Third-Line Therapy for Metastatic Colorectal Cancer

Edward Chu, MD:At this point, 1 month later, in December 2015, the patient is now presenting with disease progression in the liver, and now also there’s the presence of metastatic lung nodules. Also, I think what’s changed pretty significantly is that there are now much greater tumor-related symptoms, and it’s noted that the patient is complaining of pretty significant fatigue, which the patient really had not experienced since the initial presentation of this disease. So, it’s clear, given the evidence for disease progression with widespread metastatic disease, that a change needs to be made from the FOLFIRI/bevacizumab therapy.

I think the other important teaching point to note is that in the second-line setting, the median progression-free survival is on the order of 4 to 4.5 months. So, having disease progression occur only 1 month after initiation of second-line therapy is a bit quicker than we’re used to seeing, which I think also tells us this patient now has much more aggressive disease than what was initially at the time of presentation. This patient has what we would define as chemorefractory metastatic colorectal cancer. And clearly, these patients are incurable, and the main goal for these patients is palliation or symptomatic relief, relief of tumor-related symptoms.

Based on the NCCN guidelines, and based on the clinical evidence that has been published to date, there are really 2 main standard treatment options that would be available for this patient. The first would be the oral multi-TKI inhibitor, regorafenib, and the second would be the novel oral fluoropyrimidine, trifluridine/tipiracil, which is also known as TAS-102. In addition to these 2 standard treatment options, clinical trials with novel agents and/or novel combination regimens would also be considered. In particular, if one of the patients knew metastatic lesions were biopsied and next-generation sequencing was performed, it would be interesting to know if this patient had a potentially actionable mutation with a novel agent targeting a key mutational event.

Finally, one of the other options is if this patient had MSI-high disease, treatment with the immune checkpoint inhibitor, either pembrolizumab or nivolumab, would certainly be a consideration. I think the other thing to also consider, especially in someone whose performance status has significantly worsened, is no active therapy and to really focus purely on supportive care symptom management relief.

I think one of the potential advantages of using trifluridine/tipiracil, or TAS-102, in this patient as compared with considering regorafenib is that this patient is experiencing significant severe fatigue. The main side effect associated with TAS-102 is myelosuppression. So, while fatigue can be experienced in some patients, it really is not a significant adverse event. In contrast, I’ve been very impressed—unfortunately, not necessarily in a positive way—that regorafenib is associated with significant fatigue. Actually, in fact, the 2 main dose-limiting side effects associated with regorafenib are the dermatologic skin toxicity, or the hand-foot syndrome, and fatigue. I think because this patient is already experiencing significant fatigue, that would really make me shy away from even considering regorafenib.

The usual approach for starting any new therapy in a patient with metastatic colorectal cancer is to treat for 2 months and reassess the patient to look to see how the patient is responding. So, we would repeat CT scans of the chest, abdomen, and pelvis to determine whether or not the lesions are responding to the trifluridine/tipiracil therapy and also to determine how the patient is responding to the therapy in terms of potential side effects. If the patient is not experiencing significant side effects and is doing well, and there’s no presence of either new lesions or growth of the preexisting lesions, we would continue for another 2 months and then reevaluate at that time.

In this particular setting, the clinical activity of trifluridine/tipiracil has already been well documented by the randomized phase III RECOURSE study. In terms of overall response rates, it’s actually pretty low, on the order of only about 2% or 3%. However, the median progression-free survival is on the order of 2 months, and the median overall survival approach is 4 to 5 months. My own clinical experience with trifluridine/tipiracil, or TAS-102, is that we’ve actually had a number of patients who have been on therapy for 6, 8, or 10 months. In fact, we were involved in some of the early phase I organ dysfunction studies with TAS-102, and in some cases, patients were on therapy for well over 1 year.

So, our experience has been that even though there may not be objective responses, the disease stabilization rate is upward of 40% to 45%. Patients actually, for the most part, tolerate the therapy pretty well, and they can be maintained on therapy for quite some period of time. Again, I think our own experience at the University of Pittsburgh Cancer Institute is that regorafenib is a much tougher drug to tolerate, certainly at the prescribed dose of 160 mg per day. Patients do experience a lot of side effects, and the clinical benefit, at least in my experience, has been much, much less than what we see with TAS-102.

With respect to the side effects associated with trifluridine/tipiracil, the main dose-limiting toxicity is myelosuppression. We see grade 3/grade 4 neutropenia in about 40% of patients, but febrile neutropenia is observed in only 4% of patients. The other 2 toxicities seen are anemia, which is seen in about 30% to 35% of cases, and thrombocytopenia, which is seen in about 5% of cases. While there are other toxicities, and probably fatigue is the only other major side effect, myelosuppression is what we really look at very carefully in patients who go on TAS-102 therapy. In terms of how do we deal with myelosuppression, usually it’s dose interruption or dose delays. If need be, we may need to dose-modify and reduce the dose of the TAS-102. And I think we have also found that giving G-CSF to stimulate the white blood cells is also a very effective strategy for being able to keep patients on TAS-102 therapy.

My overall experience with trifluridine/tipiracil has been really quite positive, and perhaps a little different from what has been published to date. We have found that patients can be on TAS-102 for up to 4, 6, or 8 months and tolerate it quite well. In fact, our group at the University of Pittsburg Cancer Institute has been involved in a number of phase I studies. And in those phase I studies, some patients have been treated with TAS-102 for over 1 year, tolerated the treatment well, and had their disease under good control. So, we’ve actually been quite pleased with how patients tolerate and respond to this therapy.

Transcript edited for clarity.

December 2014

• A 51-year old Caucasian female presented with severe crampy right lower quadrant pain
  • She had a 4-month history of occult bleeding, and significant weight loss of over 10 pounds in the last 8 months
  • She sought medical treatment after experiencing severe cramping in the abdomen and bloody diarrhea
• Past medical history included GERD, managed with a proton pump inhibitor and appendectomy at age 35
• Laboratory evaluation showed grade 2 anemia (hemoglobin 8.7 g/dL) and carcinoembryonic antigen (CEA) level of 4.5 ng/mL
• Colonoscopy revealed an obstructive lesion in the ascending colon, measuring approximately 15 cm
  • Pathological findings showed invasive and poorly differentiated adenocarcinoma with ulcer
  • 10 of 15 lymph nodes sampled were positive for tumor
  • CT scan revealed widespread lesions in both lobes of the liver, and she was diagnosed with stage IV disease
  • Mutation testing; KRAS-positive (G12D) and BRAF-negative
  • Her ECOG performance status was 0
• She was treated with six cycles of FOLFOX + bevacizumab, and appeared to be responding well to treatment; follow-up imaging showed reduction in the size of the liver lesions

November 2015

• Follow-up CT showed progression in the liver with new lesions and new small masses in the abdomen and pelvis
• Her ECOG performance status was 1
• She began therapy with FOLFIRI + bevacizumab

December 2015

• The patient complained of severe fatigue
• CT scan revealed progressive disease with no improvement in the size and number of the abdominal lesions and the presence of 3 pulmonary nodules in the right lung
• She was then switched to trifluridine/tipiracil (TAS-102)
• PET/CT at 3 months and 6 months showed stable disease
• Her ECOG performance status improved (PS 0)