Real-World Data on an RAI-Refractory DTC Treatment Option

Francis Worden, MD, is a medical oncologist and a clinical professor of medicine at the University of Michigan Rogel Cancer Center.

As a medical oncologist, I have treated thyroid cancer patients for over 20 years. Differentiated thyroid cancers (DTC) are often cured with surgery and radioactive iodine (RAI); however, a small percentage of patients will become refractory to RAI (RAI-R DTC), which is associated with a poor prognosis.^1,2,3

Thankfully, the treatment landscape for patients with RAI-R DTC has evolved dramatically over time, and targeted therapies are now available to help patients live longer with their disease. Today, real-world studies are providing important insight into how these treatments are being used in clinical practice and how they impact patients’ lives.

Advances with an RAI-R DTC Treatment

In 2000, when I first started treating patients with RAI-R DTC, the only FDA-approved therapies were doxorubicin-based palliative radiation. Since then, we now have several targeted agents to offer patients as both first-line and second-line treatments in the refractory setting. For example, lenvatinib (LENVIMA), available as 10 mg and 4 mg capsules, is an oral, multiple receptor tyrosine kinase inhibitor (TKI) that was approved by the U.S. Food and Drug Administration in 2015 for the treatment of adult patients with locally recurrent or metastatic, progressive, RAI-R DTC.⁴

The approval of lenvatinib included data from the Phase 3 SELECT study, which was a multicenter, randomized, double-blind, placebo-controlled trial in patients with locally recurrent or metastatic RAI-R DTC (N=392) who have had radiographic evidence of disease progression within 12 months prior to randomization as confirmed by independent radiologic review.⁵ Patients may have received 0 or 1 prior VEGF/VEGFR-targeted therapies. Patients were randomized to receive lenvatinib 24 mg once daily (n=261) or placebo (n=131) until disease progression. Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression. The primary endpoint was PFS as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Secondary endpoints included ORR and OS.

The SELECT data also supports the recommendation of lenvatinib by the National Comprehensive Cancer Network® (NCCN®) as an NCCN Category 1 preferred first-line systemic therapy option for locally recurrent, advanced and/or metastatic, progressive RAI-R DTC.* That said, it’s important for clinicians to evaluate each patient’s case individually and determine the treatment that may be best for them, depending on their specific situation and disease characteristics.

SELECT Study Data

Overall, data from the SELECT study showed the median progression free survival (PFS) with lenvatinib was five times that of placebo. Specifically, the median PFS with lenvatinib was 18.3 months (95% CI: 15.1-not estimable) vs. 3.6 months (95% CI: 2.2-3.7) with placebo (HR: 0.21 [95% CI: 0.16-0.28]; P<0.001). In total, 107 events (41%) occurred in the lenvatinib arm vs. 113 events (86%) in the placebo arm. In the PFS evaluation, death occurred in 14 patients (5%) who received lenvatinib vs. 4 patients (3%) who received placebo. In the PFS evaluation, death occurred in 14 patients (5%) who received lenvatinib vs. 4 patients (3%) who received placebo. The data also showed a 65.0% overall response rate (ORR) with lenvatinib (95% CI: 59%-71%) (2% CR[n=4]; 63% PR [n=165]) vs. 2% ORR with placebo (95% CI: 0%-4%) (no CR; 2% PR [n=2]); P<0.001. Median OS was not estimable at data cutoff (HR: 0.73 [95% CI: 0.50-1.07]; P=0.10).

The most common adverse reactions observed in patients treated with lenvatinib (>30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (>2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Real-World Data

Real-world studies are important because they provide us with an in-depth understanding of the impact treatments have on patients in the general population versus a controlled clinical trial setting. There has been increased interest in real-world evidence studies over time, which underscores the value this data can provide.⁶

In the real-world data (RWD) study by Worden, et al., we assessed the clinical effectiveness of lenvatinib as a first-line therapy for patients with RAI-R DTC in the United States.⁷ This was the largest retrospective review to date of medical charts of 308 randomly selected patients with RAI-R DTC. All patients were treated with first-line lenvatinib monotherapy between February 13, 2015 and September 30, 2020. The patients were selected by 65 physicians from academic hospitals (38.5%), community hospitals and private practice (61.5%). Clinical outcomes assessed included real-world best overall response (BOR), real-world progression-free survival (rwPFS), and overall survival (OS), as reported by physicians.

Physician-reported responses were assessed either per RECIST criteria (RECIST v1.0, RECIST v1.1, iRECIST), or physician judgement based on radiology reports, imaging, patient/clinical factors, or a combination of these criteria.

Clinical Outcomes

The data from this real-world study demonstrated that patients treated with lenvatinib had a BOR of 72.4%, reported as a complete (26.9%) or partial (45.5%) response. The disease control rate (complete response, partial response, or stable disease) was 90.6%. The median rwPFS was 49.0 months (95% CI: 37.0-not estimable) with an estimated PFS of 83.3% (95% CI: 78.3-87.2) at 12 months, 68.5% (95% CI: 62.0-74.1) at 24 months, and 55.0% (95% CI: 43.2-65.3) at 48 months.

By the end of follow-up, 75% of patients were alive. The median OS was not reached at the data cut-off but the estimated OS rates were 90.8% (95% CI: 87.0-93.6) at 12 months, 78.4% (95% CI: 73.0-82.8) at 24 months and 57.0% (95% CI: 36.8-72.8) at 72 months.

Duration of Treatment

By the end of our follow-up, 32.5% of patients had discontinued lenvatinib, while 67.5% were still on therapy. The median duration of treatment with lenvatinib by descriptive analyses was 17.5 months overall, 9.1 months in those who discontinued treatment and 20.1 months in those still on therapy. The median time to discontinuation of lenvatinib was 49.0 months (95% CI: 38.5-54.2) by Kaplan-Meier analyses. Among the 100 patients who discontinued lenvatinib, the most common reasons were disease progression (38.0%) and death (33.0%). Among those patients who discontinued lenvatinib, 19 initiated a second line treatment.

For context, in the SELECT study, 18% of patients discontinued lenvatinib for adverse reactions. The most common adverse reactions (>1%) resulting in discontinuation of lenvatinib were hypertension (1%) and asthenia (1%).

Limitations

No direct comparisons between data from the pivotal clinical trial and the RWD study should be made, as there could be potential differences in patient populations, patient characteristics, follow-up duration, response assessment timing, frequency, and criteria that are used in clinical trials versus real-world settings. This is a retrospective, non-interventional study and could be subject to potential provider selection bias, as only providers who consent to participate in the research study would have contributed de-identified patient data to be used for analyses. As this was a single cohort non-interventional study, no data on comparative therapies were included. Information on adverse events was not collected in this study.

Takeaways

I believe looking at RWD can provide valuable insight into the use and impact of treatments in the clinical setting.

Overall, the data from this RWD set support the data on lenvatinib previously reported in the SELECT trial. It is also notable that 62% of patients in the RWD study initiated lenvatinib at the recommended 24 mg daily dose. The majority of patients (90.3%) remained on their respective starting doses throughout their treatment, with few patients (8%) requiring a dose alteration.¹⁰ 

For context, in the SELECT study, adverse reactions led to dose reductions in 68% of patients receiving lenvatinib. The most common adverse reactions (>10%) resulting in dose reductions of lenvatinib were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%).

Looking Forward

As a researcher and clinician, I am grateful for the scientific innovations that have led to the availability of more targeted therapies for patients with RAI-R DTC. Furthermore, I am thrilled to see the burgeoning use of real-world evidence in order to provide clinicians with more information about patients treated in real-world settings. The RWD study adds to the body of evidence on lenvatinib previously reported in the SELECT trial. As we continue to move into the future, I look forward to the development of new innovative treatment strategies to treat RAI-R DTC in an effort to provide a meaningful impact for patients and their loved ones.

Eisai Inc. sponsored this article and compensated Dr. Worden for his participation.

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.2.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed April 8, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

CI = Confidence interval

HR = Hazard ratio

CR = Complete response (disappearance of all target and nontarget lesions)

PR = Partial response (30% or greater decrease in the sum of diameters of target lesions)

About LENVIMA® (lenvatinib)

LENVIMAis indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)

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 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 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 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 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.

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

© 2024 Eisai Inc. All rights reserved. LENV-US10213

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¹ American Cancer Society. Treating Thyroid Cancer. https://www.cancer.org/cancer/types/thyroid-cancer/treating.html#:~:text=Most%20thyroid%20cancers%20can%20be,for%20as%20long%20as%20possible. Accessed March 21, 2024.

² American Cancer Society. Treatment of Thyroid Cancer, by Type and Stage. https://www.cancer.org/cancer/types/thyroid-cancer/treating/by-stage.html. Accessed March 21, 2024.

³ Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits __and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006 Aug;91(8):2892-9

⁴ LENVIMA® (lenvatinib). Prescribing Information. Eisai Inc. http://www.lenvima.com/pdfs/prescribing-information.pdf

⁵ N Engl J Med 2015; 372:621-630. DOI: 10.1056/NEJMoa1406470

⁶ Di Maio M, Perrone F, Conte P. Real-World Evidence in Oncology: Opportunities and Limitations. Oncologist. 2020 May;25(5):e746-e752. doi: 10.1634/theoncologist.2019-0647. Epub 2019 Dec 24. PMID: 31872939; PMCID: PMC7216461. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216461/

⁷ Worden, F., Rajkovic-Hooley, O., Reynolds, N. et al. Real-world treatment patterns and clinical outcomes in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) treated with first line lenvatinib monotherapy in the United States. Endocrine (2023). https://doi.org/10.1007/s12020-023-03638-7