Lenvatinib Plus Everolimus (Renal Cell Carcinoma)
Posted: Thursday, November 2, 2017
Just a few years ago, the treatment of renal cell carcinoma (RCC), which represents about 85% of kidney cancers,1 was limited to a handful of cytokines, such as interleukin-2 and interferon-alpha.2 They were generally poorly tolerated and had limited efficacy. Chemotherapy was not particularly effective in this tumor type, and patients with advanced disease generally had a poor prognosis.3 Since the advent of tyrosine kinase inhibitors (TKIs) and selective inhibitors of mammalian target of rapamycin (mTOR), however, the options for treating patients with inoperable or metastatic RCC have expanded and are associated with improved tolerability and efficacy.
Some of the most challenging questions in the treatment of advanced RCC currently revolve around sequencing and appropriate use of combinations in the second line and beyond. After disease progression on a first-line TKI—eg, sunitinib or pazopanib—how does the clinician decide on subsequent therapies? The NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer, for example, list two preferred options and four category 1 options for the treatment of predominant clear cell histology after disease progression on a front-line regimen.4
Lenvatinib Plus Everolimus: A Combination Second-Line Approach
In metastatic RCC, the activation of the fibroblast growth factor pathway has been proposed as a mechanism of escape from vascular endothelial growth factor (VEGF)-targeted therapies. Lenvatinib (Lenvima) is a potent TKI of the VEGF receptors (VEGFR1-FLT1; VEGFR2-KDR; and VEGFR3-FLT4) and of fibroblast growth factor receptors (FGFR1, 2, 3, 4).6 Lenvatinib also inhibits other angiogenic receptor tyrosine kinases; tumor growth; and cancer progression; as well as platelet-derived growth factor receptor alpha, KIT, and RET.7
Everolimus, an oral mTOR inhibitor approved in 2009 for adult patients with RCC after failure of sunitinib or sorafenib,8,9 was studied in combination with lenvatinib, with positive results.10 In 2016, after approval of lenvatinib for differentiated thyroid cancer, the combination of lenvatinib plus everolimus was approved for patients with RCC after one prior antiangiogenic therapy.11 A phase III clinical trial is underway to test the combination of lenvatinib plus everolimus compared with sunitinib in the first line.12
Decisions About Subsequent Lines of Therapy: The ‘Art of Medicine’
The decision to use lenvatinib plus everolimus versus the “preferred” second-line options—nivolumab or cabozantinib—is not based on definitive head-to-head trial data, according to Thomas E. Hutson, DO, PharmD, Professor and Chair, Urologic Cancer Research with Texas Oncology, Sammons Cancer Center in Dallas. (However, the same comparator drug was used as the control arm in all three studies.)
In 2017, in every country that has access to these agents, the standard of care will be either sunitinib or pazopanib in the front-line setting, based on level 1 evidence from phase III trials, he said. “Thereafter, for the second, third, fourth, and fifth lines of treatment, the choices and sequencing of agents are left to the oncologist together with the patient and enter the realm of the ‘art of medicine.’” Second-line and subsequent options include nivolumab, cabozantinib, lenvatinib plus everolimus, and axitinib,4 which means, Dr. Hutson noted, “that a patient who lives long enough will receive all five of these agents through five lines of therapy. What the sequence should be, however, has not been determined.”
In practice, Dr. Hutson reports that nivolumab is being used by more oncologists in the second line, “with cabozantinib in the third line.” Lenvatinib plus everolimus, therefore, although approved as a second-line therapy, may not be used until the fourth line. “This is the way things are playing out, without the benefit of any head-to-head data,” he said.
Subset Analyses Can Be Misleading
Subset analyses, which are fraught with biases, might indicate that poor-risk patients did well with nivolumab,13 Dr. Hutson pointed out. “That’s not to say that intermediate- and good-risk patients wouldn’t also do well or that poor-risk patients wouldn’t do as well with cabozantinib.” Likewise, he explained that a subset analysis in a cabozantinib trial14 might suggest that patients with bone and visceral metastases do better. “Again, it doesn’t mean that those patients wouldn’t do just as well with a different drug,” he said. The subset analysis from the lenvatinib plus everolimus trial suggests that patients at intermediate-to-good risk do quite well,15 but “that doesn’t mean they wouldn’t do well with something else. Without a head-to-head study,” Dr. Hutson cautioned, “you can’t make any superiority claims.”
TKIs for Rapid Response?
Having established that we cannot state one regimen is better than another in the second-line and subsequent treatment of metastatic RCC, some clinicians prefer a TKI when a rapid response is required—for instance, when the volume of disease and symptom burden are substantial,16 Dr. Hutson noted. “It usually takes longer to achieve a response with a checkpoint inhibitor,” he said. And, when bone disease is predominant, cabozantinib may be preferred.14 “At the end of the day,” he commented, “we want to have given all the drugs. What’s the ideal sequence? We just don’t know.”
Evolving First-Line Options Will Change Second-Line and Subsequent Approaches
Second and subsequent lines of therapy will necessarily change depending on how front-line therapy evolves. For instance, Dr. Hutson explained that “if a strategy that pairs cabozantinib with checkpoint inhibition is approved for first-line treatment,17 then neither can be selected for second line, which will change how we approach treatment in the refractory setting.”
If a rapid response is needed and the decision has been made to go with a TKI, “some practitioners might choose lenvatinib plus everolimus instead of cabozantinib,” Dr. Hutson speculated, “on the basis of their experience and comfort level with these respective regimens.”
Lenvatinib Plus Everolimus: Dosing
“I have used lenvatinib and everolimus in clinical trials since phase I,” Dr. Hutson said. It’s a well-tolerated regimen and is certainly easier to use than practitioners might be led to believe on the basis of reported lists of adverse events [AEs].” Lenvatinib is associated with the anticipated class effects of VEGF inhibitors, and everolimus is associated with classic mTOR inhibitor effects. In the combination trial,10 “there were a few additive effects but no synergistic AEs, ie, no excessive toxicity.”
All patients should be started on the full 18-mg lenvatinib dose plus 5 mg of everolimus, except those with severe preexisting hepatic or renal impairment, who should be started on lenvatinib at a dose of 10 mg once daily. In patients who develop excessive fatigue or diarrhea, Dr. Hutson suggested, a dose reduction to 14 mg can be considered. “I have never had to drop lower than 14 mg; about 60% of my patients stay at the 18-mg level, with about 40% dropping down to 14 mg.” Clinical trial findings indicate that the split (ie, 18-mg dose vs 14-mg dose) will often be 50:50.10 Those patients who receive a reduced dose are usually able to maintain a reasonable quality of life with manageable toxicities, once they stabilize at the lower level. “We haven’t observed anything in clinical use that wasn’t reported in the clinical studies,” Dr. Hutson noted. Clinicians who use sunitinib know how to manage the AEs of levantinib, which are similar.
The everolimus dose in RCC is half of what is used in breast cancer, so although patients will have some mucositis and may complain about it, standard mouthwashes (eg, alcohol-free dexamethasone rinse) seem to be effective,18 Dr. Hutson said. “I haven’t had to use steroids for that.”
We know that the higher dose is associated with greater benefit, so I use treatment delays and breaks to help patients stay at the higher-dose level. Some patients are able to soldier through if they know they can take a weekend off, every month or so.
Incorporate Drug Breaks
“I would encourage clinicians to start at the full dose with this regimen [lenvatinib plus everolimus] and then reduce, if necessary. I also think it is helpful to incorporate frequent breaks of a couple of days. In fact, knowing there will be a break helps patients maintain the higher-dose level,” Dr. Hutson noted. “We know that the higher dose is associated with greater benefit, so I use treatment delays and breaks to help patients stay at the higher-dose level. Some patients are able to soldier through if they know they can take a weekend off, every month or so.” If imaging reveals disease control is maintained with that kind of schedule, “that’s great. If a patient is still struggling, though, after a few days off, you may have to consider a dose reduction. It’s a judgment call,” he explained.
Managing AEs of a Combination Regimen
At Memorial Sloan Kettering Cancer Center in New York, where Patricia Fischer, RN, MSN, OCN, is a clinical trials nurse who works with many patients who have RCC, patients are assessed first by the nurse before seeing the oncologist. Issues and questions about nausea, vomiting, and diarrhea/constipation are flagged for the oncologist. “Patients are somewhat more likely to discuss something like diarrhea in detail with us than with the physician,” Ms. Fischer noted. “We also talk about energy levels and appetite and even, if relevant, about dental work. For instance, we want to know about plans for tooth extractions because of potential issues with healing. Most of the time, we are aware of how the attending oncologist and/or nurse practitioner will address certain issues, so we can start to talk about options, which are then reinforced by the oncologist.”
At Memorial Sloan Kettering Cancer Center, patient and family education starts with a FACTS card, which is a printed piece that lists all the possible AEs with lenvatinib. “We explain, of course, that this list includes all reported side effects and that they won’t necessarily all occur. Then we use the FACTS card to highlight the most common ones, namely the elevated blood pressure, the loose stools, and the diminished appetite,” Ms. Fischer explained.
Because development of hypertension is almost inevitable with a TKI such as lenvatinib, patients are advised to buy a battery-operated blood pressure cuff so they can monitor blood pressure at home, Ms. Fischer said. Additionally, in many cases, because lenvatinib plus everolimus is a second-line regimen, patients already have an at-home blood pressure cuff and are on an antihypertensive medication. “We also ask patients to bring their device to the clinic, so we can determine whether it is accurate and roughly matches readings obtained by a clinician,” she explained.
Patients are also given a calendar, where they can record each daily dose of medication when they take it as well as their blood pressure. If the reading is 140/90 mm Hg or higher 2 days in a row, patients are instructed to call the care team.
“We try to bring blood pressure under control to begin with,” Ms. Fischer said, by working with the patient’s internist or cardiologist, especially if the patient already has borderline hypertension. The first antihypertensive drug to be prescribed is often a calcium channel blocker, such as amlodipine. “That said,” she noted, “these are patients with kidney cancer. They often have a nephrologist. If that’s the case, we encourage them to follow up with the nephrologist to manage the treatment-related hypertension.”
Loss of Appetite
In general, weight loss should be avoided in patients with any type of cancer. Loss of appetite appears to be somewhat more pronounced with lenvatinib than with first-line TKIs and should be proactively addressed. According to Ms. Fischer, “We encourage patients to eat at least three meals a day to maintain their current weight. If someone has not been a breakfast eater, we encourage him or her to eat at least something small in the morning. We also suggest that meals are scheduled ‘by the clock’ rather than according to hunger cues, which may be diminished.” The first step is to determine the patient’s baseline in terms of meals and then to make suggestions, such as having small snacks between meals, to prevent weight loss.
With regard to gastrointestinal AEs, “We first establish what is the patient’s normal baseline,” Ms. Fischer said. “Then we explain that both the frequency and consistency of stools may change—the patient may have more stools, and they may be looser.” Patients are advised to use over-the-counter loperamide but to take two tablets after the first loose stool rather than follow package instructions. However, the patient is also cautioned, “if you are reaching for the loperamide, you should also be reaching for the phone so your team is aware and we can review options. You should give us a call if your diarrhea is troublesome enough to be treated.”
Patients also need to pay attention to their diets, which can often mean eliminating fatty, greasy foods. And, of course, patients should strive to remain well hydrated and in communication with the team. If those measures, plus several loperamide tablets a day (up to six to eight per day), are still not reducing diarrhea to a tolerable level, “we recommend trying a BRAT diet—bananas, rice, applesauce, and toast—to slow things down until stools stabilize,” Ms. Fischer said.
With regard to AEs of everolimus, even at the 5-mg dose, “We talk about mouth sores,” Ms. Fischer said. To prevent and reduce oral issues, patients are advised to use a mild toothpaste for a sensitive mouth, a soft toothbrush, and no harsh mouthwashes (ie, alcohol-free). Patients are instructed to call the team if any side effects develop and become troubling. “We can also recommend topical triamcinolone acetonide dental paste be applied to the mouth sores,” Ms. Fischer added. “That usually offers good relief.”
Keeping Lines of Communication Open
At Memorial Sloan Kettering Cancer Center, patients are encouraged to be in touch with the team about any questions or AEs, Ms. Fischer said, and they can call the attending’s number at any time. Or, if they need help with specific AEs, they can call a special “emergency” number that is staffed by the fellow on call. These physicians are familiar with oncology drugs and can provide immediate instructions. “Patients may call our number the next working day, and we will review and tweak the instructions, if necessary,” she said.
“Our goal is to help patients receive the highest possible dose of lenvatinib,” Ms. Fischer explained, “at least for the first cycle.” This means not holding a dose until subsequent cycles. Loss of appetite and subsequent weight loss occur over time. If the patient loses 4 kg (about 8.82 lb) within a certain period, dose reduction may be unavoidable.
An Active Regimen
“Lenvatinib plus everolimus is a highly active regimen, and I encourage cancer teams to try it,” Dr. Hutson concluded. “When you see it work in your refractory patient, you will be impressed and may want to move it up in your treatment sequence. I’ve had skeptical colleagues (either because they were concerned about toxicities or cost) who have been converted once they’ve seen how active and manageable this combination can be.”
Thomas E. Hutson, DO, PharmD, has disclosed that he serves as a speaker, is on the advisory boards of, is a consultant for, or receives research support from Bayer, Pfizer, BMS, Exelixis, Eisai, and AVEO.
Patricia Fischer, RN, MSN, OCN, has disclosed that she serves on the advisory boards of Pfizer and Novartis.
- Cohen HT, McGovern FJ. Renal cell carcinoma. N Engl J Med 2005;353:2477–2490.
- Belldegrun AS, Klatte T, Shuch B, et al. Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1985-2005): a benchmark for emerging targeted cancer therapies. Cancer 2008;113:2457–2463.
- Hutson TE. Renal cell carcinoma: diagnosis and treatment, 1994-2003. Proc (Bayl Univ Med Cent) 2005;18:337–340.
- Motzer RJ, Jonasch E, Agarwal N, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelinesâ). Kidney Cancer. Version 2.2107. October 31, 2016. Available at https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed October 24, 2017.
- Eisai Inc. Lenvatinib (LenvimaÒ) prescribing information. Available at https://www.accessdata.fInda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf. Accessed October 17, 2017.
- Kuznar W. Lenvatinib extends survival in metastatic renal-cell carcinoma. Am Health Drug Benefits 2015 Aug;8(Spec Issue):18.
- Stenger M. Lenvatinib in combination with everolimus in advanced renal cell carcinoma. The ASCO Post. June 10, 2016. Available at http://www.ascopost.com/issues/june-10-2016/lenvatinib-in-combination-with-everolimus-in-advanced-renal-cell-carcinoma/. Accessed August 29, 2017.
- National Institutes of Health. National Cancer Institute. FDA approval for everolimus. Available at https://www.cancer.gov/about-cancer/treatment/drugs/fda-everolimus. Accessed August 30, 2017.
- Novartis. Everolimus (Afinitor). Available at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/afinitor.pdf. Accessed August 30, 2017.
- Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomized, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473–1482.
- U.S. Department of Health and Human Services. FDA U.S. Food & Drug Administration. Lenvatinib in combination with everolimus. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm501070.htm. Accessed August 30, 2017.
- Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma. NCT02811861. Available at https://clinicaltrials.gov/show/NCT02811861. Accessed August 31, 2017.
- Escudier B, Sharma P, McDermott DF, et al. CheckMate 025 randomized phase 3 study: outcomes by key baseline factors and prior therapy for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. March 3, 2017 [Epub ahead of print].
- Ruiz-Morales JM, Heng DYC. Cabozantinib in the treatment of advanced renal cell carcinoma: clinical trial evidence and experience. Ther Adv Urol 2016;8:338–347.
- Hutson TE, Dutcus CE, Ren M, et al. Subgroup analyses and updated overall survival from the phase II trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in metastatic renal cell carcinoma. J Clin Oncol 2016;34(suppl):4553.
- Barata PC, Ornstein MC, Garcia J. The evolving treatment landscape of advanced renal cell carcinoma in patients progressing after VEGF inhibition. J Kidney Cancer VHL 2017;4:10–18.
- A Study of Nivolumab Combined With Cabozantinib or Nivolumab and Ipilimumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cenll Carcinoma (CheckMate 9ER). Available at https://clinicaltrials.gov/ct2/show/NCT03141177?term=cabozantinib+nivolumab&cond=Renal+Cell+Cancer+Metastatic&rank=1. Accessed August 30, 2017.
- Rugo H, Seneviratne L, Beck J, et al: Prevention of everolimus/exemestane stomatitis in postmenopausal women with hormone receptor–positive metastatic breast cancer using a dexamethasone-based mouthwash: results of the SWISH trial. MASCC/ISOO International Symposium on Supportive Care in Cancer. Abstract MASCC-0638. Presented June 23, 2016.