Fourth-line Therapy for mCRC

Tanios Bekaii-Saab, MD, FACP:Now the patient goes on regorafenib and does well with it and then eventually progresses, as all patients unfortunately do. So, what next? I think at every point of the discussion with the patient, even frankly from the first-line, the question of palliative care and no therapy should always be part of the discussion. I think it’s important to understand the patient preferences and where they stand. Most patients, the overall majority, want to be treated. There are some patients who actually prefer not to be treated at all. They may be older, they may be satisfied with their life and just accept their fate.

Most want some form of treatment, but at every line of therapy, I think it’s important to have that discussion. And with a first-line, second-line, and third-line, now the patient progressed on regorafenib, and we’ll have that discussion with the patient—palliative care versus another option. Another option outside of clinical trials would be TAS102; that is available. And we have data, as I mentioned, that suggest that patients who fail regorafenib and go on TAS102 still derive benefit from TAS102. So, I would have that discussion, and I think it’s very reasonable to consider TAS102 in this patient in this particular setting.

I think these are all examples of how far we’ve gone in terms of improvement over the last decade-and-a-half in treating patients with metastatic colorectal cancer. Our armamentarium has grown so much. Not as much as I would hope for our patients, but enough to bring the survival from a little bit less than 1 year to more than 3 years in the stage 4 setting. And for some patients, let’s say those with MSI-high tumors or with specific targets we’re able to develop, that survival is actually years and years and years. Those patients with liver-only metastatic disease or lung or oligometastatic disease that are amenable to resection, their survival is sometimes 10+ years.

So, overall, I think it’s very, very important, from day 1 when you see that patient, to individualize and strategize how many lines of therapy you are going to expose those patients to. What kind of strategies are we going to use? Are we going to use surgery, radiation, or SIR-spheres as part of our global strategy? Are we going to use EGFR or VEGF inhibitors? Who is eligible, who is not—left side, right side, those on immune therapy? And then, we have all these clinical trials that are looking at immune therapy in those patients who are microsatellite stable. How can we manipulate the microenvironment, bring those T cells, those lymphocytes, and essentially make those PD-1 inhibitors effective in disease that typically doesn’t respond to them?

Then, we start talking about HER2, an emerging target. And we talk about other targets that also are emerging—EGFR rechallenge, MET, others—and we globally are testing all these questions. So, in many patients who may have a multitude of targets, either emergent or present from the get-go, you may think about patients being exposed anywhere between 3 to 4 lines of therapy to 7 to 8 lines of therapy and all done rationally. And then, when you start complicating matters with including surgical resection, intervention radiology, radiation, etc, you can see how we can amplify the outcome of our patients even further by providing them with more of all these various options. Then comes innovation in clinical trials, which add even more options to our patients. It’s not unusual anymore to see a patient exposed to an average 4 to 5 lines of therapy, if not more, for most patients. All patients, except 5%, will respond very well to first-line therapy. So, chances are almost every patient you’re going to see in clinic is going to be exposed to 3 to 4 lines of therapy, as long as you strategize well and you’ve identified targets from day 1 in the patient’s tumor.

Transcript edited for clarity.

October 2015

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
  • CEA were elevated, 23.3 ng/mL
  • Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic
  • Imaging with PET/CT showed several lung lesions, three measuring up to 3.0 cm in size
  • Mutational status was both RAS and BRAF wild-type
  • Microsatellite stable
  • Diagnosis; high grade colorectal adenocarcinoma, stage T4N2M1
• PMH includes arterial hypertension, well-controlled on an ACE inhibitor and coronary angioplasty with stent placement 4 years ago
• The patient received systemic therapy with FOLFIRI + cetuximab; grade 1 rash and grade 2 thrombocytopenia were managed with dose adjustment of FOLFIRI
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
• The patient was continued on maintenance therapy with cetuximab

August 2016

• The patient complains of weight loss, nausea and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions
• The patient was switched to CAPEOX with bevacizumab. Her blood pressure was closely monitored and remained stable
• Follow up imaging at 2 months and at 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms
• At 4 months, oxaliplatin was discontinued; maintenance therapy with capecitabine and bevacizumab was continued

January 2017

• At 5 months, the patient reports having reappearance of her symptoms, although she continues her normal physical activity
• CEA level is rising significantly
• Follow up CT showed further progressive disease in the lung and the appearance of several small boney lesions
• The patient is motivated to try another therapy and has opted for regorafenib