Richard Kim, MD, discusses the utility of EGFR inhibitors in patients with RAS wild-type colorectal cancer, the convenience of biweekly dosing with cetuximab, recommendations for managing EGFR inhibitor–related treatment-related adverse effects, and novel combinations on the horizon.
EGFR inhibitors, such as cetuximab (Erbitux) and panitumumab (Vectibix), alone or in combination with chemotherapy, offer an effective treatment for patients with KRAS wild-type, left-sided, metastatic colorectal cancer (mCRC), said Richard Kim, MD, who added that although the management of treatment-related adverse effects (TRAEs), such as rash and gastrointestinal (GI) toxicities, remains the same, biweekly dosing with cetuximab provides a more convenient option to patients vs the traditional once-weekly dosing regimen.
“EGFR inhibitors are being [used] very commonly in patients with RAS wild-type CRC, especially in left-sided tumors. In terms of efficacy and toxicity, [cetuximab and panitumumab] are very similar. I’m not sure there is too much of a difference from that perspective,” said Kim, a service chief of Medical Gastrointestinal Oncology, and a senior member in the Gastrointestinal Oncology Department at Moffitt Cancer Center.
On April 6, 2021, the FDA approved a new dosing regimen of 500 mg/m2 of biweekly, intravenous cetuximab for the treatment pf patients with KRAS wild-type, EGFR-expressing CRC. The regulatory decision offers an alternative dosing option to the previously approved weekly dosing regimen of cetuximab alone or in combination with chemotherapy.
In an interview with OncLive®, Kim, who is also a professor of oncology at the University of South Florida College of Medicine, discussed the utility of EGFR inhibitors in patients with RAS wild-type CRC, the convenience of biweekly dosing with cetuximab, recommendations for managing EGFR inhibitor–related TRAEs, and novel combinations on the horizon.
Kim: Currently, we [complete] full molecular profiling on all patients with advanced CRC. That’s a given for anybody with advanced disease. We test for tumor profiling to see if [the patient harbors] any potentially actionable mutations. In CRC, the most common [alterations we test for] are KRAS, BRAF, mismatch repair deficiency, HER2, and microsatellite instability.
We have drugs that target RAS. If patients are RAS wild type, we use EGFR inhibitors. There are 2 anti-EGFR drugs [available]. Panitumumab is a fully humanized monoclonal antibody, [and the other agent] is cetuximab. If the patient is RAS wild type and has a left-sided colon tumor, we do have an option of using EGFR inhibitors in the first-line setting in combination with chemotherapy. [Using that approach] is up to each individual physician. In the second- or third-line setting, if patients are RAS wild type, we could definitely use an EGFR inhibitor in combination with chemotherapy or as a single agent.
Typically, in the relapsed/refractory setting, most of the data are with irinotecan. If the patient has a RAS wild-type tumor and I’m planning to use [an EGFR inhibitor] in the second-line setting, I tend to combine [irinotecan] with cetuximab. We could use panitumumab as well [instead of cetuximab].
In the first-line setting, data exist with both FOLFIRI [leucovorin calcium, 5-fluorouracil, and irinotecan] and FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin]. The bulk of the data with cetuximab is in combination with FOLFIRI, whereas the data panitumumab are in combination with FOLFOX.
There are subtle differences between cetuximab and panitumumab. Because [panitumumab is] fully humanized, patients have less chance of a hypersensitivity reaction, for example, compared with cetuximab. In some regions, [the incidence of] hypersensitive reactions is much higher [with cetuximab], at around 20%, so [providers may be more] likely to use panitumumab.
The other issue in the past was regarding the label of cetuximab. Cetuximab was given as a weekly regimen compared with panitumumab, which was given every 2 weeks. Those are the subtle differences [between the agents].
In the past, cetuximab has [proved effective] in RAS wild-type [CRC] as frontline or relapsed treatment. Per the label, the indication was for weekly dosing. [Cetuximab was given as] a bolus followed by weekly cetuximab. That was the standard.
However, it can be cumbersome to some patients. Patients have to come [into the clinic] weekly for [treatment]. During the COVID-19 era, some patients did not want to come to the clinic each week. Also, if we combine [cetuximab] with chemotherapy, chemotherapy is given every 2 weeks; therefore, giving cetuximab every week makes patients come into the clinic extra.
In the past, a lot of phase 1 or phase 2 randomized or non-randomized, [studies] compared weekly vs biweekly cetuximab. A couple of meta-analyses clearly indicated that there is no difference between weekly and biweekly [dosing] in terms of pharmacokinetics. If we look at some of the TRAEs, along with efficacy, [associated with cetuximab in combination with chemotherapy], there wasn’t much difference [between the dosing schedules].
In our practice, even though [weekly dosing] was the [only indicated dose in the FDA] label until recently, we’ve been using cetuximab every 2 weeks with chemotherapies, such as FOLFIRI. Now, with all the data that have been presented and published, the FDA [expanded the] label [for cetuximab], allowing [the agent] to be given every 2 weeks instead of weekly.
Currently, in patients with BRAF-mutant tumors, we use a BRAF inhibitor plus cetuximab. In the trial that was done with the BRAF inhibitor, cetuximab was given weekly. The question is: In that setting, can we give cetuximab every 2 weeks? To my knowledge, there are no data using [biweekly] cetuximab plus a BRAF inhibitor; however, with other available data and for the convenience of the patient, I use cetuximab every 2 weeks plus a BRAF inhibitor. However, more data are needed [in that regard].
In terms of dosing for regorafenib (Stivarga), the approved starting dose of 160 mg daily is probably too high for most patients because of toxicity. Therefore the randomized phase 2 ReDOS trial (NCT02368886) was conducted. The trial demonstrated that an escalation strategy beginning with 80 mg per day and escalating 40 mg a week to the goal dose of 160 mg was better tolerated with similar results compared with patients who started at standard dose of 160 mg per day 21 days on, 7 days off.
The gold standard is prospective studies to validate our hypothesis, but in some settings, that is not feasible. Secondly, if there is an abundance of data, like with cetuximab for example, that clearly tells us the same story, [we could be more inclined to use the data to inform treatment decisions].
[With cetuximab], I’m aware of many randomized or non-randomized trials, pharmacokinetic data, and meta-analyses that clearly tell us that the weekly vs biweekly [dosing regimen] seems to be very similar in terms of efficacy and TRAEs. If all [the data] tell the same story, we can make an exception in that case.
Another example is biomarkers with RAS testing. None of the RAS testing with EGFR [inhibitors] was done prospectively. Prospective studies were done, then [the investigators] collected and analyzed the tissue. Then, a retrospective study was done on those prospective studies and they all came to the same conclusion. That is how the FDA gave the indication that EGFR [inhibitors] should only be used in RAS wild-type [tumors].
[Data beyond those from prospective trials] should not be the rule for all trials, but there can be exceptions. [Biweekly cetuximab] is a clear exception where plenty of data [exist] to tell us that weekly vs biweekly dosing with cetuximab doesn’t matter in terms of using EGFR [inhibitors] with chemotherapy or as single agents.
[Cetuximab] has its own unique safety profile that patients dislike. One of the main AEs associated with EGFR inhibitors is rash. We discuss [the risk of rash] with patients in detail because it can be very bothersome and affect their quality of life [QOL].
Randomized data [show] that if we are proactive in managing rash with prophylactic topical antibiotics, or antibiotics, we are able to reduce the grade 3/4 rash [in a good proportion of patients]. In our practice, we tell patients that they will most likely get a rash. I prescribe antibiotics. Then, the key point is that [I] see the patient again very quickly—usually within 1 to 2 weeks—to see how the rash is doing and manage accordingly.
The second main TRAE we see with EGFR inhibitors is GI toxicities, such as diarrhea. As clinicians, we know how to manage those because of other cytotoxic chemotherapies that cause similar issues. We give Imodium [loperamide] or Lomotil [diphenoxylate] to control that.
Those are the 2 main AEs [associated with EGFR inhibitors], but hypersensitivity reaction is another AE that should be mentioned. Grade 3/4 [hypersensitivity reaction] with cetuximab occurs in about 3% of patients because it is chimeric. With panitumumab, this AE occurs much less because [the drug] is fully humanized. When we see [hypersensitivity reaction], it is during the first cycle of therapy.
In patients with KRAS mutations, EGFR inhibitors agents aren’t going to work. However, if a patient has a KRAS G12C mutation, that could be a driver in some cases, and there are available drugs [for these patients]. [Sotorasib (Lumakras)] is approved in lung cancer.
However, in CRC, similar to a BRAF inhibitor, [sotorasib] doesn’t seem to work that well [as monotherapy]. The response rates based on the published data are [under] 10% and [the responses don’t appear to be] very durable. Patients develop resistance very quickly.
The preclinical rationale tells us that we probably have to block another pathway, similar to the story with BRAF inhibitors. Whether we should combine [KRAS G12C inhibitors] with EGFR inhibitors [with or without a] MEK inhibitor is unclear. Those trials are ongoing currently.
Moving forward as a single agent, [sotorasib] is modestly efficacious at best. We need to do better, but whether that means adding an EGFR inhibitor or a MEK inhibitor, [we don’t know]. We have to wait for those data to emerge. The story is very similar to BRAF inhibitors, where single-agent BRAF inhibitors didn’t work. By preclinical rationale, if we combine [BRAF inhibitors] with EGFR inhibitors, we can see response rates as high as 30% to 40%.
In the first-line setting for patients with RAS wild-type tumors, [treatment decisions have always been] a question. Do we give anti-VEGF vs anti-EGFR therapy in the frontline setting? That has been a question that has existed for many years.
Currently, at least 3 randomized phase 3 studies are comparing anti-VEGF to anti-EGFR drugs in the first-line setting. One of the subsets that clearly seems to benefit from anti-EGFR therapy, maybe more than anti-VEGF therapy, is [patients with] left-sided RAS wild-type tumors. Those patients [comprise] about 20% to 25% of patients in our practice; however, they seem to derive higher response rates, longer progression-free survival, and better overall survival [with anti-EGFR therapy] vs anti-VEGF therapy. If there was one patient population in which we wanted to use anti-EGFR therapy in, it would be those with left-sided RAS wild-type tumors. There is a concern about QOL because of the rash issue. However, if patients derive a benefit from [anti-EGFR therapy] and if we are proactive in managing the rash, giving chemotherapy plus anti-EGFR therapy in the first-line setting for patients with left-sided RAS wild-type tumors may be doable.