NTRK-Targeted Therapy for Patients With Colon Cancer

Cathy Eng, MD, FACP, FASCO: Regarding the mechanism of action for larotrectinib, as well as entrectinib, which is one of the other NTRK inhibitors, larotrectinib is a pan-TRK inhibitor that is an oral agent and also comes in a liquid form. It's an ATP [adenosine triphosphate]-competitive binder. In comparison, entrectinib is not only a pan-TRK inhibitor, but also impacts ROS1 and ALK. They are a little bit different; larotrectinib is specifically an NTRKinhibitor.

In regard to the efficacy of larotrectinib, the response rate is quite impressive. The response rate, the last time that I reviewed the data, was 81%, with a significant number of patients in PR [partial response] and CR [complete response]. In regard to toxicities, there were no significant, major toxicities that we would consider a concern, especially for grade 3 and 4.

In the other studies however, for entrectinib, there was some grade 3/4 toxicity in regard to fatigue that was noted and some other nonspecific toxicities, such as dysgeusia.

In regard to the duration of response, what I've gathered from the data is that there is significant duration of response for the majority of patients. This obviously can be pivotal in patients who have had refractory metastatic disease.

This patient is unique in the sense that she is treatment naïve. However, the majority of patients with surgically unresectable disease will need to continue chemotherapy or some type of treatment indefinitely. It's imperative from my perspective that all patients, number 1, should be tested for MSI [microsatellite instability] high, but also for the NTRK fusion because this provides them a different, unique opportunity for the continuum of care rather than just a standard systemic chemotherapy.

In that aspect, I would say that this class of drugs is really pivotal, especially for our patients in the refractory population who have been through multiple prior lines of therapy.

Transcript edited for clarity.

Case: A 68-Year-Old Woman With Metastatic NTRK Fusion-Positive Colon Cancer

Initial presentation

• A 68-year-old woman presented with a 3-month history of intermittent abdominal pain, and alternating constipation/diarrhea
• PMH/SH: hypertension and hypercholesterolemia, medically managed; colonoscopy at age 50 was unremarkable; never smoker; no family history of cancer
• PE: abdomen tender on deep palpation in the right lower quadrant

Clinical workup

• Labs: Hb 11.9, Hct 32%, MCV 75 fL, CEA 12.8 ng/mL
• Chest/abdominal/pelvic CT showed a 5-cm right sided bowl mass and multiple hepatic lesions, and regional lymphadenopathy
• Colonoscopy revealed a 5-cm mass in the ascending colon, biopsy was taken
• Pathology: grade 3 poorly differentiated adenocarcinoma, with invasion of the submucosa
• Biomarkers: KRAS-wt, NRAS-wt, BRAF-, NTRK+; MSI-H
• Stage TXNXM1; ECOG PS 1