Treatment Sequencing in Metastatic Colorectal Cancer
An expert breaks down therapy sequencing in metastatic colorectal cancer and provides some clinical pearls.
Kanwal Raghav, MBBS, MD: For both regorafenib and TAS-102 [tipiracil hydrochloride], the trials were designed in an almost-identical clinical setting. These were all patients with treatment-refractory colorectal cancer who had progressed on 5-FU [5-fluorouracil], oxaliplatin, irinotecan, and the biologics that are clinically indicated. How do you choose 1 of those 2 agents? There are some general principles that you will use. For example, toxicities of both drugs differ. TAS-102 [tipiracil hydrochloride] is more of a chemotherapeutic or cytotoxic chemotherapy drug. Bone marrow toxicity is the limiting toxicity here, so if your patients have had a lot of chemotherapy in the past and bone marrow is their major toxicity, then TAS-102 [tipiracil hydrochloride] is not a good option. On the other hand, if somebody has a lot of diarrhea from their prior surgeries, then regorafenib is probably not a good strategy. If patients develop more hand-foot-skin reactions from regorafenib, then TAS-102 [tipiracil hydrochloride] is a great option for them.
There are some toxicity considerations, but overall, the kind of population that you would expose to both these drugs is pretty similar. The benefit is pretty similar in the RECOURSE study, which is the TAS-102 [tipiracil hydrochloride] study. The overall survival includes from 5½ months to, I think, 7 months. The disease-control rate increased from about 15% to 40%, so there’s very similar efficacy in the same population.
One of the reasons for using regorafenib prior to TAS-102 [tipiracil hydrochloride] is that when you look at the RECOURSE data and its subgroup analysis, about 20% of patients had prior regorafenib that as in the CORRECT study there was no TAS-102 [tipiracil hydrochloride]–pretreated population. When you look at the hazard ratios for PFS [progression-free survival] and OS [overall survival], they’re pretty comparable in patients who had been pretreated with regorafenib vs not treated with regorafenib.
There are some data for efficacy of TAS-102 [tipiracil hydrochloride] even in a regorafenib-pretreated population. In addition, you give them a cytotoxic chemotherapy-free interval by intervening with regorafenib in between. There are some retrospective data for this sequence, which is regorafenib followed by TAS-102 [tipiracil hydrochloride] or TAS-102 [tipiracil hydrochloride] followed by regorafenib. In that retrospective analysis, the overall survival is numerically a little better with regorafenib followed by TAS-102 [tipiracil hydrochloride]. But those are all hypothesis-generating studies. In clinical practice, we can consider both these drugs to be fairly equivalent. The reason why I usually use regorafenib before TAS-102 [tipiracil hydrochloride] is because of the RECOURSE subgroup analysis.
There was the REVERCE study, which showed that in patients with KRAS wild-type tumor, patients who got regorafenib followed by cetuximab-irinotecan vs cetuximab-irinotecan first followed by regorafenib, the regorafenib followed by cetuximab-irinotecan did surprisingly better than the other treatment option. That’s a hard study to apply to our population in the United States, especially because we tend to use anti-EGFR up front for left-sided tumors. Then again, we don’t know the rate of RAS and BRAF mutations in that study. It’s a fairly interesting phenomenon. What it shows is that bringing the regorafenib earlier did not adversely affect giving chemotherapy later and definitely did not adversely affect the outcomes with regard to overall survival. Those are the data that support use of regorafenib prior to TAS-102 [tipiracil hydrochloride], but overall, they’re fairly equal efficacy drugs.
There’s a good chance of getting disease control on this patient with regorafenib. The patient would probably be also exposed to TAS-102 [tipiracil hydrochloride] after progression on regorafenib. In this particular patient I would definitely perform HER2 testing and expanded molecular profiling. We should try and tee this patient up for a clinical trial because after this option, we have a limited range with regard to standard-of-care options. It clearly appears the patient has a preserved PS [performance status] and therefore would be a good candidate for clinical trials.
With regard to this case, I’d point out about 3 things that I take away from this case. No. 1, I see the value of expanded testing up front because despite all these options that we have as our armamentarium against colorectal cancer, sooner or later these patients stop responding to the treatment options that we have. You can see that the benefit keeps on going down. This patient responded in first line, had stable disease in second line, and has come down to third line within 1½ to 2 years. We need more testing up front and more looking for clinical trials, because it appears like all throughout this course, we haven’t explored any trial options for this patient, and we should have.
The second thing is, especially with this right-sided colorectal cancer, I wouldn’t have treated with anti-EGFR in the second line. I would have done anti-VEGF agent. I’m not going to say that I never use anti-EGFR drugs in these patients, but I try to push them down the line as much as possible, using them as the last option. This patient may be also a candidate for a rechallenge with oxaliplatin, which we don’t have clinical trials for, considering that she had a good response to oxaliplatin, only has had 4 months of treatment. Technically, she was switched to FOLFIRI [5-fluorouracil, leucovorin, irinotecan], so oxaliplatin rechallenge is definitely a good option for this patient if PS permits. Those are a few of the key takeaways from this particular case.
Transcript edited for clarity.
Case Overview: A 72-Year-Old Woman With Metastatic Colorectal Cancer
May 2018
Initial presentation
A 72-year-old woman reported a 2-month history of bloating and abdominal cramping, and an 8-pound unintentional weight loss
Her last screening colonoscopy when she was 70 years of age was negative
PMH: hysterectomy at age 60, high blood pressure well controlled with lisinopril
Clinical workup
Labs: Hg 8.4 g/dL, CEA 6 ng/mL
Colonoscopy revealed a 9-cm mass in ascending colon
Pathology: invasive, poorly differentiated adenocarcinoma
Molecular testing: KRAS, NRAS, and BRAF wildtype; microsatellite stable
CT scan revealed widespread lesions in the liver
Diagnosis: Stage 4 colorectal cancer
ECOG PS is 1
Treatment
The patient received systemic therapy with FOLFOX + bevacizumab for 6 cycles, which was well tolerated
Follow-up imaging at 2 months and 4 months showed response in liver lesions
The patient continued on bevacizumab maintenance
June 2019
- The patient presents with shortness of breath and fatigue
- CT CAP shows two new lung lesions and growth of liver lesions
- The patient is switched to FOLFIRI and cetuximab
- Follow-up imaging showed stable disease in liver and lungs
August 2020
- The patient reports severe fatigue
- CT CAP shows progression in the lungs and new bony lesions
- The patient is given regorafenib alone
Phase 3 Trials of Botensilimab/Balstilimab Move Forward, Despite FDA's Approval Setback
July 18th 2024Agenus was advised by the FDA against filing for accelerated approval of botensilimab plus balstilimab for relapsed/refractory microsatellite stable metastatic colorectal cancer without liver metastases.
Read More
