Axitinib as Second-Line Treatment for Metastatic Renal Cell Carcinoma

The US Food and Drug Administration (FDA) approved axitinib (Inlyta; Pfizer, Inc.) for the treatment of patients with advanced renal cell carcinoma after failure of 1 prior systemic therapy. This approval was granted on January 27, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289439.htm.

Axitinib is a more selective inhibitor of vascular endothelial growth factor (VEGF) receptor and thereby is the most potent tyrosine kinase inhibitor. It specifically targets VEGF 1, 2, and 3 but does not affect the platelet-derived growth factor (PDGF) receptor as do sunitinib and other less-selective VEGFs.1 Because of this, the side effect profile of axitinib is narrower and the treatment is better tolerated.
Peak plasma concentration of axitinib is noted at 3 hours after a high-fat, high-calorie meal and 2 hours after overnight fasting.1 It can be taken with or without meals and is always dosed twice daily.2 Its plasma half-life is 2.5 to 6.1 hours, and steady-state is achieved in 2 to 3 days.1,2

Mrs G, an ICU nurse, was in her usual state of health until late 2011, when she developed nonspecific rib cage pain and right hip pain. A chest x-ray showed a suspicious mass in the pleural region. A subsequent whole body bone scan and CT scan of the chest, abdomen, and pelvis revealed bone metastases, mediastinal lymphadenopathy, pulmonary nodules, and a large right kidney mass with invasion into the liver. Pathology results from a biopsy of the right kidney mass showed renal cell carcinoma, clear cell type, Fuhrman nuclear grade 4.

She was started on frontline therapy with sunitinib and completed 2 cycles. Restaging scans showed a mixed response, with decreased size of the right kidney mass but increased size of the right iliac bone metastasis and 2 new hepatic metastases, as well as progression of erosion of a rib on her left side, with pathologic fracture. Her sunitinib was stopped, and she was enrolled in a phase 2 study and randomized to everolimus. She experienced severe treatment-related hyperglycemia and was started on insulin. She also developed treatment-related hypothyroidism and hypertension. Although she showed stable disease, there was no noted decrease in her tumor burden. Because of her side effects and no real improvement in disease, she was moved to axitinib in May 2012.

Pretreatment Evaluation

As axitinib can affect blood pressure, it is important to control any hypertension prior to initiating therapy. Other important issues to review are thyroid or liver problems and a history of blood clots or bleeding disorders.2

A review of Mrs G’s history indicates 2 areas of concern: (1) her blood pressure, for which she had been prescribed lisinopril 10 mg by her primary care physician, resulting in average at-home blood pressures of 118/68 mm Hg; and (2) her thyroid, for which she had already been started on 88 mcg of levothyroxine, as she had become somewhat hypothyroid from previous treatments.

Availability of Medication

Axitinib is provided by a specialty pharmacy and often needs prior authorization or patient assistance related to the cost. Because it can take 1 to 3 weeks before the medication arrives, a great deal of anxiety can be avoided if this is made clear prior to the patient leaving the office.

Possibly because Mrs G had previously been on sunitinib and much of the paperwork was already done, she received the drug within 4 days.

Dosing

The recommended starting dose of axitinib is 5 mg twice daily.2 From this point, the dose can be titrated up or down as tolerated and indicated. The patient is usually kept on the starting dose for 2 cycles of 30 days, at which time restaging scans are done. Certainly if there are intolerable adverse effects greater than grade 2, or the patient is not tolerating the medication, then there is a need to reduce the dose. The first dose reduction is to 3 mg twice daily.2 If there are no adverse effects, specifically no increase in blood pressure, then dose escalation is indicated. On occasion, patients have been dose escalated after the first cycle. Because an increase in blood pressure is anticipated, using diastolic hypertension as a marker of efficacy is one method to determine the correct dose (this will be discussed later in this article).1

Monitoring

Stress the importance of early reporting of any symptoms, as prompt treatment of side effects and follow-up to assess the effectiveness of interventions may reduce the need for treatment interruption and/or dose reduction.3

Patients should be instructed to monitor their blood pressure daily after starting axitinib. Two weeks after axitinib initiation, liver function should be checked. At 4 and 8 weeks, blood work should include a complete metabolic panel, complete blood cell count, and a thyroid-stimulating hormone test. At 8 weeks, restaging scans are done, preferably CT of the chest, abdomen, and pelvis, both with and without contrast.

All lab work remained essentially normal. Mrs G had scans after 2 cycles of 30 days each. Her response was good, with decreases in renal mass, pulmonary nodules, and liver metastasis.

Adverse Events and Treatments

The most frequently reported side effects of axitinib treatment in clinical trials were diarrhea (55%), hypertension (40%), and fatigue (39%); the most common grade 3 and 4 adverse events were noted in these 3 side effects.1,2

Diarrhea

Diarrhea is the number one complication frequently presenting with axitinib.1 Patients should be instructed in medical management, such as being sure to take medication 30 minutes before eating. Patients can also take a combination of commonly prescribed medications, such as loperamide, diphenoxylate hydrochloride/atropine sulfate (Lomotil), and tincture of opium 10%. Psyllium fiber (Benefiber), 1 tablet with each meal, can also help.1,3,4

A nutrition consultation is always appropriate, but if unavailable or inconvenient, then be sure to discuss that eating simple foods or foods that are known to constipate, such as the BRAT (bananas, rice, applesauce, and toast) diet, can be helpful.4 Consumption of high-potassium foods, such as potatoes, nectarines, and bananas, should also be encouraged. Ensure the patient maintains an oral intake of 2 to 3 quarts of fluids daily.4 Equally important is teaching the patient about foods they should avoid, such as spicy food.1

Mrs G struggles the most with her diarrhea. She had been taking paregoric, Lomotil, and ocreotide acetate (Sandostatin). Most recently we started her on tincture of opium. Initially she had some positive results with probiotics, but she stopped taking them when they were no longer helping. She has also tried Benefiber (wheat dextrin), which did not help. Over the course of her illness she has lost more than 70 pounds; her recent BMI was 17.71 kg/m2. At this point we have exhausted diarrhea medication support options and have actually recommended short drug holidays. She took an extended (10-day) break over the Christmas holidays and was able to gain 15 pounds. However, when she went back on drug, the diarrhea started almost instantly, and she quickly lost the weight she had gained. She is now on a regimen of 5 days on axitinib and 2 days off, and she has started regaining weight. At the last office visit, her BMI was 19.8 kg/m2, with a great increase in her energy level and well-being. Although there is no evidence in the literature that supports this regimen, she is doing well and will be rescanned shortly.

Hypertension

As discussed above, if the patient already has hypertension it should be well managed before the patient starts therapy.2 Hypertension is noted as early as 3 to 4 hours after initiating axitinib therapy, and although hypertension is never a desired side effect, there is an indication that it may be associated with improved clinical outcomes.1,3,5,6

Hypertension as a biomarker. Hyper-tension can be a reflection of the axitinib dose being “on target.”1 For example, in one 8-week analysis, median progression-free survival (PFS) in the 2 metastatic renal cell carcinoma studies was significantly higher in patients with diastolic hypertension (defined as diastolic pressure ≥90 mm Hg) than in those without diastolic hypertension (16.5 months vs 6.4 months, respectively).5 It is important to note that treating the hypertension did not diminish the outcome. A subset analysis of hypertension at day 15 of cycle 1 versus baseline showed that patients with a mean increase in diastolic blood pressure of ≥15 mm Hg had a higher overall response rate than those with an increase <15 mm Hg (61% vs 53%, respectively).1,6

Treatment of hypertension. If the patient’s hypertension is already being treated with blood pressure medication, then it is best to have the prescribing doctor continue to manage it. If, however, this is a new symptom with axitinib, antihypertensive treatment should be initiated, either by the practitioner or by referral to a cardiologist.

Mrs G was advised to check her blood pressure daily, and she called within 3 days because she had noticed an increase. Her averages had gone to 135/high 80s mm Hg. As her blood pressure went up but did not exceed 140/90 mm Hg, her blood pressure medication was left as it was.

Fatigue

Unfortunately, fatigue frequently accompanies this type of targeted therapy. It is important to look for secondary causes, such as hypothyroidism, insomnia, depression, hypogonadism, anemia, and uncontrolled pain.7 Additionally, it is important to monitor the daily caloric intake. If no secondary cause of fatigue is found, then educating the patient in ways to combat fatigue would include advising the patient to take more frequent short breaks rather than a long nap; go for short walks and perform light exercise; and stay as active as possible. It is important to emphasize to patients the importance of setting realistic expectations: operating at about 70% of what they think they can normally do is an appropriate goal.7

Other Possible Side Effects

Nausea

Instruct the patient to eat frequent small meals and to avoid fatty, fried, spicy, and very sweet foods. Make sure that the patient has antinausea medications available and knows how to use them before starting treatment with axitinib. It is recommended to prescribe 8 mg of ondansetron (Zofran) to be taken every 8 hours, plus 10 mg of prochlorperazine (Compazine) every 4 hours. It is also helpful to prescribe an antacid. It is important to tell the patient that these medications can be taken concurrently.

Lack of Appetite, Weight Loss, and Taste Alteration

Giving olanzapine (Zyprexa) 10 mg at bedtime and megestrol acetate (Megace) 400 mg in the morning has shown to increase appetite. Also, again encourage frequent small meals. Be sure the patient is tracking his/her daily calorie intake.

Mrs G is struggling with weight loss. She has diarrhea, which could account for some of the weight loss, but she needs to eat a higher daily calorie count. She was asked to track her food intake for 1 week, and it was noted that her average daily calorie intake was between 1200 and 1600 calories, which is somewhat low, although from her perspective she was eating “a lot.”

Dysphonia

Encourage the patient to drink plenty of water, write things down instead of speaking, and avoid shouting and whispering; the use of lozenges is also helpful. Inform the patient that, while this is a common side effect, it does not usually last long.3

Hypothyroidism

Hypothyroidism is a possible side effect of this medication and should be closely monitored, especially when the patient complains of increasing fatigue. Thyroid-hormone replacement therapy should be used as needed to maintain a euthyroid state.

Hand-Foot Syndrome

Hand-foot syndrome (HFS) can be an issue with axitinib as well as other VEGF inhibitors. The “3C” approach can be used to treat the symptoms of HFS8:

Controlling calluses.

If a patient already has many calluses, then a referral to a podiatrist may be in order. If calluses are not extensive, then using a pumice stone or similar will be beneficial. Soaking feet in Epsom salts can also help.

Comforting with cushions.

The patient should wear thick cotton socks and well-fitting and padded soft shoes with a large toe box. Insole cushions and inserts can also help.

Covering with creams:

Frequent use of emollient creams and keratolytic agents (eg, urea, alpha hydroxy acids, and salicylic acid) can soften callused areas of palms and soles. Hemorrhoid creams for foot calluses can also help.

Summary

A phase 2 trial of axitinib by Sonpavde and colleagues demonstrated a median response duration of 23 months, as well as a median time to progression of 15.7 months and overall survival of 29.9 months.9 Official studies from Pfizer state only that results of a head-to-head study showed a median PFS of 6.3 months versus 4.6 months for those on axitinib versus sorafenib, respectively.2
The goal of treatment must always be kept in mind. As Brian Rini, MD, states: “The goal for every metastatic RCC patient is to delay for as long as possible a lethal burden of disease while maximizing quality of life and patient convenience.”10 Axitinib, with its more targeted therapy, may provide a less symptomatic and longer survival for patients with metastatic renal cell carcinoma.

References
1. Mittal K, Wood LS, Rini BI. Axitinib in metastatic renal cell carcinoma. Biol Ther. 2012;2(1):1-13. http://link.springer.com/article/10.1007%2Fs13554-012-0005-2#page-1.
2. Inlyta [package insert]. New York, NY; Pfizer, Inc; January 2012.
3. Wood LS, Gornell S, Rini BI. Maximizing clinical outcomes with axitinib therapy in advanced renal cell carcinoma through proactive side-effect management. Community Oncol. 2012;9(2):46-55.
4. National Cancer Institute. Gastrointestinal complications (PDQ®): diarrhea. http://www.cancer.gov/cancertopics/pdq/supportivecare/gastrointestinalcom plications/HealthProfessional/page5. Updated July 18, 2012. Accessed March 2, 2013.
5. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):3841-3849.
6. Rini BI, Grunwald V, Fishman MN, et al. Axitinib for first-line metastatic RCC: overall efficacy and pharmacokinetic analyses from a randomized phase II study. Symposium presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL.
7. Lindsey H. Fatigue: the forgotten symptom? Oncol Times. 2013;35(4):26-28.
8. Wood LS, Lemont H, Jatoi A, et al. Practical considerations in the management of hand-foot skin reactions associated with the multikinase inhibitors. Community Oncol. 2010;7(1):23-29.
9. Sonpavde G, Hutson TE, Rini BI. Axitinib for renal cell carcinoma. Expert Opin Investig Drugs. 2008;17(5):741-748.
10. Rini BI. Metastatic renal call carcinoma: many treatment options, one patient. J Clin Oncol. 2009;27(19):3225-3234.