Posted: Thursday, June 22, 2017
Cabozantinib is an oral small molecule tyrosine kinase inhibitor (TKI) that blocks multiple targets, including vascular endothelial growth factor receptor (VEGFR), MET, and AXL. Clear cell tumors, which represent the predominant histologic subtype in renal cell carcinoma (RCC), are characterized by inactivation of the von Hippel-Lindau (VHL) tumor-suppressor protein. When VHL is inactivated, MET and AXL are upregulated; animal studies suggest that upregulation of MET and AXL may be implicated in the development of resistance to VEGFR inhibition.1,2
Cabozantinib was approved in the United States in 20163 for the treatment of advanced RCC in patients who have received prior antiangiogenic therapy,4 on the basis of a phase III trial5 in which the TKI was compared with everolimus. Cabozantinib in capsule form (CometriqTM) had already been approved in 2012 for treatment of metastatic medullary thyroid carcinoma.6
Second-Line Treatment: Same Drug Class, Different Drug
Conventionally, when disease progression occurs during treatment with one class of anticancer drug, clinicians may switch to a different class for the next line of treatment. Within the broad classification of “chemotherapy,” practitioners switch from an anthracycline or a platinum agent, for example, to a taxane rather than to another agent in the same class.
In second-line treatment for metastatic RCC, however, cabozantinib is in the same drug category as most of the first-line options, which include anti-VEGF TKIs sunitinib, pazopanib, axitinib, or sorafenib (for selected patients).7
Cabozantinib is thought to also target MET and AXL—both involved in resistance to anti-VEGF drugs1,2—in addition to its anti-VEGF activity; however, it is essentially a TKI with a safety profile that is similar to other drugs in its class.
“Over the past 10 to 15 years, we have had experience with anti-VEGF TKIs and targeted agents in general—sunitinib, sorafenib, axitinib, pazopanib—so the adverse effects associated with cabozantinib do not come as a surprise,” explained Toni K. Choueiri, MD, the Jerome and Nancy Kohlberg Chair at Harvard Medical School. “They are generally anticipated as class effects associated with this category of medications.”
Dr. Choueiri, who is also Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, pointed out that “in the large trial of cabozantinib compared with everolimus as second-line treatment for patients with advanced kidney cancer that had progressed on VEGFR-targeted therapy, adverse effects of each drug were as expected.5 And, in a smaller, ongoing front-line trial of sunitinib versus cabozantinib,8 adverse effects are roughly similar for the two groups.”
Recognizing and Managing Adverse Effects Are Keys to Optimal Outcomes
“With continued clinical experience, we are better able to anticipate and manage these adverse effects, but they need to be recognized promptly. Certainly, when this category of drugs was new, management of side effects represented a considerable challenge, particularly with the emergence of substantial fatigue, diarrhea, and hand-foot syndrome [ie, palmar-plantar erythrodysesthesia syndrome—PPES]. Now that we are more familiar with the safety profile of these agents, we can better prepare patients and address these issues as they emerge,” Dr. Choueiri said.
“What’s interesting about these drugs is that all of them end up with their own safety profile,” observed Benjamin Gerendash, MSN, RN, AGACNP-BC, a nurse practitioner in the Genitourinary Medical Oncology program at the City of Hope.
Mr. Gerendash and his team, headed by Sumanta Kumar Pal, MD, a clinical kidney cancer researcher at City of Hope, emphasize the importance of reporting anything new or any changes as soon as they are noticed. “If you catch those adverse effects early, they may not get to grade 3 or 4. So we really encourage patients to contact us right away with whatever effect they are having—usually gut or skin issues. We have a call center, so the team is notified right away if a patient is having an issue. We then follow up directly to make sure that the patient has medication or other intervention that he or she needs.”
What Is the “Right” Dose?
In practice, Dr. Choueiri explained, roughly half of patients who are eligible for cabozantinib will need a dose reduction. “I take into consideration a number of variables, such as comorbidities and prior tolerance to TKIs. In some patients, I might start at a lower dose, such as 40 mg once a day and then cautiously increase but with the option to reduce again, as necessary. Not starting with the recommended dose is acceptable and should be customized to the individual’s health status. In truth, we really have no idea what is the ‘right’ dose, even for sunitinib, which has been in clinical use for more than a decade. Ongoing trials are continuing to explore doses and schedules for sunitinib.”9
“Having said that, in a robust patient whose disease is progressing rapidly and who didn’t experience significant adverse effects from a first-line TKI therapy, I would start with the recommended full dose of cabozantinib,” Dr. Choueiri said. But for those individuals with borderline performance status or in patients who struggled with previous TKI therapy, he prefers to start with 40 mg and adjust as needed.
“I have patients on 20 mg, who are doing well and achieving disease control, and I have patients on 40 mg and 60 mg as well. This treatment can be customized to the individual need (ie, control of disease) and tolerance,” he observed.
“Patients will develop side effects,” Mr. Gerendash stated. In the cabozantinib studies, more than 60% of subjects needed a dose reduction from the 60-mg starting dose.5 “Many patients land at 40 mg, but some need reduction to 20 mg. We generally follow the label, which means starting with 60 mg. But if the patient has liver issues or if he or she is elderly and not likely to tolerate the full dose, we start with a lower dose. Otherwise, we start with the full dose, hold treatment while adverse effects resolve, and then continue with a lower dose."
Efficacy (ie, median progression-free survival) for the second-line TKI cabozantinib is roughly similar to that seen with the first-line agents sunitinib or pazopanib,10 “but we haven’t really explored whether patients have more frequent or more severe adverse effects in the second line,” Dr. Choueiri remarked. In general, those who struggle with TKI treatment in the first line will also struggle in the second. However, there is no direct correlation, and “in fact, some patients who did not tolerate sunitinib well seem to tolerate cabozantinib better and vice versa,” he said.
Early Reporting and Management of Adverse Effects
“It would be very hard to do what we do without the support of our excellent nursing staff,” Dr. Choueiri acknowledged. At Dana-Farber Cancer Institute, a phone call is initiated either by the nurse or pharmacist when these medications are prescribed. These discussions include what to expect, how to take the medication, what medications or other substances (eg, grapefruit juice) to avoid, etc. Adherence is often enhanced by the fact that clinic visits with patients are scheduled fairly frequently, every 2 to 3 weeks, especially in the beginning. “Patients whose adherence may be affected by adverse effects can be helped quickly when we learn of a particularly bothersome issue,” Dr. Choueiri explained.
“When patients are responding to treatment, we try as much as possible to keep them on therapy.” Dose reduction is one way of helping patients who are deriving benefit from treatment to tolerate the regimen. In addition to dose reduction, Dr. Choueiri said, “We manage adverse effects aggressively. We learned many important lessons from clinical experience with other TKIs. Working collaboratively with nurses and appropriate consultants is key.”
“Anecdotally, our first line of management when patients have diarrhea is loperamide or diphenoxylate/atropine. However, for patients who report a watery stool, I’ve found that the use of fiber supplements that add bulk can be more effective.”
Dr. Choueiri and the team at Dana-Farber generally do not initiate prophylactic protocols when patients start cabozantinib. Nevertheless, patients are educated about what to expect and may be given appropriate prescriptions to have on hand. “A patient with borderline hypertension will not have a decline in blood pressure when he or she starts a TKI such as cabozantinib. So, it may be prudent to provide a prescription for an antihypertensive to have on hand. Likewise, patients might be instructed about when and how to use urea-based creams, in case signs of PPES develop. Nevertheless, it is not necessary for patients to actually start any of these interventions—eg, antidiarrheals—unless an adverse effect actually occurs.”
“In my experience, older patients struggle the most—but ‘older’ is practically defined by the patient’s physical reserves rather than strictly on the basis of chronological age,” Mr. Gerendash explained. ‘Elderly’ is determined as some combination of age and functional level. A 50-year-old with weight loss, poor functional status, and questionable organ reserves may not be able to tolerate as much as a healthy 80-year-old, he said.
Nursing Tips and Interventions That Work
Patients may take cabozantinib whenever it’s best for them (ie, morning, afternoon, or evening). However, Mr. Gerendash emphasized that it should not be taken with food because absorption can be affected. The prescribing information for cabozantinib capsules, which is the cabozantinib formulation used to treat metastatic medullary thyroid cancer, cautions against taking the medication with a high-fat meal, which increases absorption—“You have to be careful with that,” he warned.
“Anecdotally, our first line of management when patients have diarrhea is loperamide or diphenoxylate/atropine. However, for patients who report a watery stool, I’ve found that the use of fiber supplements that add bulk can be more effective,” Mr. Gerendash suggested. “The fiber absorbs some of that fluid and improves their stools, making them less watery.”
The rashes and other skin irritations associated with PPES develop around areas subject to friction. “If the patient’s shoes don’t fit well, PPES can show up where there are calluses; people who write a lot may have it on their hands for the same reason,” Mr. Gerendash said. Patients are advised to wear cotton gloves during exacerbations to reduce friction. Use of a 20% urea-based cream is also recommended. “If patients had skin issues while on a previous TKI, for instance, we might be proactive about using gloves and urea-based cream. If not, we will offer these suggestions as soon as the patient reports a problem,” Mr. Gerendash explained.
Coming to Terms With Metastatic Disease
Although patients who start second-line treatment have fewer questions about the medication (because adverse effects are roughly similar to those of the first-line agent), they often want to know how effective this second intervention is likely to be. “These are difficult questions,” Mr. Gerendash observed, “because we can only speak about statistics that were reported in trials, but no patient is a statistic.” Questions about life expectancy also come up. “My response is that whatever my answer… it would be wrong. We just have to try the medication and see whether it will work for the individual.”
Toni K. Choueiri, MD, has disclosed that he has served in a consulting or advisory role for AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine Inc, Exelexis, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, and Prometheus Labs; he also disclosed that he receives research funding from AstraZeneca, Bristol-Myers Squibb, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, and Eisai.
Benjamin Gerendash, MSN, RN, AGACNP-BC, has disclosed membership on the Exelixis Speaker Bureau.
- Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2015;35:2687–2697.
- Choueiri TK, Pal SK, McDermott DF, et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014;25:1603–1608.
- CABOMETYX (Cabozantinib). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf Accessed May 23, 2017.
- Cabozantinib (CABOMETYX). S. Department of Health and Human Services. U.S. Food & Drug Administration. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm497483.htm Accessed May 15, 2017.
- Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–1823.
- COMETRIQTM (cabozantinib). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf. Accessed May 22, 2017.
- Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer, Version 2.2107. Available at NCCN.org. Accessed May 23, 2017.
- Choueiri TK, Halabi S, Sanford B, et al. Cabozantinib vs sunitinib in metastatic RCC: results from ALLIANCE A031203 trial [abstract]. Presented at ESMO 2016; Copenhagen, Denmark; October 7–11, 2016. Abstract LBA30_PR.
- Jonasch E, Slack R, Geynisman DM, et al. Phase II study of alternate sunitinib schedule in patients with metastatic renal cell carcinoma [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 4513.
- Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722–731.