Case 2: Metastatic Colon Cancer, No Molecular Alterations



Richard Kim, MD:The second case I’ll be presenting is on a patient with advanced colon cancer with no molecular alteration. This is a 35-year-old gentleman who was referred to a gastroenterologist for symptoms of acute abdominal pain and intermittent constipation. His physical examination shows some abdominal distension, decreased bowel sounds, and pain in the left side of his abdominal area. A CT scan shows focal enhancement and some thickening of the sigmoid descending colon junction with pericolic fat stranding and 3 small liver lesions that are greater than 1 cm.

A scope was done, and a biopsy confirmed well-differentiated adenocarcinoma. The molecular testing was done as per the guidelines, and this patient was found to beRASandBRAFwild type. Consequently, the patient was started on FOLFOX [folinic acid, fluorouracil (5-FU), and oxaliplatin] plus cetuximab as palliative chemotherapy.

Now I’ll be discussing some of the data that was recently presented at the ESMO [European Society for Medical Oncology] Congress. This explored the benefits of upfront primary tumor resection according to sidedness in metastatic colorectal cancer. This is a retrospective analysis of the MACRO-2 and the PLANET randomized trials.

This study looked at patients who wereKRASwild type and had upfront resection of their tumors. In patients with stage IV disease, upfront tumor resection was associated with improved overall survival. However, it was significant only in right-sided tumors. The median overall survival in patients with right-sided tumors that got upfront resection was 20.9 months, versus 10.6 months. The patients with left-sided tumors had a better overall survival regardless of upfront resection or not. As you can see, the hazard ratio was 0.4 with aPvalue of .006. This tells us that for left-sided tumors, upfront resection didn’t really matter.

Now we’re going to look at the primary tumor location as an independent prognostic marker from molecular features for overall survival in patients with metastatic colorectal cancer. This was an analysis of the CALGB/SWOG 80405 study.

This study determined that in 728 patients, sidedness was an independent prognostic factor when adjusted for age, gender, CMS [consensus molecular subtypes], MSI [microsatellite instability], andBRAFstatus. Patients with left-sided tumors did well overall. The overall survival was close to 33 months compared with 20 months in patients with right-sided tumors. The question is, is sidedness also a predictive marker for possible biologic therapy?

In this study, in patients who got bevacizumab plus chemotherapy, there was a 38-month overall survival in the left-sided tumor group compared with patients who got cetuximab-based therapy, who had a slight improvement in overall survival—about 40 months. So there was an improvement of about 2 months in overall survival. However, in the right-sided tumor group, patients who got bevacizumab plus chemotherapy had an overall survival of 34 months. Patients treated with cetuximab had a worse overall survival—18.4 months.

Next I’ll be discussing the VALENTINO study, which is maintenance therapy with panitumumab. This is a first-line study of FOLFOX plus panitumumab, followed by 5-FU/leucovorin plus panitumumab, or single-agent panitumumab as a maintenance therapy in a patient withRASwild-type metastatic colorectal cancer. This was presented at our meeting this year. Patients withRASwild-type unresectable metastatic colorectal cancer were enrolled in the study. A total of 229 patients were randomized to FOLFOX plus panitumumab as induction therapy for 8 cycles. When their disease was stable or they showed a partial response, they were randomized to a maintenance arm with panitumumab alone or panitumumab plus 5-FU/leucovorin. They continued on until progression or unacceptable toxicity. The primary endpoint of this study was noninferiority of progression-free survival of arm B versus arm A.

For secondary endpoints, they looked at safety, response rates, duration of response, and overall survival. At the median follow-up of close to 14 months, the 10-month progression-free survival of the panitumumab arm was 52.8 months, versus 62.8 months with the combination of 5-FU plus panitumumab. The median progression-free survival favored the combination of 5-FU and panitumumab by close to 3 months—10.2 months versus 13 months. The overall response rate was very similar. During maintenance therapy, the grade 3 adverse events that occurred were diarrhea, mucositis, hand—foot skin reaction, and neutropenia. Grade 1 or 2 adverse events were 75% in arm B versus 64% in arm A.

Transcript edited for clarity.

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