First-Line Sorafenib Improves OS, While Lenvatinib Boosts Salvage Options, in Radioactive Iodine-Refractory DTC

A new analysis of a multicenter, retrospective cohort study has found that first-line sorafenib (Nexavar) improved overall survival (OS) in patients with progressive radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). Additionally, salvage therapy with lenvatinib (Lenvima) improved OS in patients with disease progression after first-line sorafenib.¹

Among 98 patients treated with sorafenib, the median OS was 41.5 months, while the median progression-free survival (PFS) was 13.5 months. The 36-month OS rate on sorafenib was 54.7%.

Among patients with progressive disease, lenvatinib salvage treatment significantly improved OS compared with those who did not receive lenvatinib (Hazard Ratio [HR] = 0.28; 95% Confidence Interval [CI], 0.15—0.53;P< 0.001). Following first-line sorafenib treatment, the median OS from the time of disease progression was 4.9 months in the treatment group that received no salvage therapy, whereas median OS was not reached in the lenvatinib salvage group.

Writing inThyroid, the authors, led by Hye-Seon Oh, MD, of Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, noted that longer observations in clinical settings are needed to conclusively demonstrate better survival with sorafenib. &ldquo;Our study suggests that sorafenib is a clinically effective treatment option for progressive RAI-refractory DTC. In this extended study, the median PFS with first-line sorafenib treatment was 13.7 months, longer than the median of 10.8 months in the DECISION [phase III] trial [of sorafenib].&rdquo;²

Oh et al added, &ldquo;[Additionally,] to our knowledge, this is the first study to demonstrate survival benefits with lenvatinib salvage therapy following first-line sorafenib treatment in the clinical setting.&rdquo;

In addition to the primary endpoint of OS, the study had a variety of secondary endpoints, including PFS, disease control rate (DCR), and disease control duration.

More than two-thirds of the study patients were women (n=68, 69%), with a median age of 66 years (range, 58-72). The most common pathology type was papillary carcinoma (68%), followed by follicular carcinoma (18%) and poorly differentiated carcinoma (12%). The median time from diagnosis of thyroid cancer to the initiation of sorafenib was 9 years (5—14 years).

About half the patients (n=53, 54%) were symptomatic when sorafenib treatment began, and all patients had distant metastases. The lung was the most common site of metastasis at 98% and the only site in 24% of patients. Other sites of metastasis included lymph nodes (55%), bones (38%), pleura (14%), liver (2%), head and neck (24%), or other organs, including adrenals, kidney, pancreas, or soft tissue (7%).

Of the 73 patients who had disease progression following sorafenib treatment, 32 (33% of the total study sample of 98 patients) received lenvatinib as salvage treatment. Oh et al noted that, in Korea, lenvatinib was approved for RAI-refractory DTC in October 2015, but reimbursement was available only for its use as first-line treatment beginning in October 2017. &ldquo;The decision to use lenvatinib as salvage therapy was thus decided based on the availability of lenvatinib, ECOG PS, the physician&rsquo;s opinion, the patient&rsquo;s preferences, and economic conditions,&rdquo; they wrote.

Of the 41 patients whose disease progressed but did not receive lenvatinib salvage therapy, the median OS was 33 months. However, the median OS of patients who received lenvatinib salvage therapy was 61 months.

The authors examined prognostic factors associated with longer OS in the entire sorafenib cohort and found that OS was not associated with age, sex, or pathologic subtypes. Nor were OS gains related to having a strong response to sorafenib treatment. Oh et al found that patients without disease-related symptoms before receiving sorafenib had a better OS than those with symptoms (HR= 0.56; CI, 0.31—0.99;P= 0.048) on univariate analysis: &ldquo;However, the statistical significance of this factor disappeared on multivariate analysis (P= 0.082),&rdquo; they wrote.

The adverse events (AEs) seen with sorafenib and lenvatinib were generally consistent with the previously known safety profiles of each drug. Nearly all patients (94 of 98, 96%) had at least one AE. Of these, 40 patients (41%) had grade 3 or 4 AEs, with the proportion the same between treatment groups. Oh et al noted that most AEs were mild and manageable with standard clinical interventions or dose modifications.

The authors found that lenvatinib as salvage therapy produced a 72% reduction in the risk of death during follow-up. This risk reduction remained when analyzing only patients with good performance (ECOG PS1—2). &ldquo;Although our study did not reach the median OS due to relatively short follow-up, our findings did suggest a true clinical survival benefit with lenvatinib salvage therapy. Further studies are needed to confirm the benefits of sequential TKI [tyrosine kinase inhibitor] therapy in patients with progressive RAI-refractory DTC,&rdquo; they wrote. &ldquo;Our study suggests there indeed is a benefit, although questions on the order of sequential therapies (sorafenib to lenvatinib or lenvatinib to sorafenib) and the optimal timing of a second agent remain to be resolved.&rdquo;

Oh et al also noted the challenges clinicians face in determining the optimal timing to initiate TKI therapy in progressive RAI-refractory DTC is, including the risk of AEs and the drugs&rsquo; high cost. Additionally, the expert consensus has been that a TKI should be given to patients with metastatic, rapidly progressive, symptomatic, or life-threatening disease, they wrote: &ldquo;[But] in our study, disease-related symptoms, and larger tumor size at the time sorafenib was begun were associated with poor survival.&rdquo;

The authors emphasize the importance of monitoring patients every six months to evaluate symptoms and tumor size before starting a TKI. &ldquo;The recent concept of tumor volume doubling time might be helpful in deciding the optimal time to initiate a TKI,&rdquo; they wrote. &ldquo;Further clinical research is needed to define individualized approaches to starting TKI therapy in patients with RAI-refractory DTC.&rdquo;

References

1. Oh H-S, Shin DY, Kim M, et al. Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study.Thyroid. doi: 10.1089/thy.2019.0246. Published online October 8, 2019.
2. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.Lancet. 2014;384:319