Third-Line Therapy for Metastatic Colon Cancer

Michael A. Morse, MD:It’s important to point out that there are 2 oral agents that are available for patients who have refractory disease. There’s trifluridine/tipiracil, and there’s regorafenib. Whenever I’m considering which agent to use, I go back to the important considerations that the patient may have. Both drugs have slightly different side effect profiles. Also, there are important considerations about their comorbidities, their tolerance of prior therapy, and their blood counts, for example—any lingering toxicities from previous drugs, such as diarrhea.

In this patient, trifluridine/tipiracil would be a very reasonable option for continuing use of the systemic chemotherapy. It’s important to point out that the clinical trial that led to the approval of trifluridine/tipiracil was a randomization against placebo plus best supportive care. In this trial, patients were treated until they had progressive disease or had intolerance to therapy. Therefore, I always tell my patients that we’re going to start on this therapy and we’re going to use it as long as it’s helping them. So, as long as the disease isn’t progressing and they’re tolerating the therapy well, we’ll continue it. In a randomized clinical trial, there was a better progression-free and overall survival for the use of trifluridine/tipiracil compared with placebo.

As part of the counseling for administration of trifluridine/tipiracil, we always warn patients about some of the side effects. The most important one is the development of neutropenia, and there were patients who developed neutropenic fever, as well, on the randomized clinical trial. Now there can certainly be other side effects, such as diarrhea, fatigue, and occasionally oral lesions. But the critical one that they need to let us know about is if they’re developing any fevers. We also do check white blood cell count during a cycle to inform whether a person is actually developing neutropenia. Furthermore, it’s critical that patients have a CBC performed prior to initiating a new cycle. If they have an ANC less than 1500, they should not be treated until the ANC rises above 1500. Similarly, if they have a platelet count less than 75,000, they should also be delayed until the platelet count exceeds that.

Because neutropenia is quite common in patients receiving trifluridine/tipiracil, we have found that it’s very important to consider whether to dose-delay or dose-reduce. Currently, we recommend that if a patient has an ANC less than 1500 on the day that they’re to start a new cycle, we delay another week and recheck their CBC. If their ANC is greater than 1500 at that point, we recommend continuing the same dose of the trifluridine/tipiracil as they received in the previous cycle. However, if the ANC continues to be less than 1500, or they’ve had other toxicities that cause a longer delay, then it is recommended to reduce the dose prior to starting that next cycle once the ANC is greater than 1500.

There are other interventions one could consider for patients who do develop neutropenia while on trifluridine/tipiracil. One of these is the use of G-CSF (granulocyte colony-stimulating factor). Now in the pivotal trial, only about 9% of patients did receive white blood cell growth factor support, but it certainly is acceptable to use it because there is a 14-day window from the time patients receive their last dose until they’re likely to start a new cycle.

There’s quite a bit of interest in administering trifluridine/tipiracil with other therapies. While this combination therapy is not the same as fluoropyrimidine, you can imagine in other areas where fluoropyrimidines have been administered that there’s considerable interest in using trifluridine/tipiracil. So, for example, there’s a clinical trial evaluating the use of maintenance therapy with trifluridine/tipiracil plus bevacizumab. Because there’s considerable interest in the use of immunotherapy in advanced colorectal cancer patients, there are also at least 2 clinical trials evaluating trifluridine/tipiracil with nivolumab. And furthermore, there are clinical trials administering trifluridine/tipiracil with other novel agents. For example, there’s an anti-NOTCH1 antibody in development that is being studied in combination with trifluridine/tipiracil. And, of course, there are at least 2 clinical trials that include an arm where oxaliplatin is being used with trifluridine/tipiracil as well.

The unfortunate reality for most people with metastatic colorectal cancer is that they will progress through all the lines of therapy. However, I found that in patients who have received oxaliplatin/irinotecan/fluorouracil/bevacizumab and, where appropriate, anti-EGFR targeted therapy, and still have a reasonable performance status, most patients do want to continue with some type of therapy to see if they can maximize survival. I’ve been very gratified to find that patients to whom I’ve administered trifluridine/tipiracil have tolerated it reasonably well.

We, of course, do have to consider the neutropenia. It is very common that we do need to dose-delay, but less frequently, we need to dose-reduce. We’ve been able to have patients maintain adequate quality of life throughout that therapy. And because it’s known to have, on average, a survival benefit, we believe that we’re giving those patients additional time for the things that are important to them. Also, I found that even at the point that they do progress, they generally maintained a reasonable performance status and quality of life, so they would be eligible yet for other therapies.

Transcript edited for clarity.

October 2014

• A 69-year old Caucasian male presented with severe left lower quadrant pain
  • He sought medical treatment after experiencing bloody diarrhea
  • PMH was remarkable for hypertension that was being managed with telmisartan
  • He was active and could perform his daily activities without restrictions or assistance
• Laboratory evaluation was remarkable for Hb 11.3 and CEA 6.5 ng/mL
• Colonoscopy revealed a fungating mass in the sigmoid colon which was biopsied
  • Pathological findings: invasive poorly differentiated adenocarcinoma
  • Molecular testing on the primary tumor was requested; no mutations were noted in KRAS, NRAS, BRAF, PIK3CA (quadruple wild type) and the tumor was microsatellite stable (MSS)
• Chest, abdominal, and pelvic CT scan showed small bilateral lung nodules, a 3-cm mass in the right lobe of the liver, and a mass in the sigmoid colon measuring 10 cm
• Diagnosis, unresectable metastatic colorectal cancer
• Treatment was initiated with FOLFIRI + cetuximab and he appeared to respond well
• CT scans at 3 and 6 months showed decreased size of liver and lung nodules

August 2015

• The patient complained of increased fatigue, and reported needing frequent breaks while performing daily activities
• CT scan showed increased size of the liver nodule (to 4 cm) and the appearance of 4 new small liver lesions (<2 cm)
• He began therapy with FOLFOX + bevacizumab

March 2016

• The patient complained of severe fatigue
• CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number
  • A new pulmonary nodule was seen in the right lung
• He was then started on trifluridine/tipiracil
• PET/CT at 3 months showed stable disease
• At 6-months, he reported less fatigue and some improvement in performing daily tasks