Therapy Outcomes for mCRC

Wells Messersmith, MD:This case is just a classic colorectal cancer case that shows some of the good things that are going on and some of the challenges for the field. First of all, we have options. We have 13 different drugs, if you start to consider the immunotherapy drugs for MSI-high patients or deficient mismatch repair patients. So, we have a lot of different agents and a lot of different combinations, and if you think about 20 years ago, when patients lived 3 to 6 months with this disease, now patients are living more than 36 months if you’re left-sided, for instance, andRASwild-type. So, there’s a lot of reason to be somewhat comforted by the fact that we’ve quintupled survival from before all these agents were used.

On the other hand, this points to a lot of deficiencies in the field. So, first of all, which cytotoxic backbone should we use? We don’t have any predictive test for that. There are some arguments about ERCC1 and topoisomerase, etc, but none of those have really panned out in large trials. The choice of a cytotoxic backbone is still completely empirical, which is surprising in the 21st century.

Second, we don’t know what targeted therapy to use, especially forVEGFR, so when you use bevacizumab, ziv-aflibercept, ramucirumab, or even regorafenib to a point—also it has antiangiogenesis properties—we really need biomarkers to predict who’s going to benefit from those. And we don’t have them. So, there are no tests you can send to ask, “Should I give this patient this expensive therapy? Granted, the side effects usually aren’t too bad, but should I be giving that?” It’s largely empirical.

And the third is that this patient was microsatellite stable, so they do not benefit, as far as we can tell so far. There are some trials going on, but they don’t benefit from immunotherapy, and that has been a very frustrating thing across the field. Why doesn’t colorectal cancer respond to immunotherapy the same way that other diseases do? We know that deficient mismatch repair and microsatellite-high patients, they benefit, but they’re only 4% to 10% depending on what you’re looking at. So, that has been a frustration as well. For over 90% of the patients, we don’t have effective immunotherapy, and so it has been a great deal of frustration in terms of moving the field forward.

On the good side, there are 13 drugs, some of them biomarker driven, quintupling of survival. On the bad side, there are still no good immunotherapy options for microsatellite-stable patients, no predictive tests for cytotoxic therapies, and no predictive tests for angiogenesis inhibitors. In this case, I think that wraps up many of those themes all in one.

Transcript edited for clarity.

September 2015

• A 71-year-old Caucasian male presented with severe left lower quadrant pain
  • He sought medical treatment after experiencing bloody diarrhea
• PMH: hypertension, managed with benazepril
• He is active and can perform daily activities without restrictions
• Laboratory findings: remarkable for CEA, 6.0 ng/mL
• Colonoscopy showed a mass in the descending colon which was biopsied
  • Pathological findings: Moderately differentiated adenocarcinoma
• NGS mutation testing results wereNRAS, KRAS, HRAS, HER2,andBRAFwild-type
  • Microsatellite stable
• CT of the chest, abdominal, and pelvis showed an 8-cm mass in the sigmoid colon
  • a 2-cm mass in the right lobe of the liver, and a 5-cm in the left lobe adjacent to the left hepatic vein
  • Impression: metastatic disease, borderline resectable
• Treatment was initiated with FOLFIRI + bevacizumab
• Imaging at 3 and 6 months showed decreased size of the liver nodules, but was not resectable

July 2016

• The patient complained of increased fatigue, requiring the need for frequent rest
• CT scan showed increasing size of the liver nodule (3 cm) and appearance of 3 new small liver lesions (<2 cm)
• He began therapy with FOLFOX + bevacizumab

February 2017

• The patient reported weight loss, increasing fatigue, and shortness of breath
• 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 switched to irinotecan + cetuximab
• PET/CT at 3 months showed stable disease
• At 6 months, he reported moderate improvement in fatigue