Clinical Data and Sequencing in Recurrent CRC

Tanios Bekaii-Saab, MD, FACP:When we discussed with this patient regorafenib, we also discussed the recent results from the ReDOS trial, which is the regorafenib dose-optimization study. And this study essentially was a large phase II randomized study. It ran through our ACCRU network, and it essentially was asking a simple question. When you go into the clinic, everyone was dosing regorafenib like it’s the Wild West. Some start at 160 mg, others start 120 mg, others do 80 mg and go up. Others skip a week here or there, and there were no data. So, we decided to go back and look at a study that tries to establish a strategy that helps us do it in a more organized way for our patients.

The study was 2 arms. One arm would be the 160 mg, so the standard dose, and the other arm was the experimental arm. Patients would start at 80 mg, go to 120 mg, then to 160 mg on a weekly basis. So, they’ll be seen in clinic every week until they reach the maximum tolerated dose, and then they’ll get their week break. And then whatever that dose was at the end of the dose escalation was the dose the patients will be on. And so, that was the design of the study. The primary endpoint of the study was essentially a primary endpoint that combined the potential gain and efficacy alongside with the potential improvement in the toxicity profile. And this was essentially a primary endpoint that would include patients who would go through 2 cycles of therapy and then get their scan and proceed with cycle 3.

So, that study’s primary endpoint was looking at a 15% improvement with a dose escalation strategy versus the 160 mg. When we concluded the study, we looked at the primary endpoint and it was close to 20% improvement with a dose escalation strategy—from 80 mg to 120 mg to 160 mg. So, this was a positive study. One of the intriguing findings of the study was also the survival was improved on the dose escalation strategy. So, it was close to 9 months versus close to 6 months of the regorafenib 160 mg.

Now interestingly, if you look historically at where regorafenib stands, most patients on agents like TAS-102, regorafenib, even unselected cetuximab have a 6-month survival benefit. So, it was very intriguing to us to see 9 months in the experimental arm and 6 months in what we call the standard arm, which was very consistent with historical controls for this patient population. So, this was a positive study for the primary endpoint with an interesting finding in overall survival. PFS was increased just by a little bit—2 to 2.5 months. This was not statistically significant.

The toxicity profile was improved with the dose escalation strategy, especially in the first month of therapy, which is a very critical month in the life of these patients in the refractory setting. The quality of life of patients also seems to be preserved in the dose escalation strategy, and there was a loss in the 160 mg. At 2 weeks specifically, there was a dip with adjusting the dose. So, overall, when we looked at the study, the study does suggest that a dose-escalating strategy makes more sense for our patients. In fact, it should establish a new standard for our patients with metastatic colon cancers that are refractory.

Also, we looked at another randomization into the study that looked at preemptive strategy versus a reactive strategy with clobetasol, essentially a steroid cream. We don’t have the data yet fully analyzed. We will be hopefully presenting this at ASCO and ASCO GI. But the goal here was to see less hand and foot syndrome hopefully from giving that steroid cream to patients. But what we’ve noticed is there were less severe hand-and-foot syndrome, at least in the first 4 weeks of treatment of the dose escalating strategy versus the standard 160 mg strategy. So, there’s certainly an effect on hand-and-foot syndrome. That doesn’t mean we’re not seeing it, that means we’re seeing a lesser rate and a lower grade. So, that’s overall what we’ve seen from that study and that’s what led essentially to the choice of this treatment or dose-escalation strategy for this patient.

The REVERCE study that we talked about a little bit really tried to inform us about whether we can move regorafenib ahead of EGFR inhibitors, whether patients had right- or left-sided tumors, and that study was pretty intriguing. It’s mostly hypothesis-generating. We need to confirm that in the United States. But what this study suggests is that regorafenib perhaps plays a more important role if it’s moved a little bit up in the sequence of therapies rather than put it as a last-ditch effort. And that’s consistent with what we’ve seen with CONCUR where patients were less pretreated than, say, the CORRECT trial now, which included a mostly Western-patient population.

So, the importance of this, and the implications, is that I think in my own clinic, I’m having this discussion with a lot of patients, especially for the right-sided,RASwild-type like this patient. On the left side, I still favor moving EGFR inhibitors a little bit closer to second-line. I haven’t moved them completely to the first-line yet. But theRASwild-type right-sided tumors definitely would consider regorafenib as a first option before EGFR inhibitors based on the REVERCE study. Although, the REVERCE study does suggest that the effect is equally good both on the right and on the left side. From the practical standpoint in my clinic, I do this primarily on the right side.

Transcript edited for clarity.

January 2017

A 62-year-old African-American man presented with recurrent CRC

• Diagnosed at age 55 with stage 3 CRC, treated with surgery and adjuvant FOLFOX
• He underwent colonoscopy with biopsy
  • 6-cm ulcerated non-obstructive mass noted in the right colon
  • Pathology confirmed poorly-differentiated adenocarcinoma
  • Staging; T3N1M0
• History
  • Former smoker, 1 pack a day; quit 20 years ago
  • Obese, BMI = 30.2 kg/m²
  • Mother had inflammatory bowel disease, died at age 70
  • Other medications: metoprolol for hypertension, omeprazole, regular NSAID use
• PET/CT scan showed recurrent disease with multiple metastases in liver
  • CEA, 28.4 ng/mL
  • Biopsy of liver lesions suggests poorly-differentiated with colon primary
  • Mutation analysis;KRASandNRAS,WT;BRAF-wild-type; microsatellite-stable
• He was started on FOLFIRI with bevacizumab and achieved partial response

January 2018

• The patient reports feeling short of breath.
• PET/CT showed progressive disease in the liver and multiple metastases in both lung fields
• Therapy options were discussed with the patient; he preferred an oral therapy
• He was started on regorafenib, 80 mg once daily
  • He experienced grade 2 dermatologic toxicity on his hands and feet (palmar-plantar erythrodysesthesia syndrome [PPES]), which was managed with dose escalation from 80 mg to 120 mg to 160 mg. With recovery, he resumed regorafenib at 120 mg/day
  • At present,he remains on regorafenib 120 mg/day with evidence of stable disease at 6-month follow-up