Eng Highlights Important Treatment Considerations in mCRC

Cathy Eng, MD

In patients with newly diagnosed metastatic colorectal cancer (mCRC), it is important for oncologists to perform molecular testing early on in the process in order to create a plan for their patients, said Cathy Eng, MD, FACP, who also emphasized the significance of sidedness in this population.

“It’s very important for oncologists to recognize the importance of molecular testing early on in the treatment [of these patients] instead of just waiting for third- or fourth-line chemotherapy,” said Eng. “You have to think ahead and [figure out] what's going to be your next step if your patient is intolerant of treatment or has an allergic sensitivity reaction. You want to have a strategic plan for your patients.”

Another important factor to consider in the frontline treatment of these patients is sidedness, she added, as data show that the location of a tumor can be used to inform which treatment should or should not be used in certain patients. Although the use of EGFR-targeted therapy has been promising in those with left-sided tumors, there have been many challenges surrounding its use in treatment-naïve patients with right-sided tumors.

However, data from the phase II VOLFI trial, which is evaluating the use of mFOLFOXIRI with the EGFR inhibitor panitumumab (Vectibix) versus FOLFOXIRI in the frontline treatment for primarily unresectable patients with RAS wild-type mCRC, suggested that the combination showed efficacy, including in those with right-sided and BRAF-mutated CRC. The overall response rate (ORR) with mFOLFOXIRI plus the EGFR inhibitor in those with left-sided disease was 90.6% versus 60.0% with FOLFOXIRI, while the ORRs were 60.0% versus 50.0%, respectively, for those with right-sided CRC.¹

Eng stressed that it is just as important to know which treatment will not work in patients, as it is to understand which ones will be effective. To that end, she mentioned the data from the COLOPEC trial that were presented at the 2019 Gastrointestinal Cancers Symposium. Results showed that treatment with adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin in patients with T4 or perforated colon cancer ultimately did not improve peritoneal metastases-free survival at 18 months.²

OncLive: What does the current treatment paradigm look like for patients with newly diagnosed mCRC?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Eng, a professor of gastrointestinal and medical oncology, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the current treatment options available for patients with mCRC and highlighted recent data in the space.Eng: In the current landscape of CRC, there are a lot of different options available, but the majority are chemotherapy backbone-based. It is important to keep that in mind. Many patients have expressed a lot of interest in immunotherapy as a potential treatment option, but the reality is that the [percentage of] patients [with mCRC and stage IV disease] who are eligible to receive [this therapy] is going to be less than 5%.

Have any recent advances been made in the frontline treatment of these patients?

There are still the standard chemotherapy regimens such as FOLFOX and FOLFIRI. I would highly recommend the FOLFOXIRI regimen if your patient is well enough to receive treatment, has great performance status, and their laboratory tests are within normal limits. It is a good idea to be aggressive. It is more important for a treatment-naïve patient to know which side their original tumor is on because that will help determine whether or not they would benefit from EGFR-directed therapy. It’s an exciting time, in all fairness.Some of the advances that have been made for the frontline treatment for this patient population is the recognition for tumor sidedness. This is obviously something that is very important nowadays, recognizing that right-sided treatment-naïve patients with metastatic disease should not receive anti-EGFR therapy.

What are some maintenance strategies being used for this patient population?

There are some data from the VOLFI trial, which looked at the role of FOLFOXIRI plus anti-EGFR therapy in RAS wild-type patients. Once again though, you have to be very selective about its utilization for the patient who is not surgically resectable. The progression-free survival (PFS) was trending in favor [of the combination], but it was not statistically significant. Unless [a patient] has surgically resectable disease, I don't know if you want to be that aggressive. There was also some grade 3 diarrhea associated with that regimen. [This was a] small study, with less than 100 patients, but it is informative and gives the patient a potential option. However, if I want to be aggressive, I tend to utilize FOLFOXIRI plus bevacizumab (Avastin).There have not been a lot of advances made in regard to maintenance chemotherapy. All of us believe that after about 4 months to 6 months of treatment, you should consider maintenance chemotherapy with your frontline treatment—really to give the patient a break in terms of their energy level, and obviously, the degree of myelosuppression that can occur with treatment. Most of us do continue bevacizumab with 5-fluorouracil (5-FU) or capecitabine (Xeloda) as part of the maintenance regimen. There are 2 other drugs that are available for patients—aflibercept (Zaltrap) and ramucirumab (Cyramza)—although I don't think they're being used quite frequently for part of the maintenance regimen.

What data from the 2019 Gastrointestinal Cancers Symposium were you the most excited about?

Could you discuss the BEACON CRC trial and the preliminary data?

For [following] frontline therapy, there was a study called MODUL that looked at including immune checkpoint inhibition in combination with bevacizumab and 5-FU as part of the maintenance regimen. That study, unfortunately, did not demonstrate any additional benefit versus 5-FU and bevacizumab alone. Therefore, I would say that there have been no advances but now we know what not to do.It is very important that people are aware of the COLOPEC study, which is looking at the role of adjuvant HIPEC in the setting of a patient with either a perforated colon carcinoma or T4 tumor—a patient population [at high risk for peritoneal metastases]—and there appeared to be no role for adjuvant HIPEC. This is another indication that HIPEC is not necessarily beneficial in [patients with] CRC. We already know from the PRODIGE 7 study from [the 2018 ASCO Annual Meeting] that cytoreductive surgery and HIPEC were not beneficial in the mCRC population. Thus far, [we have] 2 negative phase III trials regarding the role of HIPEC in the early- and late-stage setting.The BEACON study is a 3-arm trial of which [all of] the results have not been reported as of yet. However, the most impressive investigational arm involves 3 drugs, encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux); this includes a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor as a triplet.

In the first 30 patients enrolled in this phase III study, they did a quick [safety lead-in] analysis. In those patients, the response rate was quite high and very favorable at a little less than 50% for all patients. For those patients who received only 1 prior line of therapy, [the response rate was] close to 60%. The PFS was close to 8 months and the overall survival was about 15 to 16 months.

What is your take-home message to your colleagues treating these patients in the field?

These data do suggest that for BRAF-mutant patients with mCRC, [it may be more beneficial] to provide more directed therapy in the earlier setting. There was obviously a greater response rate. The phase III trial results will come out hopefully in the next couple of years, but this is very encouraging, and that's why it resulted in an early indication for the FDA for this rare patient population.My take-home message for all oncologists and providers is to test your patients early on for any type of molecular analysis. There are some very interesting trials that are ongoing at this time. I hope that we will derive further information from them in the future. We want to understand the biology of our patients early on so that we can create a strategic plan for them. That’s the most important thing.

References

1. Geissler M, Riera-Knorrenschild J, Tannapfel A, et al. mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer m(CRC): a randomized phase II VOLFI trial of the AIO (AIO-KRK0109). J Clin Oncol. 2018;36(suppl 15, abstr 3509). doi: 10.1200/JCO.2018.36.15_suppl.3509.
2. Klaver CEL, Wisselink DD, Punt CJA, et al. Adjuvant HIPEC in patients with colon cancer at high risk of peritoneal metastases: primary outcome of the COLOPEC multicenter randomized trial. J Clin Oncol. 2019;37(suppl 4, abstr 482). doi: 10.1200/JCO.2019.37.4_suppl.482.