John H. Strickler, MD, medical oncologist, Duke Cancer Center, Duke Health, discusses dosing strategies with regorafenib (Stivarga) in colorectal cancer (CRC).

Findings from the phase 2 ReDOS trial showed that a dose-escalation dosing strategy with regorafenib has comparable activity and fewer adverse effects compared with standard dosing.

As such, rather than pushing for the 160-mg dose of regorafenib, dosing should be tailored based on individual patients’ tolerability, says Strickler. The goal is to offer patients maximum quality of life without compromising efficacy. 

Additionally, the data from ReDOS do not suggest that patients who start at lower doses of regorafenib, such as 80 mg or 120 mg, and then gradually escalate treatment derive less benefit than those patients who begin at the full dose. As such, it is important to focus on tolerability, because higher doses of regorafenib do not necessarily confer more favorable outcomes, concludes Strickler. 

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John H. Strickler, MD, discusses dosing strategies with regorafenib in colorectal cancer.  



Dr. Strickler on Dosing Regorafenib in CRC 

John H. Strickler, MD, medical oncologist, Duke Cancer Center, Duke Health, discusses the rationale for the phase 2/3 MOUNTAINEER-02 trial (NCT04499924) in HER2-positive gastric/gastroesophageal junction (GEJ) cancer. 

MOUNTAINEER-02 is a trial in progress evaluating tucatinib (Tukysa) in combination with trastuzumab (Herceptin), ramucirumab (Cyramza), and paclitaxel versus paclitaxel and ramucirumab in patients with HER2-positive gastric/GEJ cancer. 

Tucatinib is a potent small molecule inhibitor of HER2, says Strickler. Additionally, tucatinib is highly selective for HER2, which limits off-target effects and allows the agent to be well tolerated by most patients. The adverse effects observed with tucatinib appear to be manageable based on previously reported data, Strickler says. Moreover, the tolerability of the agent allows it to be combined with other therapies, such as trastuzumab or cytotoxic chemotherapy.

Tucatinib, in combination with capecitabine and trastuzumab, is currently approved for patients with pretreated HER2-positive breast cancer. However, the agent likely has applications in other HER2-positive malignancies, such as gastric/GEJ cancer, concludes Strickler.

John H. Strickler, MD, discusses the rationale for the phase 2/3 MOUNTAINEER-02 trial in HER2-positive gastric/gastroesophageal junction cancer.  



Dr. Strickler on the Rationale for the MOUNTAINEER-02 Trial in HER2+ Gastric/GEJ Cancer 

John Strickler, MD, assistant professor of medicine at Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses genomic variants in patients with gastrointestinal (GI) cancers that can be detected by liquid biopsies.

In the GI cancers space, there are distinct scenarios in which liquid biopsies are already being utilized, including but not limited to cases where there is not enough tissue to test or when a re-biopsy of the tissue is not feasible. Additionally, it appears there are certain instances in which the sensitivity of a liquid biopsy confers an advantage over a standard tissue-based procedure, Strickler says.

Based on recent data, there may be genomic variants in the blood that may predict benefit from targeted therapies. For example, researchers have reviewed cases of 

 may be a potential targetable alteration that liquid biopsies alone can detect. In addition, a common challenge in GI cancers is when patients develop resistance to anti—EGFR therapy like cetuximab (Erbitux). Strickler notes that a liquid biopsy might be able to identify patients who could benefit from an EGFR antibody rechallenge. This entails detecting signals in the patient’s blood that signal that they may derive benefit from a therapy they progressed on.

John Strickler, MD, assistant professor of medicine, Duke Cancer Institute, discusses genomic variants that can be detected by liquid biopsies in patients with gastrointestinal cancers.

Dr. Strickler on Genomic Variants Detected by Liquid Biopsies in GI Cancers

John Strickler, MD, assistant professor of medicine at Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses therapies for rare variants of relapsed/refractory colorectal cancer (CRC).

Most of the emerging therapies and targets in patients with relapsed/refractory CRC have been in the rare genetic alterations discovered through comprehensive molecular profiling, Strickler says. Most recently, patients whose tumors express microsatellite instability—high and mismatch repair deficiency have been shown to respond to single-agent and combination checkpoint inhibitors, such as pembrolizumab (Keytruda) and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

In addition, genomic targets that have recently been evaluated include 

 mutations, which Strickler says researchers have known about for a while. When patients come into the clinic with 

-mutated CRC, there are a number of targeted therapies being evaluated that they can be matched with. For patients with 

-positive fusions, there was recently a tumor agnostic FDA approval for larotrectinib (Vitrakvi), an NTRK inhibitor that has been shown to be quite active in those patients. Strickler notes that like the other aforementioned patient populations, this genomic variant is very rare.

John Strickler, MD, assistant professor of medicine at Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses therapies for rare variants of relapsed/refractory colorectal cancer.

Dr. Strickler on Therapies for Rare Variants of Relapsed/Refractory CRC

John Strickler, MD, assistant professor of medicine, Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses the value of liquid biopsies in the treatment of patients with colorectal cancer (CRC).

Patients who are treated with targeted therapy will eventually develop resistance to those drugs. As such, acquired resistance to anti-EGFR therapy is commonly seen among patients with CRC, says Strickler. However, cell-free DNA or liquid biopsies can be used to help clinicians understand the genomic drivers of acquired resistance to these anti-EGFR antibodies.

There are several common mechanisms of resistance, including 

 ectodomain mutations, which affect antibody binding. There are also alterations such as 

 amplification. These alterations are most likely present in very low quantities in tumor tissue prior to receiving anti-EGFR therapy, notes Strickler. They will then expand under selective pressure as a result of conferred resistance to the antibody. With routine blood draws, physicians can identify those mutations and select appropriate treatment.

Dr. Strickler on the Value of Liquid Biopsies in CRC

John Strickler, MD, assistant professor of medicine, Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses applications for liquid biopsies in gastrointestinal (GI) cancer.

Currently, tissue biopsies are still the standard in routine clinical practice, but liquid biopsies are being used in select circumstances to help guide treatments for patients. Sometimes, Strickler says, there is simply not enough tissue in a patient’s tumor to perform an effective biopsy. Then, a liquid biopsy would be used. If a patient’s tumor biology is thought to have evolved over some period of time, the best choice would be to use a liquid biopsy, as a tissue biopsy may no longer be representative of the current tumor. He adds that liquid biopsies should also be used if a re-biopsy is determined to be infeasible or not in the best interest of the patient.

Researchers also believe that liquid biopsies can provide a more precise snapshot of a patient’s tumor histology because certain alterations can only be picked up in the plasma. There are several ongoing trials looking to confirm the clinical utility of this procedure.

John Strickler, MD, assistant professor of medicine, Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses applications for liquid biopsies in gastrointestinal cancer.

Dr. Strickler on Applications for Liquid Biopsies in GI Cancer

John Strickler, MD, assistant professor of medicine, Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses improvements in the treatment of metastatic colorectal cancer (mCRC).

It is an exciting time for clinical development in mCRC and gastrointestinal malignancies in general, Strickler says. There have been incremental improvements in survival with new therapies, as well as new strategies for selection. One of these strategies is cell-free DNA (cfDNA), also known as liquid biopsy, which is being used to aid in understanding the genomic drivers of acquired resistance. cfDNA has been useful thus far in the treatment of patients with mCRC, as it can identify markers that inform treatment decisions.

The paradigm is shifting, Strickler says, particularly with the use of microsatellite instability (MSI) as a tool to select patients for immunotherapy. For example, patients with mCRC who are microsatellite instability-high can receive pembrolizumab (Keytruda). There are also patients with rare alterations that are highly actionable. These patients can experience exceptional benefit if these alterations are identified and targeted, Strickler says.

John Strickler, MD, assistant professor of medicine, Duke University School of Medicine, gastrointestinal oncologist, Duke Cancer Institute, discusses improvements in the treatment of metastatic colorectal cancer.

John Strickler, MD

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