Expert Discusses Finding the Optimal Treatment Strategy in CRC

A. David McCollum, MD

Treatment plans for patients with colorectal cancer (CRC), both in first-line and subsequent lines, are growing and changing, said A. David McCollum, MD. Selecting the optimal regimen, managing initial induction therapy and moving into maintenance therapy, means harnessing multiple individual data points and balancing efficacy with toxicity, he explained.

“There are some evolving strategies in the management of colon cancer. It's not as simple as one regimen and then there's not much else we can do,” said McCollum. “It's really a strategy of using the tools we have in our arsenal and trying to optimize the effectiveness and individualizing that to patients, not just through molecular features but also patient characteristics, such as sidedness.”

For previously treated patients with metastatic disease, McCollum said the dose-escalation regimen of regorafenib (Stivarga) explored in the phase II ReDOS trial and recommended by the National Comprehensive Cancer Network in March 2018 is likely to have widespread use. ReDOS showed that starting regorafenib (Stivarga) at a weekly dose of 80 mg and escalating to a weekly dose of 160 mg over 3 weeks induced less toxicity than the standard 160-mg dose, allowing patients to stay on treatment longer.

“That is going to become probably a more frequently utilized dosing strategy and probably benefit patients in the long run by exposure to more effective therapy,” McCollum said.

In ReDOS, the median overall survival (OS) was 9.0 months in the dose-escalation arm versus 5.9 months in the standard arm (P = .0943). The OS rate at 6 months (66.5% vs 49.8%) and at 12 months (34.4% vs 26.7%) favored the escalation arm.

The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated a third. Patients in the dose-escalation arm were more likely to meet that endpoint (43% vs 24%; P = 0.281) while demonstrating improved quality-of-life parameters and experiencing less toxicity.

The FDA approved regorafenib in 2012 for the treatment of patients with metastatic CRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if KRAS wild-type, with an anti-EGFR therapy.

OncLive: Can you provide a summary of your presentation?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, McCollum, an attending oncologist at Baylor University Medical Center, discussed the need for greater use of molecular profiling, the importance of tumor sidedness when selecting a treatment regimen, and the value of maintenance therapy in patients with metastatic disease.McCollum: We spoke about the modern-day management of colon cancer, looking at lines of therapy, progressing through different lines of therapy, and then talking about ways to manage patients who have refractory disease. The majority of the first part of the presentation focused on how to choose an appropriate frontline treatment option, then how one tries to navigate induction therapy and move into maintenance therapy.

There were a lot of different data discussed looking at the different options, incorporating things like patient preferences in terms of toxicity they might be more accepting of, and also tumor sidedness of the cancer, which is something that's come to light more recently. Along with that, there are specific side effects that we see with different monoclonal antibodies that are used in the management of colon cancer, such as VEGF- and EGFR-directed therapy.

What is your position on the use of regorafenib in metastatic disease?

We discussed how to segue from that active, intense regimen into this maintenance treatment, and the options available there for patients, which, helps to optimize the balance between quality of life and prolonging life.We have 2 approved agents in that space: trifluridine/tipiracil (Lonsurf) and regorafenib. These 2 drugs have never been compared head-to-head, but they have each been compared in pivotal data to supportive care because that is the standard in patients with refractory disease. Both offer an advantage. Using them early enough in the course of illness is important because they can provide benefit for patients.

With the regorafenib data there was some concern, and once the drug was used in practice outside of a clinical trial setting, it got a bit of a reputation for creating more toxicity than maybe providers and patients wanted to deal with when you're in that difficult decision between prolonging survival and accepting toxicities—where quality of life becomes a real key feature that we're focusing on. ReDOS looked at trying to use a different dosing strategy. It started at a lower dose as opposed to the standard dose of 160 mg daily. They started patients at half of that dose and, each week that they were on therapy, the dose was escalated to individual patient tolerance.

What do physicians need to keep in mind when choosing a frontline therapy?

The study was pretty convincing in that it showed better tolerance. More patients were able to stay on the drug for a longer period of time, and hopefully provide benefit for those patients.It's a broad topic. The summary is that there are a lot of options and there's probably not one absolute best option for any patient. However, we look at sidedness as an option; where does the primary tumor originate? Does it arise on the right side of the colon, which is largely the cecum up to the hepatic flexure? The transverse colon gets a little murky—that's the transition portion of the large bowel—and then we spoke about the descending colon through the rectum being left-sided. The data are pretty consistent, though not always prospective, suggesting that patients who have right-sided tumors probably don't do well with an EGFR antibody-containing regimen.

That's something most of us in the field are incorporating into our routine practice. We've been using RAS as a way to stratify an appropriate antibody therapy for some number of years, but sidedness also has to come into that decision.

Therefore, you look at the molecular features of the RAS, NRAS, KRAS, and RAF profile and the sidedness of the tumor. That helps us direct between an EGFR- or VEGF-targeted antibody. Then, which chemotherapy platform we pair that with comes down to patient preference, provider comfort level, and toxicities. If you have a patient that is going to do better on a regimen that spares neuropathy, you will usually use an irinotecan-containing regimen, such as FOLFIRI.

How widespread is molecular testing for these patients?

If a patient has more gastrointestinal (GI) toxicities to begin with…and you don't want to run the risk of diarrhea or enteritis, you might stray more toward oxaliplatin-based therapy. We certainly know from population-based usage that oxaliplatin-based therapies are more commonly used in North America—probably 75% of patients get that in the frontline setting.That's a very interesting question—one that maybe gets overlooked a bit. We think that when we're at a larger tertiary or quaternary referral center that, "Oh, this is how it's done everywhere." But when we try to look at population-based studies and try to understand what percentage of patients in 2018 are getting appropriate molecular testing to help guide and direct, perhaps not even frontline therapy but subsequent lines of therapy, it may be far less than we think.

It's not too uncommon that I’ll have a referral from a center that's not even that far of a large metropolitan area, and patients have had basic or no molecular testing. I saw a case just this week where there was a basic pathology report, but there was absolutely no molecular profiling of the cancer. It is probably not as many as we expect, and by “we,” I mean people who work at larger centers and mostly see GI cancers or exclusively CRC. We think it's being done everywhere, and it may not be. That's a message that needs to get out there.

Metastatic CRC is quite difficult to treat. Why is maintenance therapy important and what research is being done to determine the optimal maintenance regimen?

The important tests we think of in 2018 are extended RAS profiling, KRAS and NRAS, looking at the common sites of mutation but also the less common sites. [There are] the BRAF V600E mutations but there are some non-V600E mutations that, although less common, are probably important to know about. Increasingly in the era of checkpoint inhibitors, we want to know about the microsatellite instability status and the mismatch repair gene expression. Those are the foundational molecular features we need these days.We have 4 studies that helped to establish the role of maintenance: OPTIMOX1 and 2, CAIRO3, and the more recent PROT-AGE. These studies have shown the basic principle that some form of maintenance is probably better than a chemotherapy-free interval. Although there are select patients for whom a chemotherapy-free interval might be appropriate, that's probably not the best the strategy for the majority of patients.

The best strategy is likely deintensifying to some form of maintenance therapy. However, whether that's fluoropyridine, or fluoropyridine plus an antibody, or an EGFR-directed antibody alone is still open for discussion. The PROT-AGE study suggested that bevacizumab (Avastin) as a single agent in the maintenance setting is probably not a good idea; it doesn't provide much benefit over a chemotherapy-free interval. It's certainly costly in that setting and we want to be conscious of that in the field.

Those are all options for patients, but the concept of transitioning from induction to a maintenance-type of treatent is an important concept that we want to get out there.

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study. J Clin Oncol. 2018;36(suppl 4S; abstr 611).