Lenvatinib demonstrated promising antitumor activity and a manageable toxicity profile in 3 main subtypes of thyroid cancer, according to findings recently published in <em>Future Oncology.</em>
Lenvatinib (Lenvima) demonstrated promising antitumor activity and a manageable toxicity profile in 3 main subtypes of thyroid cancer, according to findings recently published inFuture Oncology.
“This phase II study was undertaken to assess the safety of once-daily lenvatinib in predominantly Japanese patients with advanced thyroid cancers,” Lead study author Shunji Takahashi, MD, of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, et al wrote.1“Lenvatinib demonstrated a manageable toxicity profile and promising antitumor activity across all thyroid cancer subtypes tested.”
Lenvatinib is currently approved in Japan and the United States, amongst other countries, to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC); however, new therapies are needed to treat other disease subtypes, such as medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), that have metastasized beyond the stage that can be treated with localized therapy or resection.
In this nonrandomized, open-label, multicenter study, 51 patients with RR-DTC (n = 25), MTC (n = 9), and ATC (n = 17) were enrolled to receive once-daily oral lenvatinib at 24 mg in 28-day continuous cycles. Treatment continued until disease progression according to RECIST version 1.1 or the development of unacceptable toxicity.
Patients were eligible if they were aged ≥20 years, had an ECOG performance status 0 to 2, and had histologically or cytologically confirmed advanced thyroid cancer of any of the specified subtypes. Ineligibility criteria for the study included concomitant brain metastases, history of cardiovascular impairment, bleeding or thrombotic disorders, proteinuria, or previous therapy that included lenvatinib.
The primary objective was to evaluate safety of lenvatinib in patients with advanced thyroid cancer treated at 3 different study sites in Japan. Secondary measures included efficacy endpoints of progression-free survival (PFS), overall survival (OS), objective response rates (ORR), disease control rate (DCR), and clinical benefit rate. An exploratory analysis was undertaken to investigate the neutrophil-to-lymphocyte ratio (NLR) at baseline and its effect on PFS.
For the primary analysis, all patients experienced ≥1 treatment-emergent adverse event (TEAE); similarly, all patients experienced ≥1 TEAE related to lenvatinib as determined by study investigators. In addition, a majority of patients (82%) had ≥1 grade 3/4 TEAE and roughly half (53%) experienced serious adverse events (SAEs) that led to death, hospitalization, or were considered life-threatening. Five patients experienced a fatal SAE, yet these were reported to be unrelated to the study drug by the investigators.
TEAEs led to lenvatinib dose reduction in 49 patients (96%); all of these events were grade 2/3 except for 1 instance each of grade 4 thrombocytopenia and grade 4 hypocalcemia. TEAEs led to dose interruption in 34 patients (67%).
The most frequently reported TEAE was hypertension which occurred in 46 patients (90%), followed by decreased appetite in 40 (78%), palmar-plantar erythrodysesthesia syndrome in 39 (77%), fatigue in 37 (73%), proteinuria in 31 (61%), stomatitis in 29 (57%), diarrhea in 28 (55%), and dysphonia and nausea in 21 each (41%).
Stratified by disease subgroup, 15 patients with RR-DTC, 2 with MTC, and 5 with ATC experienced grade 3/4 hypertension. Four patients experienced 1 or more grade 3/4 TEAEs which included hypocalcemia, hyponatremia, laryngeal stenosis, suicide attempt, and thrombocytopenia. The grade 4 TEAEs resolved with treatment or study-drug dose reduction except for hypocalcemia, laryngeal stenosis, and suicide attempt.
The median PFS rates recorded in patients with RR-DTC, MTC, and ATC were 25.8 months (95% CI; 18.4-not reached [NR]), 9.2 months (95% CI; 1.8-NR), and 7.4 months (95% CI; 1.7-12.9), respectively. The median OS in patients with RR-DTC was 31.8 months (95% CI; 31.8-NR) compared with 12.1 months (95% CI; 3.8-NR) in patients with MTC and 10.6 months (95% CI; 3.8-19.8) in patients with ATC.
The ORR was 68% in RR-DTC, with all 17 patients experiencing a partial response (PR) to therapy and no complete responses (CRs); 22% in MTC, with all 2 patients similarly experiencing PRs; and 24% in ATC, with all 4 patients having PRs. The DCRdefined as the proportion of patients with CR, PR, or stable disease—was 100% in both RR-DTC and MTC, and 94% in patients with ATC with 1 patient experiencing progressive disease in this subtype. The clinical benefit rates, defined as the proportion of patients with CR, PR, or durable stable disease, were 84% (n = 21), 78% (n = 7), and 71% (n = 12) in patients with RR-DTC, MTC, and ATC, respectively.
The exploratory analysis into the effect of NLR on clinical outcomes in this population suggests an association between baseline levels of NLR and PFS, although significance was not reached (P= 0.06). Pending a further study, NLR could potentially be a prognostic marker for PFS and be used as an indicator for timely initiation of lenvatinib. Currently, the optimal timing of lenvatinib treatment initiation is unclear.
The trial continued enrollment until lenvatinib was approved for unresectable thyroid cancer in Japan; after approval, the trial continued as a postmarketing study until the trial drug was available at each site, but the endpoints and analyses were not changed.
Patients with RR-DTC and MTC had tumor assessments every 8 weeks after the first dose of lenvatinib and patients with ATC were assessed at 4, 8, 12, and 16 weeks following the first dose, and every 8 weeks thereafter.
Takahashi et al concluded that lenvatinib has a manageable safety profile in patients with all 3 disease subtypes examined in the study. Response rates were highest in RR-DTC and were similar to those seen in the SELECT trial (NCT01321554) that led to the approval of lenvatinib in the United States for this indication. In the more aggressive subtypes of MTC and ATC, efficacy results with lenvatinib were more promising than those observed in a phase II study of Japanese patients treated with sorafenib (Nexavar). The ORR and DCR rates observed with sorafenib for patients with ATC were 0% and 40%, respectively, compared with 25% and 75% in MTC.2