Colorectal Cancer Coverage from Every Angle

Encorafenib (Braftovi®) Plus Cetuximab (Erbitux®) or Panitumumab (Vectibix®)

Posted: Thursday, May 28, 2020

[Editor’s Note: On April 8, 2020, the doublet of encorafenib plus cetuximab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation after prior therapy.1]

Advanced Colorectal Cancer: Defining Molecular Drivers

Information about a tumor’s molecular subtype is critical for the selection of appropriate treatment for patients with advanced or metastatic colorectal cancer. Currently, treatment decisions, particularly after the first line, depend on the RAS, BRAF, and HER2 status of the tumor, as well as microsatellite instability (MSI- high or MSI-low) and “sidedness.” According to a growing number of experts, these characterizations of the molecular drivers of tumor biology are best determined with comprehensive molecular profiling techniques.

BRAF V600E mutations occur in 8% to 15% of metastatic colorectal cancers,2 and this minority segment of the overall colorectal cancer population has a poor prognosis.3 Of note, RAS and BRAF mutations are almost always mutually exclusive.4 Although patients with wild-type RAS may be eligible for targeted treatment with an anti-EGFR inhibitor, the presence of a BRAF V600E mutation will decrease the likelihood that such treatment will be effective unless given in combination with a BRAF inhibitor (eg, encorafenib).

Improving on Current Practice

Current care for initial therapy in patients eligible for intensive therapy with BRAF V600E–mutated advanced/metastatic colorectal cancer is either a triplet or doublet chemotherapy regimen plus or minus bevacizumab.5 “We know BRAF-mutated tumors will not respond to EGFR inhibition unless the EGFR blocker is used to combat the feedback loop related to the BRAF mutation,” explained Axel Grothey, MD, Director of GI Cancer Research at the West Cancer Center and Research Institute in Memphis. “So, the biologic agent has to be bevacizumab.”

With regard to the chemotherapy backbone, Loupakis and colleagues suggested a triplet (ie, FOLFOXIRI [leucovorin, fluorouracil, oxaliplatin, irinotecan]) is necessary to combat the aggressive biology of BRAF-mutated disease.6 Dr. Grothey told JNCCN 360 that he agrees that it makes sense to consider a triplet regimen, FOLFOXIRI, in patients who can tolerate it because of the aggressiveness of BRAF-mutated disease. However, he added, “there isn’t overwhelming evidence that this is preferable. A doublet regimen (FOLFOX or FOLFIRI) plus bevacizumab is also an acceptable option.”

Building a Better Treatment Regimen

In an effort to improve outcomes for patients with advanced BRAF-mutated colorectal cancer, researchers developed a triplet regimen comprising a small-molecule BRAF inhibitor and a MEK inhibitor plus an EGFR inhibitor. Asked to explain the rationale for this combination after the 2019 Gastrointestinal Cancers Symposium, Scott Kopetz, MD, PhD, Deputy Chair for Translational Research, Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, said: “BRAF inhibitors alone are minimally effective in this population due in part to feedback through growth factor receptors such as EGFR. By adding an EGFR inhibitor and a MEK inhibitor to the BRAF inhibitor, feedback reactivation of the MAP kinase pathway is blunted.”7

Further explaining the hypothesized mechanism of triplet-targeted therapy, Dr. Grothey noted: “Research has shown that BRAF-inhibitor monotherapy can actually increase signaling through EGFR and can restore MAPK [mitogen-activated protein kinase] signaling activity through RAS and an alternate RAF, CRAF,” Dr. Grothey noted. “Therefore, inhibiting RAF, MEK, and the cell-surface signaling through EGFR with an EGFR antibody such as cetuximab is thought to be critical to effectively ablating the MAPK signaling in BRAF V600E–mutant colorectal cancer.”8

Combination Regimens

The triplet regimen used in the BEACON trial (ClinicalTrials.gov identifier: NCT02928224)9,10 consists of encorafenib (300 mg daily), an oral small-molecule BRAF kinase inhibitor; binimetinib (45 mg twice daily), an oral small-molecule MEK inhibitor that targets key enzymes in the MAPK signaling pathway; and cetuximab (loading dose of 400 mg/m2, then 250 mg/m2 once weekly), an EGFR antibody.

Data were presented in the winter of 2020 demonstrating that the triplet of encorafenib, bimetinib, and cetuximab was not superior to the doublet of encorafenib plus cetuximab in terms of overall survival.11,12 In a video interview after his presentation at the 2020 Gastrointestinal Cancers Symposium,13 Dr. Kopetz commented on the doublet: “This regimen is well tolerated. Maintenance of quality of life, combined with overall survival improvements and increased response rate, represent a new standard of care for our patients.” The doublet of encorafenib plus cetuximab was approved by the FDA on April 8, 2020.1

The triplet of encorafenib, bimetinib, and cetuximab was not superior to the doublet of encorafenib plus cetuximab in terms of overall survival.

This finding, namely that the doublet is as effective as the triplet, “suggests that binimetinib may be safely dropped,” Dr. Grothey told JNCCN 360. This would reduce the cost of the regimen and toxicity. “Binimetinib is the component of the regimen that causes most of the diarrhea, the fluid collection in the retina that presents as transient blurry vision, and some cardiotoxicity,” he continued.

On the other hand, binimetinib may prevent squamous cell carcinomas of the skin. In the melanoma setting, “If you have BRAF-mutated disease without MEK inhibition, you might have an increase in these other types of skin cancers. This is meaningful,” Dr. Grothey explained, “because patients with melanoma now survive a long time and may indeed develop squamous cell cancers, which need to be monitored and treated. In the setting of second- and third-line metastatic colorectal cancer, squamous cell carcinoma of the skin is less of an issue, because most patients do not live long enough for it to become significant.”

With the encorafenib plus cetuximab doublet as a backbone, Dr. Grothey suggested future studies explore the addition of another biologic agent to overcome resistance mechanisms. Moreover, he pointed out, adding the doublet to chemotherapy may also be an effective strategy in the first line. Such a trial is currently being planned.

According to Jamie Faber, PA-C, who works with Dr. Kopetz in the Department of GI Medical Oncology at The University of Texas MD Anderson Cancer Center: “We had been using the triple-drug regimen until recently. The data presented at the 2020 Gastrointestinal Cancers Symposium and the FDA Priority Review of the data for a supplemental indication provide additional evidence of the doublet’s efficacy and safety. This has resulted in approval of the doublet regimen.”

Treatment Preference in BRAF-Mutated and MSI-High Tumors

About 20% of patients with BRAF-mutated colorectal cancer14 have disease that is characterized as MSI-high or mismatch repair–deficient. Therefore, a majority of these patients are not eligible for treatment with immune checkpoint inhibitors, such as nivolumab or pembrolizumab.

“For the 10% to 20% of patients with BRAF-mutated disease who also have MSI-high tumors—which are mainly right-sided—my preference is to use an immune checkpoint inhibitor initially,” Dr. Grothey said, “particularly because response is more durable.” Although those with MSI-high tumors were not excluded from the BEACON trial, many preferred to opt for immunotherapy. Nevertheless, because BEACON was an international study and immune checkpoint inhibitors are not approved in Europe, about 5% to 10% of the patient population in the study did have MSI-high tumors.

Survival in BRAF V600E– Versus Other BRAF-Mutated Tumors

Researchers have reported that 2.2% of all metastatic colorectal cancers are BRAF-mutated tumors, but not V600E.15 Patients with these tumors actually “do better,” Dr. Grothey observed. An overview of three different classes of BRAF mutations was published recently: the majority were V600E; the other two differed by how dependent they were on the EGFR pathway.16 “There’s a BRAF 596 mutation, which is actually an endogenous mutation that deactivates BRAF. Patients with this mutation have better survival, a median of 60 months, which is even better than that for patients with BRAF wild-type tumors,”17 Dr. Grothey told JNCCN 360. They have a more smoldering, less aggressive type of disease and do not usually need a triplet chemotherapy regimen upfront; thus, they would not respond to the biologic combination evaluated in the BEACON trial, he noted.

“If you just do polymerase chain reaction to identify the V600E mutation,” Dr. Grothey emphasized, “You will not find the BRAF 596 mutation. So, the clinical goal should be to move toward next-generation sequencing so you can look at the whole gene.”

The clinical goal should be to move toward next-generation sequencing so you can look at the whole gene.

Administration Details for the Doublet Regimen 

To accommodate global and international regulatory input, Dr. Grothey explained, cetuximab was given in the BEACON study on a weekly basis with a loading dose. “Hardly anyone does that anymore,” he noted. “We tend to give 500 mg/m2 of cetuximab every 2 weeks. In practice, what we do is follow the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer,5 which list panitumumab, at 6 mg/kg, every 2 weeks.” [Editor’s Note: The NCCN Guidelines also list cetuximab at 400 mg/m2 first infusion, then 250 mg/m2 IV weekly.] The encorafenib component (300 mg orally, once daily) is added to that. Dr. Grothey continued: “This way, patients have to come to the center only twice a month for infusions and once a month for a toxicity check.”

All medications are started on the same day, Ms. Faber told JNCCN 360. “That means patients receive the cetuximab infusion and also start the encorafenib [and binimetinib] orally.”

For the first cetuximab infusion, “We give diphenhydramine as a premedication to prevent any infusion reactions,” Ms. Faber said. “We also slow the first infusion and give it over a 2-hour period.” She noted that subsequent doses are given over 1 hour, without diphenhydramine.

Commenting on the complexity of the oral triplet regimen, Ms. Faber said: “Encorafenib is taken once a day, and binimetinib is given as three 15-mg pills taken twice a day, so there’s a certain amount of ‘pill burden’ involved with the triplet regimen. We need to make sure patients have adequate swallowing function. There are no specific instructions about taking either of these oral medications with or without meals, and encorafenib may be taken at any time of day, as long as it is consistently once daily.

Toxicities: Better or Worse Than With Combination Chemotherapy?

In view of the fact that the encorafenib-containing doublet [or triplet] is a fully nonchemotherapy regimen, Ms. Faber observed: “Patients usually find the doublet easier to tolerate than chemotherapy-based regimens, such as FOLFOXIRI or FOLFOX plus bevacizumab.  There tends to be less nausea, vomiting, and fatigue with the nonchemotherapy combinations,” she noted. “Nevertheless, the nonchemotherapy combinations are associated with skin toxicity, which usually lasts longer than a few days, so neither regimen is free of side effects.”

This is the longest overall survival in this setting without chemotherapy.

From the patient’s perspective, Dr. Grothey stressed that the biologic doublet (and even the triplet) comprising encorafenib plus cetuximab (with or without binimetinib) is much more easily tolerated than combination chemotherapy. “There’s no comparison. Most of the adverse effects observed in the BEACON trial were EGFR-inhibitor side effects that come with cetuximab. When the binimetinib is removed from the regimen, the doublet of encorafenib plus panitumumab, for instance, is a ‘walk in the park’ compared with something like FOLFOXIRI plus bevacizumab,” he told JNCCN 360. “Patients feel better, and this is the longest overall survival in this setting without chemotherapy. There’s no neuropathy; patients don’t have to carry an infusion pump; there’s less diarrhea and fatigue…. It’s pretty remarkable.”

Ms. Faber continued: “Although we haven’t had as much clinical experience with the doublet of encorafenib plus EGFR inhibitor as with the triplet regimen used in the BEACON trial, it appears that dropping the binimetinib reduces hematologic toxicities (eg, anemia), cardiac toxicities, and GI side effects (eg, diarrhea), as well as eliminates associated retinal issues. Some of these toxicities have required a dose reduction.”

Less Dermatologic Toxicity?

Ms. Faber observed that with regard to skin toxicity associated with EGFR inhibition, the use of the BRAF inhibitor seems to have a positive effect. “The rashes that emerge during treatment with the combination are often less severe than those seen with monotherapy or when the EGFR inhibitor is combined with chemotherapy.”

As Dr. Kopetz explained: “When these agents [BRAF and EGFR inhibitors] are combined, there is a mitigation in the dermatologic toxicity. This is due to the fact that some of the feedback mechanisms in normal healthy tissue can involve activation of these pathways. It is a fascinating finding; it is one of the few scenarios in oncology when a combination [of anticancer agents] has less toxicity, in this case dermatologic, than the agents individually. This finding is certainly of benefit to our patients.”13

Fatigue and asthenia have been observed with the biologic regimen, Dr. Grothey added, but “not with the severity associated with irinotecan-based treatments. Moreover, combining a BRAF inhibitor with an EGFR inhibitor mitigates the classic skin rash seen with cetuximab or panitumumab as monotherapy.” The incidence of any grade of acneiform rash in the BEACON study was 29%; however, “When we use an EGFR inhibitor, we can anticipate a 70% incidence of skin rash,” he commented.

Preventing Adverse Effects and Improving Tolerability

As a preventive strategy, Ms. Faber said patients are started on a prophylactic antibiotic (doxycycline or minocycline) because of the expected skin toxicity associated with cetuximab or panitumumab. In addition, “We send patients home with a topical steroid (high-potency hydrocortisone 1%) and sometimes with a topical antibiotic, to be used as needed. We also advise patients to have loperamide (or potentially diphenoxylate/atropine) on hand for diarrhea.”

“I would encourage providers to obtain appropriate baseline measurements, such as skin evaluation and cardiac studies, before treatment begins,” Ms. Faber recommended. With the doublet, “at minimum, we want an ECG looking for QT prolongation.

For triplet therapy, Ms. Faber suggests “performing an echocardiogram to check for adequate ventricular activity, as binimetinib may be associated with cardiomyopathy. Moreover, I would emphasize the importance of being proactive about prophylaxis of skin toxicity and monitoring laboratory values regularly, managing anything that emerges promptly.”

As part of patient education, Ms. Faber talks with patients about bowel management, which usually centers on home treatment of diarrhea. In addition, “we talk about managing skin toxicity, and I ask them to call about skin lesions that look abnormal. When we use the triplet regimen, we also advise patients to call us if they experience visual changes.”

Moving Into the First Line: ANCHOR-CRC Trial

As with most anticancer regimens that are first tested in patients with advanced or metastatic disease, effective strategies are next evaluated in the setting of earlier disease. “We just completed accrual to the ANCHOR-CRC trial [NCT03693170],” Dr. Grothey reported. “Ninety patients with BRAF-mutated metastatic colorectal cancer were treated upfront [first line] with this triplet regimen.”

An interim analysis of 40 patients was conducted, and the criteria for moving forward with the trial were met, so it was expanded to 90 patients. “We anticipate seeing data later this year to address the question of using this nonchemotherapy regimen in the first-line setting,” Dr. Grothey said.

Different Patient Populations: BEACON Versus ANCHOR-CRC Trials

Differences among the patient populations for BEACON versus ANCHOR-CRC are interesting and important, Dr. Grothey pointed out. In the first-line ANCHOR-CRC trial, “We encountered problems with bowel obstruction; peritoneal disease; and perforation, which were independent of the treatment. These patients had advanced, aggressive disease and may not have made it to the point where a second-line treatment with an active regimen was feasible.”

Dr. Grothey continued: “Perhaps ironically, patients who are still considered candidates for a triplet biologic regimen in the second line are in better shape. This may be a sort of selection bias in that patients eligible for second-line treatment have an adequate performance status. That’s why we could not extrapolate from the BEACON data about the effectiveness in the first line, and that is why we need to expand beyond ANCHOR-CRC and test the BEACON regimen in a phase III first-line study.”

Future Directions

The full potential of this doublet regimen “will probably come to light when it is moved into the first line,” Dr. Grothey noted. “We are going to have to pin down the right patient population.” Perhaps even more important, he added, is to see whether this approach may be applied in the adjuvant setting.

“We know patients with BRAF-mutated colorectal tumors fare roughly the same as those with wild-type tumors in the early disease setting. It is only when disease recurs that those with BRAF-mutated tumor biology have significantly worse outcomes. Use of this regimen in the adjuvant setting may increase the potential for some of these patients to be cured,” Dr. Grothey told JNCCN 360.  

DISCLOSURES

Axel Grothey, MD, reported institutional grant funding and honoraria for consulting activities from Array/Pfizer, Bayer, Roche/Genentech, Daiichi Sankyo, OBI Pharmaceuticals, and Boston Biomedicals.

Jamie Faber, PA-C, reported no conflicts of interest.

 

REFERENCES

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