Anti-EGFR Treatment Grows in Prominence for CRC

With an influx of new trials examining the use of anti-EGFR treatments in patients with advanced colorectal cancer (CRC), attention must be paid to finding the optimal window in which to give these therapies to maximize benefit, according to Kristen K. Ciombor, MD, MSCI.

“We are learning that there are many ways to utilize anti-EGFR therapy for patients,” Ciombor said. “Moving forward, studies need to be designed in ways that will help to optimize patient outcomes, regarding the use and reuse of anti-EGFR therapy, as well as to manage toxicity and other things that affect quality of life.”

In the interview with OncLive^®, Ciombor, an assistant professor of medicine in the Division of Hematology/Oncology, Gastrointestinal Research Program, at the Ingram Cancer Center of Vanderbilt University, discussed the latest updates in the treatment of patients with advanced CRC, and ongoing research efforts examining the use of anti-EGFR therapy in this population.

OncLive^®: Could you speak to some of the developments made with anti-EGFR therapies in metastatic CRC? Specifically, what are the key advances that have been made in the first-line setting for the subset of patients with RAS and RAS wild-type disease? 

Ciombor: There is the phase 3 CALGB/SWOG 80405 trial [NCT00265850], as well as some more recent data, including [those produced in] the phase 2 DEEPER study [NCT02515734]. In that study, [investigators evaluated] the combination of FOLFOXIRI plus cetuximab [Erbitux] vs FOLFOXIRI plus bevacizumab [Avastin] for patients with previously untreated RAS wild-type CRC. That study had an interesting primary end point, which was depth of response, [and this] did favor the cetuximab-containing arm. Clinically, we are not sure how that translates into overall survival [OS] and other end points that are important for patients. That is always a question: Which biologic [should we] use in the first-line setting for these patients with RAS wild-type disease?

In the maintenance therapy realm, the phase 2 PanaMa [NCT01991873] trial, [the data of] which [were] presented at the 2021 ASCO Annual Meeting, looked at patients who received up-front FOLFOX plus panitumumab [Vectibix], and then went on to receive 5-fluorouracil and leucovorin plus or minus panitumumab maintenance therapy. That was an interesting study in terms of the end points, as well as the number of patients who did get reinduced with the panitumumab after the panitumumab-containing maintenance therapy. It gives a better idea of what the options are for patients who start with up-front anti-EGFR therapy. However, given the toxicity, that may not be always the optimal option for patients in the maintenance setting.

[We should also discuss] anti-EGFR therapy in BRAF V600E–mutant CRC, both in the first and second line. There is the BEACON study [NCT02928224], and encorafenib [Braftovi] and either cetuximab or panitumumab is now a second-line standard of care for [those with] BRAF-mutant CRC in the metastatic setting.

Then there is the phase 2 FIRE-4.5 trial [NCT04034459], which looked at patients with BRAF-mutant disease who received similar treatment to the DEEPER study, but in a different patient population. This examined FOLFOXIRI plus cetuximab vs FOLFOXIRI plus bevacizumab. Interestingly, the bevacizumab-containing arm was the preferred option in the first-line setting, which confirmed what is already commonly done for patients with BRAF-mutant disease in this setting.

Given the results of the BEACON study, [it will be important to] consider moving this regimen to the first-line setting. Recent updates from the phase 2 ANCHOR-CRC trial [NCT03693170], which were presented at the 2021 ESMO Congress, showed some decent response rates in the [now fully enrolled trial], but [we did] not [see] the progression-free survival [PFS] we were looking for in the first line compared with the cytotoxic backbone that is commonly used. Looking forward, even past that in the first line, it may be preferable to combine these regimens, which is what the phase 3 BREAKWATER [NCT04607421] study is examining; [here, investigators are] combining chemotherapy with targeted therapies, such as encorafenib and cetuximab. That is an interesting area [of research] where we will have a lot of data in the next few years that will help us further refine how we treat these patients.

What is known thus far about anti-EGFR rechallenge therapy?

Several [ongoing] studies, some that have been presented and published, and some that are ongoing, are looking at patients who have received anti-EGFR therapy, experience disease progression, at some point discontinue the therapy, and come back to it later. These studies are trying to optimize how to do that to help more patients with BRAF wild-type disease.

I [should also mention] the CRICKET study [NCT02296203], which looked at third-line cetuximab plus irinotecan given after a prior anti-EGFR–containing regimen. [This approach elicited] response rates of approximately 21%. The study also examined ctDNA to identify patients who might benefit from this approach, which is the key. Additionally, the phase 2 CHRONOS study [NCT03227926], data of which [were] presented at the 2021 ASCO Annual Meeting, examined patients in that same setting, but who had achieved a prior response to anti-EGFR therapy, came back to it, and received anti-EGFR therapy again. In this case, the drug was panitumumab, which had a good response rate for refractory patients. Moreover, ctDNA was helpful in identifying patients who may benefit from this [strategy].

Finally, the phase 2 CAVE study [NCT04561336] was recently published and [examined] the same type of patient population. The ongoing phase 2 POLE study [NCT03435107] is also looking at anti-EGFR therapy with panitumumab rechallenge vs standard therapy, either regorafenib [Stivarga] or TAS-102 [trifluridine/tipiracil; Lonsurf]. The results of this study are anticipated.

Is there any research that you or your institution is participating in that you would like to highlight?

We are excited about several up-and-coming or enrolling trials. One of the studies that is being enrolled through The COLOMATE Platform is the phase 2 FIGHT-202 study [NCT02924376] in metastatic CRC; this is for patients [whose tumors harbor] any kind of FGFR or FGF alteration. This [alteration] is seen frequently in patients—especially in the refractory setting. We are investigating whether, like in biliary cancers and other types of tumors, the FGFR-inhibition approach can be helpful for patients with genomic alterations.

Another study that is open through the Eastern Cooperative Oncology Group is looking at nivolumab [Opdivo] plus ipilimumab [Yervoy] and short course radiation in the locally advanced rectal cancer population who are going to undergo potentially curative resection. That [research] is exciting, because it may mean, [that we may be able to avoid] chemotherapy [in the future] for patients with microsatellite instability–high rectal cancer.