GI Experts Discuss Treatment Dosing, Sequencing, and Future Directions in CRC

Zev A. Wainberg, MD

The newly approved biweekly dosing regimen for cetuximab (Erbitux) in colorectal cancer (CRC) reflects what has become common practice in the community setting over the past several years, explained Jaffar A. Ajani, MD, and Zev A. Wainberg, MD.

On April 6, 2021, the FDA approved a new biweekly dosing regimen of 500 mg/m² as a 120-minute intravenous infusion for cetuximab for patients with KRAS wild-type, EGFR-expressing CRC.¹

With this regulatory decision, a biweekly dosing option is now available in addition to the weekly dosage regimen that had previously been approved for all approved indications when the agent is used either as a monotherapy or it is combined with chemotherapy.

During an OncLive® Insights program, Wainberg and Ajani discussed FDA updates regarding the dosing schedule of cetuximab for mCRC and the value of real-word data on clinical practice patterns in the community when administering this drug, the importance of aligning second-line treatment decisions with patient goals, and the benefits of treating patients with biweekly cetuximab.

Additionally, Wainberg and Ajani discussed their recommendations for treating patients with relapsed/refractory disease with regorafenib (Stivarga) or TAS-102 (trifluridine/tipiracil; Lonsurf), best practices for managing skin rashes associated with anti-EGFR therapy, and current data and interest with potent KRAS G12C selective inhibitors.

Ajani is a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. Wainberg is an associate professor of medicine and surgery, David Geffen School of Medicine, University of California, Los Angeles (UCLA), co-director, UCLA Gastrointestinal Oncology Program, and director, Early Phase Clinical Research Program, Jonsson Comprehensive Cancer Center.

Changes in Cetuximab Dosing Schedule in mCRC

Wainberg: Cetuximab has been around for a long time. Some centers have veered away from it because of a rash, and some centers have veered away from it because of infusion reactions that are seen with chimeric antibodies. However, it’s still part of the mainstay therapy for most patients getting EGFR antibody therapy in the United States. We had some recent studies showing changes in the label after many years. I wonder if you could comment on some of that and what the implications of that are.

Ajani: The label approved 500 mg/m² every 2 weeks, and there are some comparative studies, especially PK [pharmacokinetic] modeling with weekly dosing. Some studies and meta-analyses show there’s no difference in the end points, such as [overall] survival and PFS [progression-free survival]. There are at least 3 retrospective trials that I saw at [the prior] ESMO [European Society for Medical Oncology] and ASCO [American Society of Clinical Oncology] meetings, and ASCO GI [Genitourinary Cancers Symposium]. The advantage of every 2 weeks is that you can synchronize it with your oxaliplatin-based regimen, except for capecitabine-oxaliplatin—that could be an issue. But the FOLFIRI [5-fluorouracil, leucovorin, irinotecan] or FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] every-2-week regimen is popular, and it’s been used at my center even before the FDA approval. It’s well tolerated, it’s not excessive, and you get a spectrum of adverse effects [AEs], but most of us know how to manage those or prevent from them becoming severe.

Wainberg: All these years later, we see a package label on a drug that has been around for so many years. Cetuximab has been approved for colon cancer—it’s gone through different iterations—for nearly 20 years. Now we see a package label that changes based on mostly retrospective data, which reinforce what we’ve been doing in the real world. One of the interesting things that these presentations show is that real-world evidence can sometimes be used to change a package label.

Real-world evidence has probably gained a lot more credibility scientifically. We’re using databases that are not necessarily prospectively aligned but that take large numbers of people being treated and look at efficacy and toxicity end points. One of these studies was a meta-analysis, which compared biweekly cetuximab with weekly cetuximab. I really didn’t see any jeopardy as it relates to efficacy or toxicity. The other 2 were primarily real-world data presented at ESMO and ASCO GI, but could you comment briefly on what you think about using real-world data to guide regulatory decisions?

Ajani: That’s not necessarily very common. One example that comes to mind is the story about KRAS. It was all retrospective: the KRAS mutation and lack of anti-EGFR therapy. Initially there was a lot of doubt about retrospective data driving decisions, but eventually it panned out in every prospective study and every study later when the KRAS status was known. There is some merit to probing different characteristics like that, but it’s certainly not common.

I just changed to other drugs. There are not a lot of solid prospective data. It will be nivolumab [Opdivo] every 4 weeks or pembrolizumab [Keytruda] every 6 weeks. There are some good data, but it’s not like nivolumab or pembrolizumab data. The level of quality is not that high, but they’re still useful.

Wainberg: I agree. They’re never going to replace approvals or accelerated approvals for agents, but it is interesting. As time goes on, [there’s] recognition by the FDA and the [European Medicines] Agency that we do take some elements of real-world data and use them to inform community practice. It was a good example, and the KRAS example is another good story of how that’s evolved with cetuximab. And this, with this biweekly regimen, is what people have been doing for several years. It’s a reflection of what’s going on in the community. There’s increased recognition, primarily based on studies in Europe, that 500 mg/m² of cetuximab given biweekly is just as good. Now it can be incorporated with FOLFOX or with FOLFIRI or whatever biweekly regimen you choose, and you feel good you’re not jeopardizing safety and efficacy.

Sequencing Anti-EGFR Therapy in mCRC

Wainberg: When we’re talking about someone with second-line disease, who hasn’t received an EGFR inhibitor, in the United States we tend to use FOLFIRI. If I haven’t used an EGFR inhibitor by now, I would use it then in left-sided RAS wild-type tumor patients. The response rate in a very large series, CALGB 80405, was only 10% or 15%. There’s a huge drop-off from the first- to second-line therapy response rate in colon cancer. However, the same rules apply. In essence, the way I see it is the FDA allows us to use these new dosing schedules in both first- or second-line setting with some degree of comfort.

Ajani: Also, patient convenience is a big thing. We hardly ever talk about the burden on the patient and caregivers: economic distress and loss of wages.

Wainberg: Taking a day off work and coming in for weekly infusions. Especially during COVID-19, which has accelerated a lot of the way we think about it. I agree with you, Jaffer. We’re not just asking someone to come in, we’re asking someone and their partner and their caregiver to come in once a week. It meant that the caregiver had to wait in the parking lot or around the corner. Fortunately, COVID-19 is getting much better, but we should keep that in mind. We should think about the inconveniences. I agree with you about that.

Ajani: COVID-19 certainly complicates the matter, but this still is a big burden on the family, and it would be easier for them to come every 2 weeks instead of coming weekly.

Later-Line Treatment Options for mCRC

Wainberg: Colon cancer struggled once we get past 2 lines of therapy. We have FDA-approved agents such as regorafenib and TAS-102, but we’re still struggling with the optimal combinations. You might have seen recently a TAS-102–bevacizumab [Avastin] combination that improved PFS. Do you think there is value in that? How do we compare that with regorafenib in third-line patients?

Ajani: Both molecules, regorafenib and TAS-102, can produce considerable AEs and provide some advantage. But I’m intrigued by the little value that antiangiogenic agents provide even with repeated use. Regorafenib is nothing but another antiangiogenic agent, yet patients would receive bevacizumab for a long time and then use regorafenib. I’m not totally surprised that bevacizumab provided some benefit added to TAS-102 based on that, but the degree of benefit is always fairly limited. There’s minimal improvement.

Wainberg: We struggle with it. It’s hard to develop drugs in this space that we know that response rate for. Traditionally, a quick readout in colon cancer almost never happens in third-line colon cancer. We struggle with developing drugs in this space, and we’re forced to do these combinations sometimes, even though we’re not as enthusiastic as we’d like to be. Outside BRAF—we’ve talked about the importance of BRAF testing and starting patients if they’re eligible for encorafenib-cetuximab, which is now approved in the second-line setting; there’s a big trial in the frontline setting looking at that—in comparison with chemotherapy, we are still struggling in the third-line setting.

EGFR Therapy for mCRC: Dermatologic Toxicity

Wainberg: I want to talk about the AEs and some of the new directions, such as EGFR antibodies. This is timely because we just published a paper. I want to get your take on this, Jaffer. Cetuximab and panitumumab [Vectibix] have been around for a long time, and we all know that upward of 90% of patients get an acne from rash of some degree. It’s usually managed—though it depends on your institution—with a variety of topical creams, whether it’s steroids or some element of Cleocin or 1 of those soothing gels along with daily antibiotics, which usually include doxycycline and minocycline.

Sometimes that’s very cumbersome, and sometimes you have a lot of patients who have adverse effects with the antibiotics themselves. But we know that if we treat the rash aggressively, and patients are gaining benefit from the EGFR therapy, they’re going to stay on longer.

We participated in an interesting study, which just got published in Cancer Discovery, looking at a new topical treatment for rash induced by an EGFR antibody. A topical cream works essentially through the paradoxical effect of inhibiting the EGFR-induced rash on the skin of patients. It’s being tested in burn victims as well for similar reasons, but we also tested it. Antoni Ribas, MD, PhD at UCLA shepherded this idea because he tested in melanoma.

We tested [this cream] recently in a pilot study in patients who haven’t been treated with antibiotics to see if we could reduce with this new topical BRAF cream rash. It does work, interestingly. It does downgrade the rash. It doesn’t make it go away, but it downgrades it.

The next step is that we’re doing next is to see if it’s better than the standard-of-care steroid creams and all those things because it’s a more mechanistic way. It’s very elegant science that went into the development of this drug. It’s funny how an old AE like rash can be repurposed and thought about differently. The reason why it was interesting is because as we were developing the clinical trial, it turns out there are no directly FDA-approved treatments of the EGFR rash. To design the study, you’re not sure what the control arm should be.

Ultimately, this is important in study design. What should your control arm be? If there’s no FDA approval, what should you do? There’s a lot of discussion about how to design the study. It was interesting to me, even though we all manage it in a certain way. You think about something that’s been around forever and you say, “How could you improve it if there’s a more scientific way to study this and extend it?” That drug’s moving on to the next phase. I find that for now, the best way to manage it is to keep patients on doxycycline or minocycline.

Future Directions in mCRC

Wainberg: You know all about what’s going on in gastric cancer, but how about in colon cancer? Anything you can think about that’s worked in gastric cancer that may have a future in colorectal cancer, whether it’s immunotherapy drugs or something along those lines?

Ajani: It’s a real challenge at or after the third-line setting if the patients are not doing well. Of course, we must find novel targets and then develop drugs that have reasonable safety. Moving forward, this may apply to multiple tumor types—all these oncogenes that cancer cells use, they’re also manipulating their environment.

There are a few exceptions. For an MSI [microsatellite instability]–high tumor, the oncogenes cannot manipulate the stroma because there are too many new antigens, and the immune system is alerted to all that. But if you think about run-of-the-mill colon cancer, which is a cold type in which the whole stroma is orchestrated by the oncogenes. We’ll have to not only treat the cancer cell with a targeted agent but also treat the stroma at the same time. If you just manipulate the immune system, the cancer reprograms. If you just go after the tumor cell, then also you don’t win because tumor cells are much too smart; 1 clone you can eliminate or reduce but the other will emerge. I wanted to ask you on the review article that rich gold bargain you wrote, there are some interesting hypotheses there about the KRAS. I didn’t know that the KRAS status can change based on liquid biopsy. Tissue-based studies may not be all that reliable. Can you talk about that a little? Why would a KRAS-mutant clone subside if you give like a treatment-free interval?

Wainberg: That’s interesting. It’s a controversial thing to be sure because some studies have shown that it changes in 1 direction or it changes in the other direction. As you know, this may just be a product of clonal heterogeneity more than anything. It may not be that the tumor is losing its RAS status or gaining its RAS status as much as a different clone. I do agree with you that ctDNA [circulating tumor DNA] has allowed us to study this more comprehensively. There’s a nice study being done, a very prospectively designed study called the CRICKET study [NCT02296203], looking at this question of rechallenge with an EGFR inhibitor. Historically, we never rechallenge with an EGFR inhibitor; when they progress, they progress. But in these patients, in whom they had RAS wild type, some of these patients on ctDNA did convert somehow to become mutated.

The question is: When you combine an EGFR inhibitor with something else, will it work? There’s a new study that suggested that 1 of the elements of that is a MET, which has been around for a while, of course—MET amplification as a resistance mechanism to EGFR inhibitors. There’s a nice new study starting in patients with progression on EGFR inhibitors who lose their RAS status or mutate and become MET amplified in the studies combining the MET inhibitor with an EGFR inhibitor.

There are different prospective studies being done to look exactly at that question, which are easy to do nowadays. Now you don’t have to do serial biopsies. You can just rely on ctDNA to both make the assessment of where the mutation is as a resistance mechanism and also to follow prospectively. We’ve developed enough retrospective experience with ctDNA that we should start putting some of these assays to the test in prospective studies. That one is interesting as well.

KRAS G12C Inhibitors in mCRC

Wainberg: Just to wrap up, everybody talks about KRAS G12C. That’s a RAS mutation too, which we don’t use an EGFR inhibitor for. Until 2 or 3 years ago, we didn’t even know it was G12C, but now we clump them all in with KRAS. Now we have potent drugs, selective KRAS G12C inhibitors that are effective. These drugs in colon cancer don’t have a lot of single-agent activity in my view. They have stable disease, a few responses, not like in lung cancer—which isn’t a big surprise, I suppose.

What’s interesting is that there was a study published 6 months ago or so in Cancer Discovery. It suggested that 1 of the elements of resistance mechanisms to KRAS G12C inhibitors in colon cancer was EGFR upregulation. There’s this surge of interest in looking at FGFR combinations with KRAS G12C inhibitors, particularly in that group, which is only 4% or so of metastatic colon cancer. What do you think about combining these 2 elements of drugs together in select patients?

Ajani: That’s very important and interesting. You remember the BRAF story in melanoma and in colon cancers and in melanoma if your BRAF inhibitors are very active. That’s because the EGFR is buried in the DNA, it cannot be transcribed. But in colon cancer, EGFR is a resistant mechanism. If you inhibit BRAF, EGFR takes over. But if you inhibit both, then you can get an advantage. Even for KRAS, all these loops must be closed because the survival circuitry is just fascinatingly fantastic.

Wainberg: It’s a very similar paradigm to what we saw in BRAF and like lung cancer in which kinase inhibitors can work a lot more effectively [as] single agents. But in diseases like colon cancer, where there’s more bypass, perhaps mechanisms of resistance, the concept of oncogene addiction isn’t as clear. We need 2 drugs, and there are already big trials being planned to combine these KRAS G12C inhibitors with EGFR inhibitors—even registrational trials. The field is moving fast in that regard, and that’s 1 of the things I’m looking forward to seeing. There are other KRAS isoforms, which we may very well have drugs for in the next few years too. Some of those things really excite me, Jaffer. We’ve got to keep busy in the world of drug development in these diseases to improve outcomes for our patients.

Reference

1. FDA approves new dosing regimen for cetuximab. News release. FDA. April 6, 2021. Accessed July 13, 2021. https://bit.ly/3mpj2Qj