The Evolving Advanced RCC Treatment Landscape

Thomas E. Hutson, DO, Pharm.D., FACP, is the Director of the Urologic Oncology Program and Co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas, TX.

Thomas E. Hutson, DO, Pharm.D., FACP

At the start of the millennium, advanced and metastatic kidney cancer was on a short list of cancers with limited systemic treatment options¹. Median overall survival with the standard of care at the time wasn’t encouraging² and sadly, the expectation among many people diagnosed with advanced renal cell carcinoma (RCC), the most common type of kidney cancer, was that their cancer would not be treatable.² Fortunately, there has been a distinct shift over the past 20 years and the advanced RCC treatment landscape has evolved tremendously¹. Now, there are more treatment options for the estimated 81,800 Americans who will be diagnosed with kidney cancer this year,⁴ and RCC accounts for 80% to 85% of those diagnoses.⁵ Nevertheless, survival is highly dependent on the type and stage at diagnosis, and approximately 15% of patients with RCC will be diagnosed with metastatic disease.² So working with patients to determine and understand the treatment options that are best for them is especially important. As both a researcher and clinician who has cared for people with advanced RCC for the past two decades, I can confidently say we have come a long way and I am optimistic about the future.

The Current Advanced RCC Treatment Landscape

Thanks to clinical research and scientific advancements, we have seen significant progress in treatments for advanced RCC. Today, there is an array of approved options--from immunotherapies to combination therapies--and oncologists are increasingly more educated on how to best use them. Learnings from the adjuvant setting have been applied over the years and more treatment combinations are being investigated in other settings than ever before.¹

The Modern Patient Journey

As available treatment options have evolved, so too has awareness and education among the patient community. Early on in my practice, patients would come to their first appointment post-diagnosis with a grim outlook. Back then, many were initially told to get their affairs in order and in doing their own research, they would find that there were few therapies available or none at all. Now I often hear a sigh of relief when I tell my patients that there are treatment options we can consider together. Given the variety of educational content and advocacy group resources available online, my patients often come in with a baseline understanding of their disease and an expectation of receiving treatment.

A two-way dialogue with patients is important to assess their needs--physically, mentally and emotionally--and help them understand the available treatment options that are most appropriate for them.

It's also important to recognize that those needs may change throughout a patient’s treatment journey. A best practice I follow is to ask if they have previous experience with an oncologist, about their family history and if they are already familiar with treatment options. I often ask my patients to consider what support they may need while living with advanced RCC, from managing side effects and impact on their day-to-day life to discussing their disease with an employer or seeking financial support if they’re unable to continue working. Guidance, support and resources are critical for this patient community.

Evaluating Treatment Options

There are many available treatment options for advanced RCC and it’s not uncommon for multiple therapies to be appropriate for any given patient. That’s why, when I see a patient initially, I like to take the time to walk them through the history of advanced RCC treatment, the current standard of care and discuss which treatments I think might be most appropriate for them.

For most patients, it's an unfortunate reality that their advanced RCC may continue to progress while on first-line treatment. So, when it comes to determining the optimal second-line therapy (or therapies), I’m grateful to have options. I always encourage fellow oncologists to also consider using combination regimens when appropriate for previously treated patients in accordance with their respective FDA-approved indications. For example, LENVIMA^® (lenvatinib) in combination with everolimus is an option to consider for adult patients with advanced RCC previously treated with one anti-angiogenic therapy. Providing a dual mechanism of action, LENVIMA plus everolimus is the only tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTOR) combination approved in advanced RCC for second-line use⁶, and is a regimen I often choose for appropriate patients with advanced RCC previously treated with an anti-angiogenic therapy.

Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. Based on the severity of the adverse reaction, LENVIMA should be interrupted, reduced, and/or discontinued.

In the near term, I hope to see continued education about how to use combination therapies, facilitate open and honest conversations with patients and access support and resources. In the decades to come, I hope we’ll have the opportunity to reach more people with advanced RCC than ever before and together as clinicians, we can continue striving to make a meaningful impact on these patients and their families.

This sponsored article is brought to you by Eisai Inc.

Dr. Hutson was compensated for participating.

References:

1. National Library of Medicine. The Therapeutic Landscape of Renal Cell Carcinoma: From the Dark Age to the Golden Age https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8858035/
2. National Cancer Institute. Cancer Stat Facts: Kidney and Renal Pelvis Cancer. https://seer.cancer.gov/statfacts/html/kidrp.html
3. ACS. What Is Kidney Cancer?
   https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html
4. American Cancer Society. Key Statistics About Kidney Cancer.
   https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html
5. National Library of Medicine. Renal Cell Cancer
   https://www.ncbi.nlm.nih.gov/books/NBK470336/#:~:text=Renal%20cell%20carcinomas%20%28RCCs%29%2C%20which%20originate%20within%20the,originate%20in%20the%20renal%20pelvis%2C%20comprise%20approximately%208%25
6. LENVIMA® (lenvatinib). Prescribing Information. Eisai Inc. http://www.lenvima.com/pdfs/prescribing-information.pdf

About LENVIMA® (lenvatinib) 10 mg and 4 mg Capsules

LENVIMAis indicated in combination with everolimus, for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy

Important Safety Information

Warnings and Precautions

Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Embryo‐Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.

Adverse Reactions

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus-treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

Use in Specific Populations

Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC (endometrial carcinoma) and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

For more information about LENVIMA please see available full Prescribing Information.

LENVIMA^® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.
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