Minimizing Dose Interruptions With Lenvatinib Improves PFS in Thyroid Cancer, Posthoc Analysis Shows

Minimizing dose interruptions of lenvantinib (Lenvima) improved progression-free survival (PFS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC), according to an exploratory post-hoc analysis from a phase III randomized trial.¹

The trial authors wrote in theEuropean Journal of Cancerthat patients whose lenvatinib dose interruption lasted <10% of their total treatment duration derived more PFS benefit compared with those whose dose interruption was 10% or more of their total length of treatment. Patients with shorter dose interruption also had further improved objective response rates (ORR) and clinical benefit rate compared with patients who required more time off treatment.

&ldquo;Lenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions,&rdquo; the authors, led by Makoto Tahara, MD, PhD, of National Cancer Centre Hospital East, Kashiwa, Chiba, Japan, wrote. &ldquo;This analysis highlights the importance of timely management of lenvatinib toxicities to minimize dose interruptions and maximize lenvatinib efficacy in patients with RR-DTC.&rdquo;

In the phase III SELECT study of lenvatinib in differentiated thyroid cancer, lenvatinib significantly improved efficacy outcomes versus placebo in patients with RR-DTC.²PFS among patients treated with lenvatinib was 18.3 months versus 3.6 months (HR, 0.21; 99% CI, 0.14-0.31; P < 0.001). Based on the results of SELECT, lenvatinib monotherapy was approved for the treatment of RR-DTC in the United States, Europe and Japan.

However, lenvatinib-treated patients in SELECT experienced more adverse events (AEs). The trial protocol required dose modifications for grade 3 or intolerable grade 2 AEs, including possible dose interruption.

All 261 patients randomized to the lenvatinib group required a dose interruption. Of these, the dose interruption of 134 patients was <10% of their total treatment duration, with a median accumulated interruption of 19 days. Among the remaining 127 patients, the median dose interruption was 61 days. The 10% threshold was chosen to define the post-hoc groupings because the median time spent off lenvantinib was about 9% of the total treatment duration (median treatment, 13.8 months).

The targeted dose was 24 mg of lenvatinib daily. Patients in the shorter dose-interruption group had a median lenvatinib dose intensity of 20.1 mg/day or a median 83.8% of the planned dose. In contrast, the median dose intensity of patients in the longer dose-interruption group was significantly less at 14.6 mg/day or 60.9% of the planned dose.

All lenvatinib patients experienced at least one treatment-emergent adverse events (TEAEs), with the exception of 1 patient in the longer dose-interruption group. Hypertension was the most common TEAE in each group, affecting 93 patients (69.4%) in the short dose-interruption group and 88 patients (69.3) who experienced longer dose interruptions.

Overall, patients in the longer dose-interruption group had lower incidences of diarrhea and weight loss but were more likely to have decreased appetite, fatigue, palmar-plantar erythrodysaesthesia, proteinuria and constipation than their counterparts. As expected, more patients in the longer dose-interruption group experienced TEAEs that led to dose reduction or interruption versus the shorter dose-interruption group (95.3% versus 83.6%).

At the time of primary data cut-off in November 2013, the median follow-up was 17.1 months. In the shorter dose-interruption group the median PFS had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% CI, 9.3-16.5). The HRs for PFS in the shorter and longer dose-interruption groups compared with placebo were 0.14 (95% CI, 0.09-0.20) and 0.31 (95% CI, 0.22-0.43), respectively. The investigators used a multivariate model to determine that dose interruption was significantly associated with lenvatinib efficacy, even after adjusting for patient characteristics.

Patients in the shorter dose-interruption group had a better ORR (76.1%) than those in the longer dose-interruption group (52.8%). The investigators attributed most of this difference to the gain in partial responses in the shorter dose-interruption group, achieved by 73.1% of patients (versus 52.8% of patients in the longer dose-interruption group).

Given that the post hoc analysis examined post-randomization performance and that the dose-interruption groups were by definition not randomized, the authors note several limitations in their study. For example, tumor assessments were conducted only every 8 weeks, but dose interruption could begin at any time. Additionally, PFS was SELECT&rsquo;s endpoint, so the post hoc analysis could not measure lenvatinib&rsquo;s effect on overall survival (OS) or determine how dose interruptions may have affected OS.

The authors also noted that some patients may have developed disease progression during dose interruption. &ldquo;It is important to note that this particular type of progression is likely unrelated to resistance to lenvatinib,&rdquo; they wrote. &ldquo;Although SELECT did not allow study treatment beyond disease progression, it is possible that some patients with disease progression during a dose interruption could benefit from resuming lenvatinib therapy after AE resolution, as has been observed in a recent study of patients with metastatic renal cell carcinoma.&rdquo;³

References:

1. Tahara M, Brose MS, Wirth LJ et al. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer.Eur J Cancer2019;106:61-68.
2. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer.N Engl J Med2015;372:621-630.
3. Ornstein MC, Wood LS, Elson P et al. A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma.J Clin Oncol2017;35(16):1764-1769.