Treatment Strategies for Left-Sided KRAS-Mutated CRC

Cathy Eng, MD, FACP:When considering treatment options for this patient, number 1, I want to make sure that she’s fully recovered from her surgical resection. I presume that the patient went on to surgical resection more likely because she had a near-obstructing tumor, and, as a result, that would be the most beneficial way to address this at the time. But now if the patient has healed appropriately, I would consider initiating chemotherapy. And it would also be with a targeted agent, as she has a left-sided tumor and isRASmutant.

Unfortunately, because of theRASmutation, she would not benefit from anti-EGFR therapy in the treatment-naïve setting. So I believe the patient went on to receive FOLFOX [folinic acid/fluorouracil/oxaliplatin] and bevacizumab, which is a very reasonable option. But one of the other treatment options I would like to consider is FOLFIRI [folinic acid/fluorouracil/irinotecan hydrochloride] as well. That’s another option for the patient.

For a 38-year-old patient with a good performance status of 0, I do like to be extremely aggressive. I am a big advocate of the FOLFOXIRI regimen, which is basically irinotecan, oxaliplatin, and 5-FU [fluorouracil] all together in 1 combination. It has a very high response rate, and I think it’s very reasonable for a patient that’s young with a good performance status. This is largely based upon the TRIBE trial, and that, once again, would be combined with bevacizumab, or Avastin.

The way that I would normally provide it to that patient is I would do 6 months of FOLFOXIRI, and then following the 6 months of therapy or at least as long as there’s no neuropathy, I would go on a maintenance chemotherapy. But in this case, this woman has opted for FOLFOX plus Avastin, which may be the case because some individuals do not like to have potential hair loss. Irinotecan will result in hair loss.

So FOLFOX/Avastin is a very reasonable regimen. I would recommend that the patient be followed closely because of the risk of neuropathy, which usually occurs after the third month. If that was the case then I would remove the oxaliplatin or reduce the dose of the oxaliplatin to prevent or reduce the development of neuropathy, and then move on to maintenance chemotherapy.

It sounds like she has unresectable disease, so it is unlikely that surgical resection of the liver would be feasible.

Other treatment options, as I mentioned, could be FOLFIRI plus Avastin, which is one of my other favorite regimens. I believe it’s tolerated extremely well. And excluding the hair loss, other than that, I think patients can be put on it for a very prolonged period.

So those would be the 3 potential options for a left-sideRAS-mutant tumor: FOLFOX, FOLFIRI, or FOLFOXIRI if the patient has a good performance status. And that would all be combined with bevacizumab.

The expected outcomes for a patient on FOLFOX and bevacizumab: It’s likely that the progression-free survival would be anywhere from 10 to 12 months. And as I mentioned earlier, if possible, as long as the patient has stable disease or is responding and is tolerating the treatment well, I would go on to maintenance chemotherapy. And at some point, if the disease appears to be progressing again and there’s no evidence of significant neuropathy, then I would reintroduce the oxaliplatin-based therapy if possible. Otherwise I would have to switch her out to FOLFIRI.

If the patient had an all-RASwild-type tumor, and I presume alsoBRAFwild-type tumor, some other options would include not only FOLFIRI, FOLFOX, or FOLFOXIRI, but instead of using bevacizumab you could consider an anti-EGFR therapy, such as cetuximab or panitumumab. Although I would not necessarily advocate for FOLFOXIRI plus anti-EGFR therapy upfront at this time. There’s very little data in the treatment-naïve setting. There was a small study—actually I apologize, I can’t recall the name of the study—of less than 100 patients and it didn’t note any improvement in progression-free survival versus standard treatment with FOLFOXIRI. And there can obviously be a lot of significant toxicities because FOLFOXIRI can cause myelosuppression and EGFR therapy causes significant rash. So in that case, in an all-RASwild-type patient, I would probably favor FOLFIRI, FOLFOX, or FOLFOXFIRI with bevacizumab. Or, if we’re considering anti-EGFR therapy, FOLFOX plus anti-EGFR therapy, or FOLFIRI plus anti-EGFR therapy.

For any patient on FOLFOX plus bevacizumab, we would highly encourage maintenance chemotherapy because oxaliplatin may result in neuropathy after approximately 3 months of treatment. You would continue the maintenance chemotherapy until there’s evidence of progression of disease and then resume the oxaliplatin as long as we don’t have any significant neuropathy.

In this patient who isRASmutated with a left-sided tumor and is started on FOLFOX plus bevacizumab, your next treatment option would be FOLFIRI plus bevacizumab. That would be your next best treatment option off study, or if a clinical trial is available. We always encourage clinical trial enrollment if possible.

Transcript edited for clarity.

Case: A 38-year Old Woman WithKRAS-Mutated mCRC

Initial presentation

• A 38-year old woman was referred to gastroenterology after experiencing several bouts of bloody diarrhea
• PMH: unremarkable
• PE: unremarkable

Clinical workup

• Colonoscopy: suspicious sigmoid mass, partial obstruction
• Biopsy: poorly differentiated adenocarcinoma
• Imaging: CT scan of the chest/abdomen/pelvis revealed multiple small bilateral liver metastases
• Molecular testing on tissue biopsy:
  • Positive forKRASexon 2 codon 12 mutation
  • Negative forNRAS,BRAF
  • Microsatellite-stable
• Diagnosis: stage IV colorectal cancer
• ECOG PS 0

Treatment

• She underwent laparoscopic sigmoid resection
• She was initiated on treatment with FOLFOX + bevacizumab; well-tolerated
• Follow-up imaging at 3 and 6 months showed a partial response