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Keiser Compares the Use of 2 Agents for Patients With Metastatic CRC

Samantha Hitchcock
Published Online:2:47 PM, Fri December 14, 2018

L. Wayne Keiser, MD

During a Targeted Oncology live case-based peer perspectives presentation, L. Wayne Keiser, MD, talked about the treatment considerations and decisions he makes when treating patients with colorectal cancer (CRC). Keiser, a medical oncologist at St. Joseph Health Medical Group, Santa Rosa, California, explained his treatment decisions for the based on a case scenario of a patient with KRAS-mutated metastatic CRC.

Case

March 2016

A 50-year-old otherwise healthy woman received her first routine colonoscopy, and a suspicious mass in the sigmoid colon was detected. Her biopsy revealed poorly differentiated adenocarcinoma.

April 2016

She underwent a laparoscopic sigmoid resection and staged at T3N2 (stage IIIc).

June 2016

The patient began 6 months of adjuvant capecitabine plus oxaliplatin (CAPEOX).

May 2017

A CT of the abdomen, pelvis, and chest later showed diffuse bilateral liver nodules (≤5 mm). Her ECOG performance status was 0 at this time. Additionally, molecular testing on tissue biopsy was positive for KRAS exon 2 codon 12 mutation. No mutations were noted in NRAS or BRAF and she was microsatellite stable.

What are the first-line options for systemic therapy?

Folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX) plus bevacizumab (Avastin) is an option, which is what 85% of US oncologists will choose. About 15% will use folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab. It is almost the reverse in Europe. They favor FOLFIRI [in the frontline setting].


June 2017

The patient initiated FOLFOX plus bevacizumab for 8 cycles and tolerated it well. A 4-month CT scan showed reduction in liver lesions, and the patient switched to maintenance. She continued on fluorouracil and folinic acid plus bevacizumab maintenance.

April 2018

Ten months after initiation of FOLFOX, the patient complained of a dry cough and shortness of breath on exertion. A CT of the abdomen, pelvis, and chest later showed multiple lung nodules in right pulmonary lobe. It was decided to start the patient with FOLFIRI and bevacizumab was continued.

July 2018

An increase in the patient’s carcinoembryonic antigen (CEA) was noted on last 2 follow-up labs. A CT of her abdomen, pelvis, and chest showed progression of lung disease, new lesion in the liver in close proximity to the bile duct, and diffuse peritoneal disease. Her ECOG performance status at this point was 1.

The patient continued to work in an office setting but reported that she sometimes left work early due to fatigue. She wanted to know her options for additional therapy, but she wanted to avoid infusion-based therapy and toxicities.

What are your general impressions at this point?

This patient received FOLFOX plus bevacizumab for 4 months. It is well tolerated, and at the 4-month mark, she has nice reduction, so she flips over to maintenance. After 10 months, she starts to end the maintenance [due to] dry cough and shortness of breath. She gets a CT of the abdomen, pelvis, and chest, and she has multiple pulmonary nodules. We need to remember that she already has liver metastases.

She then flips over to FOLFIRI plus bevacizumab, and 3 months later it turns out that she has an increase in CEA, and her CT of the abdomen, chest, and pelvis showed progression of disease in multiple areas. She still has a great performance status and is still working. She no longer wants infusion-based therapies because of the process and the toxicities. I can't think of any infusion-based therapies one would offer to this patient at this point anyway.

What is the rationale for trifluridine/tipiracil (TAS-102; Lonsurf) after the patient progresses on FOLFIRI plus bevacizumab?

Oral agents are all we have at this point. The RECOURSE trial got TAS-102 on the map.1 About 60% of the patients on the trial had received 4 or more prior regimens. They were heavily pretreated and had basically seen everything. They were randomized 2:1 to either placebo and best supportive care or TAS-102 with the standard-dosing regimen. Some people call this the working man's drug. I call it Monday to Friday. This is because it is 5 out of 7 days. I always start on Monday because it is easier to remember. So, 5 days in a row, 2 days off, 5 days in a row, 2 days off, 2 weeks off. The primary endpoint was overall survival (OS) in the RECOURSE study.

The hazard ratio (HR) is 0.68, and there was a 32% reduction in risk of mortality with TAS-102 versus placebo. The confidence interval is tight, and the P value is .001. When I'm talking with the patients, however, I learned a long time ago that I should not talk about HRs and other statistics such as this. So, what I like to talk about is landmarks. At the 6-month landmark, TAS-102 has an OS rate of 58% versus 44% with placebo. At the 1-year landmark, the OS rate for TAS-102 is 27% and 18% for placebo. From an efficacy point of view, I think this is worthwhile. I personally would use TAS-102 because of its efficacy in addition to its toxicity profile.

What are the adverse events (AEs) associated with TAS-102?

The deal with TAS-102 is that it is easy to remember the toxicities because it is myelosuppression. The rate of neutropenia is 38% grade 3/4, but it breaks down into 23% grade 3 and 11% grade 4. There was also a 4% [rate of] febrile neutropenia. So, despite grade 3/4 neutropenia, febrile neutropenia was low, and there was 1 neutropenic death out of over 530 patients. I think the point there is that it is [a] myelosuppressive drug and that is it.

Additionally, it is not very thrombocytopenic. There is a 5% risk total of grade 3/4 [thrombocytopenia]. I bring that up because patients have been through FOLFOX and FOLFIRI and are often left with a platelet count sitting at 70,000 to 80,000. Physicians can get a little anxious about using a myelosuppressive agent. But this drug just doesn't pop the platelets. Additionally, in my mind anyway, if there is anything oncologists know how to manage it is myelosuppression.

Sometimes I get asked about growth factors. In the RECOURSE trial, 9.4% of patients had growth factor support. I am not a big proponent of using growth factors in metastatic disease. However, the important point with this drug is to keep the dose up.

What is the rationale for regorafenib (Stivarga) for a patient such as this?

Regorafenib was approved based on the CORRECT trial.2 Participants were randomized 2:1 to regorafenib or placebo, with a primary endpoint of OS. The median OS is 6.4 months with regorafenib versus 5.0 months with placebo. The HR was 0.77, with a decent confidence interval and a decent P value of .0052.

We can't compare cross trial, but in the end, we all do it because that is all we have. The 2 agents are pretty close in efficacy, with a HR of 0.77 for regorafenib and 0.68 for TAS-102.

What are the AEs associated with regorafenib?

The main issue is hand-foot syndrome. Anybody who has ever used regorafenib knows that hand-foot [syndrome] is the biggest issue. There is about 17% of patients in the CORRECT trial who experienced hand-foot grade 3/4.

Can you explain the outcomes of the ReDOS trial?

This was a very simple trial with 123 patients with pretreated metastatic colorectal cancer.3 Patients were randomized into 4 cohorts, but it is really just 2. The first cohort started treatment at a low dose and dosed up. The endpoint was the percentage of patients who completed 2 full cycles and were able to start a third cycle. It is an unusual endpoint, but the endpoint they were looking for was tolerability. How can we make this drug more tolerable? Because this can be a tough drug.

The first cohort started low at 80 mg and dosed up to 160 mg. The arm was randomized with or without clobetasol (Temovate) steroid cream. In the second cohort, it was started at the normal 160-mg dose and, if necessary, dosed down. Again, randomized with or without steroid cream.

In the escalating-dose group, 43% of people were able to get to cycle 3. In the standard 160-mg dose, only 24% of people were able to get to cycle 3. This reflects what we all already felt—that starting at the standard dose is very tough. So, this dosing scheme is now in the National Comprehensive Cancer Network guidelines. It is still hard to use, but it is certainly better to start low and work up. The toxicity profile is largely the same, with about half of the hypertension in the dose-escalating cohort.

What is your personal experience with TAS-102?

If the patient is going to have a good course of treatment, you will have a good course of treatment. If they are having trouble, you'll have trouble. The patient and their family will be in your office, and your 15- to 20-minute visit will not be 15 to 20 minutes. 

I've used TAS-102 for some of my patients, and just like everybody, I've had times where it didn't work at all. I see largely stable disease, a couple of partial responses, and my latest patient is a guy with metastatic CRC who has been on therapy for about 8 years. I just started him on TAS-102, he had a CA 125 of about 5800 that dropped to about 2800. He looks better, so I would say he has stable disease. I see usable benefit, and I haven't had a lot of toxicity associated with TAS-102.
 
 
References:
  1. Mayer RJ, Van Cutsem E, Falcone A, et al; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi: 10.1056/NEJMoa1414325.
  2. Grothey A, Van Custem E, Sobrero A, et al; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-31 doi: 10.1016/S0140-6736(12)61900-X.
  3. Bekaii-Saab TS, Ou F-S, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dose strategies for regorafenib in refractory metastatic colorectal cancer (mCRC): an ACCRU Network Study. 2018;36(suppl 4; abstr 611). ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.611.


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