. I had a patient with metastatic CRC who had no detected genetic mutations and received an EGFR inhibitor for only a cycle or two before he progressed. That didn’t make sense to me, as patients typically respond to this therapy. I reviewed his history and found that he never had been tested for HER2; we tested him, and he was HER2 positive.

Several HER2-targeted agents may be useful options for patients with HER2-positive metastatic CRC, including the HER2-targeted antibodies pertuzumab and trastuzumab, the HER2-targeted tyrosine kinase inhibitors lapatinib and tucatinib, and the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd). Pertuzumab, lapatinib, and tucatinib each have been associated with high response rates in combination with trastuzumab for patients with HER2-positive metastatic CRC. Results from the phase II MOUNTAINEER trial of tucatinib plus trastuzumab for patients with HER2-positive, chemotherapy‑refractory, RAS wild‑type metastatic CRC recently were presented at the 2022 European Society for Medical Oncology World Congress on Gastrointestinal Cancer and showed a 38% ORR with this combination in this patient population. It is important to note that none of these options is currently approved for CRC, but national guidelines recommend the use of HER2-targeted agents for specific patients with HER2-positive metastatic disease.

What data support the use of trastuzumab deruxtecan in patients with gastric cancer?

Manish A. Shah, MD:
T-DXd is approved for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. T-DXd was approved based on results from the randomized DESTINY-Gastric01 study in patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer and progression on ≥2 prior regimens. In this study, ORR was 51% with T-DXd vs 14% with physician’s choice chemotherapy, and median overall survival was 12.5 months vs 8.9 months, respectively (HR: 0.60). Median progression-free survival also was improved at 5.6 months for T-DXd vs 3.5 months for chemotherapy.DESTINY-Gastric02 was a single-arm phase II study of T-DXd in Western patients with HER2-positive advanced gastric/gastroesophageal cancer after progression on first-line trastuzumab. In this trial, ORR was 38%, and median progression-free survival was 5.5 months.

If patients with pancreatic cancer are platinum sensitive, do they still need BRCA testing?

Michael J. Pishvaian, MD, PhD:
Next-generation sequencing testing remains important in this situation. We need to know if the patient has a BRCA mutation or if they developed a BRCA reversion, or if they have completely different alterations. Platinum sensitivity or refractoriness does not necessarily indicate DNA damage repair alterations.

Your Thoughts?
How do you employ biomarker testing to guide the treatment of patients with gastrointestinal cancers? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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