Vemurafenib (Zelboraf®) Triple Regimen
Posted: Monday, July 23, 2018
Vemurafenib, a tyrosine kinase inhibitor, was initially approved by the FDA for the treatment of patients with BRAF (V600E mutation)–positive unresectable or metastatic melanoma in 2011.1 Researchers who treat gastrointestinal cancers recognized that a small but important subpopulation of patients with metastatic colorectal cancer also may harbor BRAF mutations.2 Although BRAF-mutated disease affects about 6% to 7% of patients with metastatic colorectal cancer, this subset of patients represents a group with an urgent need for more effective, more targeted treatment.2-4 Patients with BRAF-mutated colorectal cancer generally have a particularly poor prognosis,4-6 despite recent advancements in treatment options for non–BRAF-mutated disease.
Although the results of monotherapy with vemurafenib have been disappointing, preclinical data demonstrated synergistic activity with epidermal growth factor receptor (EGFR) inhibitors.7 In 2015, on the basis of a phase IB study,8 SWOG initiated a randomized study of a vemurafenib-containing protocol for patients with BRAF-positive metastatic colorectal cancer, which included EGFR inhibition as well as a standard cytotoxic agent (irinotecan). The results, which were reported at the 2017 Gastrointestinal Cancers Symposium, demonstrated a significant improvement in progression-free survival.9
The principal investigator of the SWOG 1406 trial, E. Scott Kopetz, MD, PhD, explained, “It is well recognized that this population (ie, with BRAF mutation) has poor outcomes. Experimental therapies were needed, so accrual to this trial, SWOG 1406,10 was brisk across the country at multiple sites.” When asked about the selection of EGFR inhibitor, Dr. Kopetz, who is Associate Professor of Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, told JNCCN 360, “this particular trial was done with cetuximab as the EGFR inhibitor, but as noted in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®),11,12 panitumumab may be used as well.3,13 There’s no reason to expect that we wouldn’t see similar activity with panitumumab.”
In view of the current NCCN recommendation to obtain KRAS-, NRAS-, and BRAF-mutation testing for all patients diagnosed with metastatic colorectal cancer,11 those findings from SWOG 1406 led to an update of the NCCN Guidelines for Colon Cancer11 and the NCCN Guidelines for Rectal Cancer,12 which is not yet reflected by FDA labeling. Nevertheless, for a patient with metastatic colorectal cancer who has BRAF-mutated disease, a targeted therapy exists—vemurafenib—that may be combined with an EGFR inhibitor and a cytotoxic agent to improve progression-free survival in this fairly small patient subset.
About BRAF Mutations in Colorectal Cancer
“BRAF mutations are slightly underrepresented among patients with metastatic colorectal cancer, with estimates roughly about 6% in metastatic disease,2” Dr. Kopetz told JNCCN 360. BRAF testing is typically done as part of the test panels for KRAS and NRAS, he noted. “That’s included in most guidelines, such as the NCCN and American Society of Clinical Oncology/College of American Pathologists/American Society of Internal Medicine.11,15 What’s important to note, with regard to this triple regimen, is that BRAF mutations and NRAS mutations are [almost always] mutually exclusive. Therefore, a tumor that harbors a KRAS mutation—and therefore would not be treated with an EGFR inhibitor—would not also have a BRAF mutation. And vice versa,” he explained.
Statistically, there are more BRAF-mutated tumors among female patients, older patients, and those with right-sided disease. Nevertheless, those are statistical findings and are not necessarily clinically meaningful,” Dr. Kopetz said, observing that BRAF-mutated tumors may also occur in younger patients, males, and those with left-sided disease. “We don’t recommend trying to use clinical features to identify who should be tested for BRAF mutation. Everyone should be tested, even though we recognize there’s a slight predominance among certain groups,” he said.
Rationale for Combination Therapy
Tumors with BRAF mutations are not innately sensitive to EGFR inhibition. We don’t see tumor regression with an EGFR inhibitor alone.”7 Likewise, when only the oncogenic mutation, the BRAF mutation, is inhibited, the tumor rapidly adapts and is able to restore signaling through the pathway. “Neither the EGFR inhibitor nor the BRAF inhibitor alone is active,”7 Dr. Kopetz reported. “When BRAF is inhibited, signaling that includes the EGFR receptor is upregulated. So, inhibiting both BRAF and EGFR signaling is synergistic in its effect on the pathway, which results in a significant response,” he explained. In view of this mechanism, other BRAF inhibitors are being studied in clinical trials for this population.4,16
Inhibiting both BRAF and EGFR signaling is synergistic in its effect on the pathway, which results in a significant response.
More Drugs, Less Skin Toxicity?
Of note, even though vemurafenib and cetuximab or panitumumab each are associated with dermatologic toxicities, when they are combined, the effects on skin seem to be reduced rather than intensified.3,13,17 With vemurafenib alone, researchers have reported the development of keratoacanthomas18—a premalignant subtype of squamous cell skin cancer. However, when vemurafenib is used in this triple regimen for metastatic colorectal cancer, these keratoacanthomas occur at a much lower rate3,13,17 than that seen in studies of vemurafenib as a single agent. And the acneiform rash associated with EGFR inhibition does not appear to be worse when vemurafenib is added.16
Before starting the triple regimen, patients should have a baseline dermatologic examination, with periodic exams throughout the treatment period, advised Ryanne Coulson, PA, a former member of the team at The University of Texas MD Anderson Cancer Center. If any keratoacanthomas develop as a result of therapy, they are likely to be identified while they are quite small and can be promptly addressed surgically. Because neutropenia is also seen at higher rates with the addition of vemurafenib, patients who have a history of neutropenia on the regimen should be educated about how to prevent infection in any biopsy sites, she cautioned.
“What we learned in the single-agent studies of vemurafenib was that the dermatologist could remove the keratoacanthomas during treatment,” Dr. Kopetz observed. “In other words, vemurafenib could be continued while the skin lesion was addressed. In the context of the combination regimen, we don’t see many of these keratoacanthomas, but it is good to know that the regimen can be continued even if they occur.”
Although the rash associated with EGFR inhibition does not appear to be different with the addition of vemurafenib, “some patients treated with vemurafenib are bothered more by the tenderness that occurs with hand-foot syndrome,” Ms. Coulson said. She told JNCCN 360 that many clinicians who use an EGFR inhibitor plus irinotecan will start patients on a prophylactic skin regimen when these agents are initiated, but some practitioners may be more reactive, perhaps waiting for patients to present with or complain of a skin rash before addressing dermatologic toxicities. “In our experience, patients who either were not given a preventive protocol or who did not adhere to instructions were likely to have more severe, immediate skin toxicity when the triple vemurafenib-containing regimen was started. In addition,” she said, “some patients had more redness/tenderness of the hands and feet, which had an almost a ‘beefy’ appearance with the triple regimen.”
With cetuximab or panitumumab, “we initiate a standard skin toxicity prevention protocol,19 which includes a preemptive topical steroid, oral antibiotic, and sunscreen. However, we don’t do any additional dermatologic mitigation for vemurafenib,” Dr. Kopetz said.
Ms. Coulson noted that dosing of the antibiotic, such as doxycycline or minocycline at once or twice daily, depends on the patient’s history and individual sensitivities. Once the antibiotic dosage is established, it would be given along with the EGFR inhibitor for the duration of treatment. “At MD Anderson,” she pointed out, “we have patients maintain the antibiotic for 2 weeks after discontinuing the EGFR inhibitor because of the antibody’s long half-life. Stopping the antibiotic abruptly after discontinuation of cetuximab or panitumumab has resulted in a flare-up of the dermatologic symptoms.”
Managing Adverse Effects
The treating community is aware of the adverse effects related to standard treatment with irinotecan and cetuximab (or panitumumab). 20,21 With the addition of vemurafenib, higher rates of nausea, neutropenia, and anemia, have been reported. Occasionally, delays or dose reductions are required, but these adverse effects are considered manageable. These increased adverse effects, which were reported in the SWOG 1406 trial,9 may also reflect the longer period that patients who received the experimental arm were on therapy, Dr. Kopetz pointed out.
The team at MD Anderson uses a pretreatment antiemetic protocol already in place for the irinotecan/cetuximab or panitumumab infusion, which typically includes a 5-HT3 inhibitor. “We have not needed to add or change it with the addition of vemurafenib,” Dr. Kopetz said.
Vemurafenib Plus 5-HT3 Antagonists: Potential Interaction
Vemurafenib may cause some QTc prolongation. When vemurafenib is used in combination with several classes of medications that may also cause QTc prolongation, including higher doses of certain antiemetics (eg, 5-HT3 antagonists), there is a potential for interaction. After a baseline cardiologic assessment, regular monitoring is advised. Any QTc values that exceed 500 ms “should trigger holding and then reducing the vemurafenib dose. QTc higher than 500 ms is not a very strict cutoff, so the vast majority of patients will be fine,” Dr. Kopetz said.
“Because of the potential for prolonging the QTc interval when vemurafenib is used with high doses of 5-HT3 antagonists, we keep a close eye on the antiemetic regimen that is given before and during the chemotherapy infusions,” Ms. Coulson told JNCCN 360. “Where things might get a little complicated is at home, when the professional staff is no longer overseeing what the patient is taking. We prefer that patients do not ‘max out’ their 5-HT3 antagonist at home; rather, we instruct them to alternate with a different class of rescue agent, such as prochlorperazine or promethazine.” She also explained that if patients report experiencing significant early, acute nausea or vomiting at home, “we can be more vigorous with antiemetic use on or immediately after the infusion day. For instance, we can use a short course of oral steroids for a few days after treatment or another class of long-acting antiemetic, such as fosaprepitant, with the pretreatment chemotherapy regimen.”
We prefer that patients do not ‘max out’ their 5-HT3 antagonist at home; rather, we instruct them to alternate with a different class of rescue agent.
Laboratory values are monitored every 2 weeks before each infusion, “so we keep an eye on the development of neutropenia or anemia,” Dr. Kopetz noted. For grade 3 toxicities, such as nausea, diarrhea, or neutropenia, “we will first hold the dose and then dose reduce. Typically,” Dr. Kopetz added, “we will reduce the dose of irinotecan first from 180 mg/m2 to 150 mg/m2.”
With regard to educating patients about neutropenia, “patients are instructed to call the team if they have any signs of infection or develop a fever without other symptoms,” Ms. Coulson explained. “And, of course, patients are encouraged to follow ‘flu season precautions,’ including washing their hands frequently, avoiding individuals who are sick, and staying away from crowds. And, if neutropenia is a consistent issue, our preference is to dose reduce first rather than attempt other management strategies, such as the use of growth factor support. In my experience, patients who develop neutropenia, particularly early on in a regimen, also report more fatigue and may take longer to recover after each chemotherapy infusion. So, for those patients, dose reduction definitely makes sense,” she remarked.
Vemurafenib may cause some grade 1 or 2 arthralgias, which were also seen in the melanoma setting. However, practitioners who treat patients with gastrointestinal malignancies are not accustomed to seeing or treating this adverse effect, Dr. Kopetz noted. Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is often effective. “And sometimes it may be necessary to give short breaks rather than reducing the dose. Only when neither NSAIDs nor 2- to 3-day breaks reduce the arthralgias sufficiently would we consider dose reduction,” he explained.
As an international comprehensive cancer center, “MD Anderson tends to have a younger and/or more fit patient population compared with the community setting,” Ms. Coulson said. Many patients still work. “These arthralgias, especially because they affect the hands and feet, can have a significant impact on the patient’s ability to continue working. Moreover, unlike with chemotherapy infusions, where patients take a few days to recover and then get back to ‘normal,’ Ms. Coulson pointed out, “these vemurafenib-associated arthralgias persist throughout the day, every day.” When cumulative skin toxicities, such as paronychia or skin fissuring, occur in conjunction with arthralgias, Ms. Coulson explained, these effects are intensified. “At times,” she said, “the skin sensitivity overlying achy joints can result in dysfunction, wherein patients are unable to work or engage in activities they previously were able to do.”
Providers using this vemurafenib regimen for patients with BRAF-mutated advanced colorectal cancer should ask themselves, “What is different about this regimen?” Ms. Coulson suggests that clinicians who prescribe a vemurafenib-containing triple regimen should:
- Perform a baseline skin exam.
- Initiate a proactive, robust skin care protocol that includes the use of appropriate antibiotics.
- Recognize the potential for interaction with 5-HT3 antagonists, because those antiemetic agents are ubiquitous in the chemotherapy infusion setting. Be creative about designing antiemetic strategies that do not use maximal doses of 5-HT3 drugs.
- Be willing to dose reduce to improve treatment-related toxicities and allow patients with this rare subtype of cancer to continue therapy.
E. Scott Kopetz, MD, PhD, disclosed that he has served on the advisory board for Amal Therapeutics, Biocartis, Merck KGa, Navire Pharma, Roche/Genentech, and Symphogen.
Ryanne Coulson, PA, disclosed no relevant relationships.
- Genentech USA, Inc. Zelboraf® (vemurafenib). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s016lbl.pdf. Accessed July 10, 2018.
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- Benson AB, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2018. Accessed July 10, 2018. To view the most recent version of these guidelines, visit NCCN.org.
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