426P A multicenter, randomized, double-blind, phase II study of lenvatinib (LEN) in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) to evaluate the safety and efficacy of a daily oral starting dose of 18 mg vs 24 mg

Brose, Marcia S.; Panaseykin, Y.; Konda, Bhavana; Fouchardière, Christelle De La; Hughes, Brett Gordon Maxwell; Gianoukakis, Andrew G.; Park, Y.J.; Romanov, I.; Krzyzanowska, M. K.; Binder, Terri A.; Dutcus, Corina E.; Xie, Ran; Taylor, Matthew H.

doi:10.1016/j.annonc.2020.10.418

Cited by 12 publications

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“…The data suggest that antitumor activity can continue to occur with reduced dosages of lenvatinib; however, lower starting doses could lead to inferior efficacy and not necessarily less toxicity [21]. This is supported by a recent study of lenvatinib in patients with differentiated thyroid cancer, which found that ORR was not noninferior in patients who started treatment at a lower starting dose compared with a higher dose [22]. Similar outcomes were also seen in a recent prospective study of lenvatinib plus everolimus in patients with renal cell carcinoma, in which a reduced starting dose of lenvatinib (14 mg/day) was not found to be noninferior to the approved lenvatinib starting dose of 18 mg/day [23], suggesting that optimal lenvatinib therapy may be achieved by starting at a higher dose and reducing as medically necessary following maximization of supportive care.…”

Section: Discussionmentioning

confidence: 97%

“…Although the results of How et al are hypothesis‐generating as to whether a lower starting dose of lenvatinib could be considered in some patients, the retrospective nature of the analysis, which included 16 patients who received lenvatinib 20 mg/day as the starting dose, should be considered. Results from prospective cohort studies published to date (across various indications) do not support alternative lenvatinib starting doses [22, 23]. Additionally, patient‐reported health‐related quality‐of‐life data among patients with endometrial cancer from Study 309/KEYNOTE‐775 were recently presented [25] and showed that, over 12 weeks of follow‐up, similar changes in Global Health Score/quality‐of‐life outcomes were observed for patients receiving lenvatinib and pembrolizumab and those receiving treatment of physician's choice (doxorubicin or paclitaxel; −5.97; 95% CI, −8.36 to −3.58 vs. −6.98; 95% CI, −9.63 to −4.33).…”

Section: Discussionmentioning

confidence: 99%

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Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab

et al. 2021

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Background. The combination of lenvatinib plus pembrolizumab has shown efficacy in treatment of advanced endometrial carcinoma that is not MSI-H or dMMR following prior systemic therapy in any setting in the open-label, single-arm, phase 1b/2 Study 111/KEYNOTE-146. With the exception of hypothyroidism, the safety profile of the combination was comparable to that of each monotherapy. Given the medical complexity and fragility of endometrial carcinoma patients, further characterization of adverse reactions (ARs) associated with treatment will help healthcare professionals to optimize treatment with lenvatinib plus pembrolizumab combination therapy. Patients and Methods. In Study 111/KEYNOTE-146, patients received lenvatinib at a starting dose of 20 mg orally once daily and pembrolizumab 200 mg IV every 3 weeks. Selected ARs (hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria) were chosen for detailed post hoc analyses. Results. Median times to first onset of the selected ARs in this analysis all occurred within the first 10 weeks of treatment. Of the selected ARs, grade ≥3 severity of fatigue, hypertension, and nausea occurred in ≥5% of patients. Overall incidence of hypothyroidism was 51%, primarily of grade 2 severity (46%). Most of the ARs assessed were managed with a combination of study drug dose modifications and concomitant medications. Conclusion.No new safety signals were identified and the toxicity profile in this study was manageable with supportive medications, dose interruptions, and/or lenvatinib dose reductions. This analysis provides AR management guidance for endometrial cancer patients receiving lenvatinib plus pembrolizumab combination therapy.Implications for Practice statement: Lenvatinib plus pembrolizumab has shown efficacy in the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR following ≥1 prior systemic therapy in any setting. Patients may experience toxicity associated with this combination, including but not limited to adverse reactions of hypertension, fatigue, nausea/vomiting, diarrhea, decreased appetite/weight loss, hypothyroidism, palmar-plantar erythrodysesthesia syndrome, musculoskeletal pain, stomatitis, and proteinuria. These adverse reactions may be managed with a combination of concomitant supportive care medications and judicious lenvatinib dose modifications. This article provides context and guidance for the recognition and management of adverse reactions in patients receiving lenvatinib plus pembrolizumab. The Oncologist 2021;9999:• •

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab

et al. 2021

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“…This indicates it is difficult to achieve 60% of 8w-RDI when the dose of lenvatinib is reduced to less than 14 mg/day in the early phase of the treatment. Most recently, in Study 211, a randomized phase 2 study, 18 mg/day lenvatinib starting dose did not show non-inferiority to 24 mg/day in terms of ORR [15,16]. It is reported that dose reduction and interruption is required even in patients who started lenvatinib at a reduced dose [17].…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of 8 weeks’ relative dose intensity of lenvatinib in treatment of radioiodine-refractory differentiated thyroid cancer patients

et al. 2021

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Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cutoff value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cutoff value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

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“…Nevertheless, there is no evidence showing maintained efficacy and reduced toxicity in RR-DTC patients treated with VEGFR-targeted TKI that is started at a reduced dose. A randomized phase II clinical trial which investigated if a lower starting dose of lenvatinib of 18 mg yielded comparable efficacy to 24 mg in patients with RR-DTC did not demonstrate the noninferiority of 18 mg vs. 24 mg based on the overall response rate as of week 24 (40.3% vs. 57.3%) [ 120 ].…”

Section: Other Factors For Appropriate Management Of Anti-vegfr Tkis Therapymentioning

confidence: 99%

Management of VEGFR-Targeted TKI for Thyroid Cancer

Enokida

Tahara

2021

Cancers

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Recent advances in the development of multitarget tyrosine kinase inhibitors (MTKIs), which mainly target the vascular endothelial growth factor receptor (VEGFR), have improved prognoses and dramatically changed the treatment strategy for advanced thyroid cancer. However, adverse events related to this inhibition can interrupt treatment and sometimes lead to discontinuation. In addition, they can be annoying and potentially jeopardize the subjects’ quality of life, even allowing that the clinical outcome of patients with advanced thyroid cancer remains limited. In this review, we summarize the potential mechanisms underlying these adverse events (hypertension, proteinuria and renal impairment, hemorrhage, fistula formation/gastrointestinal perforation, wound healing, cardiovascular toxicities, hematological toxicity, diarrhea, fatigue, and acute cholecystitis), their characteristics, and actual management. Furthermore, we also discuss the importance of related factors, including alternative treatments that target other pathways, the necessity of subject selection for safer administration, and patient education.

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426P A multicenter, randomized, double-blind, phase II study of lenvatinib (LEN) in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) to evaluate the safety and efficacy of a daily oral starting dose of 18 mg vs 24 mg

Abstract: A multicenter, randomized, double-blind, phase II study of lenvatinib (LEN) in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) to evaluate the safety and efficacy of a daily oral starting dose of 18 mg vs 24 mg

Cited by 12 publications

References 0 publications

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab

Prognostic significance of 8 weeks’ relative dose intensity of lenvatinib in treatment of radioiodine-refractory differentiated thyroid cancer patients

Management of VEGFR-Targeted TKI for Thyroid Cancer

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