Sponsored by Eisai Inc.
Patients diagnosed with advanced differentiated thyroid cancer may be referred to an endocrinologist or an oncologist depending on the stage and complications of their disease and the healthcare network in which they seek treatment. Oftentimes it may be curable with surgery and radioactive iodine (RAI) treatment. The most common types of thyroid cancer, papillary and follicular (including Hürthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases. Approximately 5% to 15% of patients diagnosed with DTC and 50% of patients with metastatic DTC are RAI-refractory and may require systemic therapy.
We spoke with experts Dr. Andrew Gianoukakis, an endocrinologist and professor of medicine at UCLA, and Dr. Ann Gramza, a practicing oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center, who shared their insights on the dynamic of co-managing patients in practice as well as their approaches to treating patients with locally recurrent or metastatic, progressive, RAI-refractory DTC with targeted therapies such as LENVIMA® (lenvatinib). This sponsored article is brought to you by Eisai Inc. Drs. Gianoukakis and Gramza were compensated for participating in this article.
At what point should an endocrinologist refer patients with differentiated thyroid cancer (DTC) to an oncologist?
Dr. Gramza: I have seen a few different approaches from endocrinology professionals, and it can vary based on the level of comfort or expertise he/she may have with patients with DTC. I’ve worked with experienced endocrinologists who retain patients through first- and second-line treatment as well as endocrinologists who refer patients to oncologists at the earliest stages where RAI-refractory status or systemic metastases are evident. I understand that not all endocrinology practices have the sort of infrastructure to care for patients who have metastatic cancer and symptomatic metastatic cancer. I also understand that it can be challenging to know when a patient with DTC is RAI-refractory, even when following national guidelines and clinical best-practices. It’s difficult to educate every single medical oncologist out there for a very small number of RAI-refractory DTC patients they’re going to see. That’s why co-managing the treatment of this cancer between an endocrinologist and oncologist is so important. It also helps patients feel that their care is both a priority and a seamless experience.
Dr. Gianoukakis: I agree that it certainly varies from practice-to-practice and across individual endocrinologists, which is why it’s hard to pinpoint that perfect time to refer. Furthermore, I would suggest that the referral be accompanied by continued involvement of the endocrinologist and a potentially long period of co-management. I think the biggest challenge occurs when both the endocrinologist and the oncologist are not ‘in the know,’ which could lead to either acting too quickly or acting too late. As a participant in the clinical development of newer therapies for advanced DTC, I’ve developed an expertise in this area and am more comfortable in prescribing and managing systemic therapy. While the configuration and timing will be specific to each practice, it’s important to take a multi-disciplinary teamwork approach when it comes to managing patients with radioiodine-refractory differentiated thyroid cancer, especially as the disease progresses.
Once patients are confirmed to have RAI-refractory disease, what is your general treatment approach?
Dr. Gianoukakis: Treatment options and approaches need to be a joint discussion and partnership with patients themselves. Once a patient is identified as having progressive, RAI-refractory DTC, if the disease is localized, it may initially be addressed surgically or by localized radiation therapy. If a patient is exhibiting systemic disease that’s growing in multiple areas and cannot be treated with localized therapy, then they start to become candidates for systemic therapy. Single lesions, if not amenable to local therapy, may also warrant initiating a certain targeted TKI therapy sooner.
Dr. Gramza: That is how I would approach it, too. Once patients have presented RAI-refractory status, I would recommend systemic therapy following RAI for a patient who has symptomatic metastatic disease, or for a patient with locally recurrent disease that has rapidly progressed. Before putting a patient on systemic therapy, there are certainly individual factors for consideration, too, such as age. So for an elderly patient, I may try to hold off on therapy a little bit longer, particularly if the patient isn’t having symptoms from the metastatic disease, but I will typically go by the location of the metastasis, disease progression and symptoms.
Do you have a preferred first-line treatment for patients with RAI-refractory DTC?
Dr. Gramza: For me, my first-line choice for patients with locally recurrent or metastatic, progressive, RAI-refractory DTC is LENVIMA® (lenvatinib), which is a multiple receptor tyrosine kinase inhibitor. It’s a therapy I’ve been using in appropriate RAI-refractory DTC patients since it was FDA-approved, and I would say it is still my go-to first-line choice for these patients.
Dr. Gianoukakis: LENVIMA would be my first-line choice for patients with locally recurrent or metastatic, progressive, RAI-refractory DTC. In the SELECT study, LENVIMA demonstrated superior progression free survival (PFS) benefit with a median PFS of 18.3 months (95% CI:15.1-NE) versus 3.6 months (95% CI:2.2-3.7) with placebo. There was a 79% reduction in the risk of disease progression or death with LENVIMA versus placebo (HR: 0.21; [95% CI: 0.16-0.28]; p<0.001).
For the responders (those who demonstrated partial or complete response), however, the duration of response (DOR) can be significantly longer, with a median DOR of 30 months (95% CI: 18.4-36.7) along with a median PFS of 33.1 months (95% CI: 27.8-44.6) in patients treated with LENVIMA versus a median PFS of 7.9 months (95% CI: 5.8-10.7) in nonresponders (those who did not demonstrate a complete or partial response).1
Are there any other considerations before starting a patient on LENVIMA?
Dr. Gramza: One thing that is important is to make sure the patient knows that if they experience side effects, their LENVIMA dose may need to be modified. Treatment may be stopped until the side effect resolves or improves and then resumed at a reduced dose. For certain side effects, the person may need to permanently discontinue treatment with LENVIMA. Before starting a patient on treatment, I make sure they understand what to expect, so I go through the potential benefits as well as LENVIMA warnings and precautions and possible serious or common side effects, noting that each patient’s treatment goals or experience with LENVIMA can be different.
I usually explain that 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, and osteonecrosis of the jaw. Based on the severity of the adverse reaction, we would then determine whether LENVIMA should be interrupted, reduced, and/or discontinued. Before initiating and while on treatment with LENVIMA, I also monitor my patients for hypertension, proteinuria, liver function, electrolyte abnormalities, thyroid function, and osteonecrosis of the jaw.
Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman, so I would advise my female patients to use effective contraception during treatment with LENVIMA. Serious potential side effects include pneumonia, hypertension and dehydration, while some of the most common side effects include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, and nausea, among others.
Dr. Gianoukakis: Setting expectations with patients from the get-go is critical. It’s so important to have the patient buy-in and believe that ‘this is the right approach for me at this time.’ We want them to work with us and trust us to deal with the side effects in good faith so that we can manage the therapy and side effects together as a team in order to get the most out of the treatment. Another point of consideration is that LENVIMA is an oral drug administered at home and does not require an infusion center visit.
Has COVID-19 affected your practice or how you approach treatment for patients with RAI-refractory DTC?
Dr. Gramza: While COVID-19 has certainly disrupted healthcare, shifts to telehealth services have assisted in ensuring that doctors are able to reach and communicate with patients. At the start of the pandemic, patients weren’t always able to come into medical facilities, which sometimes caused a delay in routine procedures like imaging, blood work, and urinalysis for about a six-month period. This has since improved considerably, and most of my patients are back to seeing me in person.
Dr. Gianoukakis: Yes, telehealth has definitely fostered continued communication in the midst of the pandemic, however there are some aspects of in-person visits that you may not get from a telehealth visit. We also rely on physical exams to complement lab data so as to obtain a more complete picture of patients’ disease progression.
How do you think the overall management of RAI-refractory patients between endocrinologists and oncologists could further improve in the future?
Dr. Gianoukakis: A lack or inconsistency of co-managing treatment for patients with RAI-refractory DTC can create challenges for endocrinologists and oncologists alike. Increasing a co-management approach would help align practices and keep local medical professionals informed on when to refer patients or begin systemic therapies. Across specialties, a meeting of the minds, a co-understanding, and a co-education of endocrinologists and oncologists as they co-manage patients are certainly steps in the right direction, such as having annual endocrinologist and oncologist roundtables organized by professional societies. Other solutions that can be implemented at the practice-level can include designating a specialist within each group practice to specialize in advanced thyroid cancer care.
Dr. Gramza: Ideally you would have the endocrinologist be in early contact with either an endocrinologist who is an expert in thyroid cancer, or a medical oncologist who is an expert in thyroid cancer, or even a surgeon, frankly, because anyone who has a lot of experience in managing these patients will know who to refer to in the event that a patient needs to be treated. So, just reaching out to whoever you might know with experience or expertise in the area I think would be helpful in regard to making treatment decisions for the patients. Offering clinical training programs on thyroid cancer to medical professionals, both within endocrinology and oncology, I think is also an achievable step towards incremental progress in co-managing the treatment of patients with RAI-refractory DTC. Though progress takes time, I’m hopeful that we will get there.
About LENVIMA® (lenvatinib) Capsules
LENVIMA is indicated:
- For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC)
Important Safety Information
Warnings and Precautions
Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, 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, 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. 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 1,327 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 1,823 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 at least 30 days after the last dose.
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).
Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to
discontinue breastfeeding during treatment and for at least 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 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.
LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.
For more information about LENVIMA please see available full Prescribing Information.
 Gianoukakis AG, Cutcus CR, Batty N, Baig M. Prolonged duration of response in lenvatinib responders with thyroid cancer. Endocr Relat Cancer. 2018; 25(6):699-704