Cathy Eng, MD, FACP, FASCO

 fusion resistance to larotrectinib and also specifically for the NTRK inhibitors, and that is 

 G595R. There is a drug specific to that called LOXO-195, which is approved to be utilized in that setting.

I would say that basically this literature regarding the 

fusion and its significance is important across all malignancies. Although I focus specifically on colorectal carcinoma, the 

 fusion is more common in other malignancies, such as papillary thyroid carcinoma, salivary gland carcinoma, and more common in pediatric tumors.

It is advantageous for other malignancies, not necessarily colorectal carcinoma, but it appears to have a role, specifically even higher in the MSI [microsatellite instability]-high positive colorectal cancer tumors. And the fact that it's an oral agent with such significant response.

Once again, if the patient tolerates it well and given that there are several patients who we treat, on a day-to-day basis, with refractory colorectal carcinoma that are surgically unresectable, if they're 

positive, obviously this is another drug that would be advantageous in the armamentarium to treat our metastatic colorectal cancer patients.

Case: A 68-Year-Old Woman With Metastatic 

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

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

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NTRK Fusion–Positive Colon Cancer: Final Thoughts

In regard to the dosing for larotrectinib, the standard dosing is 100 mg bid [twice a day]. Once again, it comes in an oral and a liquid form. And obviously that’s advantageous for some of our patients, not necessarily just colorectal cancer patients, keeping in mind that 

There were some grade 3 toxicities, but no grade 4 or 5 toxicities.

Of the toxicity seen with larotrectinib, for grade 3 toxicities, they were fairly mild, one being anemia. That was in about 14% of patients. I would say for any oral agent, obviously you have to be very mindful of how well the patient is adhering with taking the medications as directed.

You still have to follow the patients regardless of the fact that it is more convenient for them to take an oral agent. My tendency for any oral agent is to follow the patients at least every 2 weeks for the first month. Then, give or take, maybe considering that as well for the second month. And then after that, I may cut it back to just once a month. That is my tendency with all patients on oral agents, not just the NTRK inhibitors.

NTRK-Targeted Therapy in Colon Cancer: Dosing and Management

 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 

. 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 

 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.

NTRK-Targeted Therapy for Patients With Colon Cancer

The treatment options for this newly diagnosed patient with surgically unresectable disease based upon the fact that she reportedly has multiple liver metastasis, if her performance status is quite good, which it appears to be, with an ECOG [Eastern Cooperative Oncology Group] performance status of 1, obviously your treatment options may be to consider standard chemotherapy up front.

Secondly, you can consider immunotherapy, which now has been not only considered in the refractory setting of patients who have received at least 1 prior therapy, but as many of you know, it is already approved as per the NCCN [National Comprehensive Cancer Network] guidelines for patients who may not tolerate chemotherapy well. There are a lot of data, not only looking at single agent, but also doublet therapy with nivolumab and ipilimumab.

Then obviously the third option in this setting, which would be important if she tests positive for 

 fusion, is to consider the role of one of the NTRK inhibitors.

Patients who are MSI [microsatellite instability] high are more likely to test positive for the 

So although is it going to be less than 1% of all patients with colorectal cancer who will have an 

 fusion, it’s reportedly between 25% and 30% of MSI-high patients who are 

In the setting of this patient, when I would want to consider utilizing larotrectinib, my preference would be to consider immunotherapy up front, and utilize one of the NTRK inhibitors at progression of disease. That would be my preference at this time, and that is because most of the literature regarding immunotherapy has a little bit more history and is longer-standing with greater median follow-up.

Are there any circumstances in which I would not want to provide targeted therapy in the setting of this driver mutation? I think based upon this case and based upon the literature that exists, my preference would not be to not pursue targeted therapy in this setting. I think is the most appropriate setting, in this patient who has an MSI-high tumor as well as an

Cathy Eng, MD, FACP, FASCO | Authors

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