Many patients with metastatic colorectal cancer will ultimately progress on standard first- and second-line therapy while maintaining a good performance status, placing importance on the optimal use of third-line treatments.
Tara E. Seery, MD
Many patients with metastatic colorectal cancer (CRC) will ultimately progress on standard first- and second-line therapy while maintaining a good performance status, placing importance on the optimal use of third-line treatments.
In September 2012, the multikinase inhibitor regorafenib (Stivarga) gained FDA approval for patients with advanced CRC, providing a much-needed third-line option. Since its approval, researchers have explored approaches for managing adverse events (AEs) while optimizing efficacy. Additionally, another therapy, TAS-102 (Lonsurf), has gained approval as a treatment for patients following regorafenib.
To help characterize treatment with regorafenib, researchers from the University of California (UC) at Irvine published a case study in the journal of Cancer Management and Research. This review focused on a 73-year-old Indian woman with a past history of hypertension who achieved stable disease for over 11 months and continued treatment with regorafenib beyond progression.
In the case scenario, the woman was diagnosed in September 2010 with stage 3B KRAS wild-type CRC; however, rather than receiving upfront chemotherapy she decided to move back to India. The patient presented again in March 2011, and began treatment with capecitabine, oxaliplatin, and bevacizumab. In early 2012, she was restaged and found to have diffuse metastatic disease. Second-line cetuximab and FOLFIRI was administered from February 2012 to August 2013.
After progression on first- and second-line therapy, the patient was started on regorafenib as a third-line option in September 2013. Initially, due to problems with hypertension and fatigue, treatment was held for 2 weeks, and the dose was adjusted. After resolution of AEs, an 80 mg/day dose of regorafenib was selected, which is half the FDA-approved dose.
In August 2014, after nearly a year on regorafenib, a PET/ CT scan indicated that the patient’s cancer had progressed; however, after discussing with the patient, regorafenib was continued at 80 mg/day, due to a lack of AEs and the patient’s comfort level with the medication.
In August 2015, the patient remained on regorafenib, with continued progression and a consistent performance status of 1. At this point, the patient did not mention any AEs and felt as though she had an improved quality of life. Later that year, she was moved to hospice care.
OncLive: What sets this apart as a unique case study?
To gain more insight into this unique case, OncLive spoke with the senior author Tara E. Seery, MD, assistant professor at UC Irvine.Seery: With most cancers, when someone progresses on a drug, you take him or her off it. In this case, however, even though the patient has progressed, the rate they’re progressing at is much slower than if they were on no drug at all.
At the time, there really was nothing else, because Lonsurf was not approved yet. The patient was really feeling good, so we came to an agreement and continued regorafenib, because it was really helping her quality of life.
In your case report, did regorafenib extend the patient’s life, and reduce the symptoms of her disease?
We’re one of the first teams of researchers to talk about using it after progression, but using it at a reduced dose is more common.Oh, completely. It’s exciting, because we’re trying to make colon cancer more of a chronic disease. We’re doing more surgery, therapies on all the metastases, and we’re just being more aggressive on the whole. Survival is getting longer and longer. In the past, they used to say, "You have 24 to 26 months," but now a lot of us are seeing patients living a whole lot longer. But there’s still a whole lot of room to grow.
Was her treatment considered palliative at the end?
Have you seen other patients who experienced responses that are similar to this case study?
I have a lot of patients who are sick of all the chemo side effects, and want freedom from the infusion center. A lot of times people will recycle chemotherapies, and this particular patient knew they wouldn’t cause her any great benefit, so she was excited to try the oral medication which would give her more freedom, so she can get moving and be able to travel and enjoy her remaining time.When she went into hospice, she wanted to continue to take regorafenib, but the hospice wouldn’t allow it. They’re typically just supplying palliative treatment, such as pain medications and diuretics. If you’re giving patients a third-line agent, you know you’re not curing them. Plus, it’s an expensive agent, and when you come to terms with the fact that you’re going to die of your disease, they’re not going to let you continue on therapy for it.I had another patient who was on regorafenib for over a year. She had mainly lung metastases from colorectal cancer. She had a very hard time with systemic therapies, and I was very worried that she would have tons of side effects when we started her on regorafenib, but she tolerated the full dose at 160 mg.
If trying to duplicate these results, what advice would you give a practicing oncologist?
Are adverse events the main deterrent to regorafenib use?
You kind of don’t know who is going to be that one patient who has a wonderful response, but you can know by the first CT scan whether the patient is benefitting or not. When you look at the data, you see the separation of the curve.When we first start, I—or my nurse practitioner as a physician extender—do see the patient weekly. It’s good symptom management, and a way to keep the patients on the drug, because when you see the side effects, like hypertension and fatigue, they get them early. They also get hand skin reaction, ulcerations and blistering, almost like sloughing of the skin. People need their hands and feet to do things, so you have to stay on top of it, hold the drug, give them creams, and let them improve.Hypertension is not a contraindication, but I would never start anyone on regorafenib if his or her blood pressure weren’t controlled. But a patient can easily be on blood pressure medications and take the drug.
How has treatment with regorafenib evolved since its approval?
What are current best practices for sequencing therapy?
In the beginning, everybody was very used to starting an oral agent and seeing the patient every couple of weeks. With this one, always check the blood pressure once a week, or if they don’t have high blood pressure, ask them to check it at home. If it becomes grade 2 hypertension, you have to hold the drug, and restart it at a lower dose, or give them a new medication.The issue is that when the drug first came out, everyone started at the full dose used in CORRECT, which was 160 mg. A lot of us realized that is almost impossible, because the patients were having significant side effects, so a lot of oncologists were very fearful of using it again, or patients would read on websites about other patients’ reactions and get fearful. Now, I don’t even start at the full dose, I start at 120 mg, and manipulate it based on the patient’s toxicities. There is a resurgence of using this drug, because people are more comfortable using it and more comfortable with the starting dose.Everyone who’s progressed on standard therapies goes on to regorafenib, and then after that they try Lonsurf, which works in a completely different way. Its main side effect is more hematologic, while regorafenib doesn’t cause a lowering of the blood count. You can get hypertension from the antiangiogenesis. In the RECOURSE trial, which led to Lonsurf’s approval, 20% of the patients had already progressed on regorafenib.
Tang R, Kain T, Herman J, Seer T. Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report. Cancer Manag Res