Second-Line Therapy for Metastatic Colon Cancer

Michael A. Morse, MD:This patient, who previously received FOLFIRI/cetuximab, is now having progressive disease in the liver. We still have some of the same considerations we did with first-line therapy. How did they tolerate that therapy? How have their comorbidities impacted their ability to tolerate the treatment and subsequent treatments? What are their goals? In the case of this patient, the assumption is that they wanted to continue to take an aggressive approach and they tolerated their previous therapy well. Of course, we always change the chemotherapy. In this case, they received FOLFIRI, so we would change to FOLFOX.

As far as the targeted therapy, again, this is a patient who has a wild-type status forRAS, and so they would be a continued candidate for anti-EGFR targeted therapy. In the CAPRI-GOIM trial—where patients were randomized in the second-line setting, having received cetuximab with FOLFIRI in the first-line setting when they were randomized to FOLFOX/cetuximab versus FOLFOX alone—there was a better progression-free survival and a trend toward an overall survival benefit for those patients continuing on the cetuximab.

There are other options as well. We know from the E3200 trial that patients receiving second-line bevacizumab with FOLFOX also have a survival benefit compared with FOLFOX alone.

Again, the CAPRI-GOIM trial had a number of important features, one of which was that they specifically performed an additional analysis in those quadruple wild-type patients and saw the greatest response rates in that group. So, if I were considering using anti-EGFR targeted therapy, that would be an important driver: they are wild-type for all the important mutations.

We know that cetuximab and panitumumab, when compared directly with each other in a randomized clinical trial in more refractory patients, showed similar progression-free and overall survival benefit. We do have data for panitumumab in the second-line setting, but when given in conjunction with irinotecan-containing regimens—for example, there’s the PICCOLO trial, where patients were randomized to irinotecan/panitumumab versus irinotecan alone—there was a better progression-free survival for patients receiving the irinotecan/panitumumab. We also have a clinical trial of FOLFIRI/panitumumab versus FOLFIRI alone in the second-line setting. And again, in theRASwild-type patients, there was a better progression-free survival for the addition of panitumumab to FOLFIRI.

This is a patient who has now had first-line therapy with FOLFIRI/cetuximab, they’ve now had second-line therapy of FOLFOX/bevacizumab, and they’ve progressed in the liver and the lungs. So, our considerations here are now the oral agents. The first consideration with any patient with metastatic disease is: Are they resectable, are they borderline resectable, or is it very unlikely they’ll ever be resectable? This patient is demonstrating that they will never be a candidate for resection. Therefore, considerations continue to be lengthening survival while trying to maintain quality of life. Also, in a patient with theRASwild-type tumor, we have the potential for 5 lines of therapy. Therefore, we want to maximize each line of therapy but also make sure that people maintain an adequate performance status so that they can receive all the other lines of therapy that are available to them and that can lengthen survival.

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