Ten Years’ Real-Life Experience on the Use of Multikinase Inhibitors in Patients with Advanced Differentiated Thyroid Cancer

doi:10.21203/rs.3.rs-4021318/v1

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Research Article

Ten Years’ Real-Life Experience on the Use of Multikinase Inhibitors in Patients with Advanced Differentiated Thyroid Cancer

https://doi.org/10.21203/rs.3.rs-4021318/v1

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Journal Publication

published 20 May, 2024

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Purpose

To evaluate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) associated with tyrosine kinase inhibitors (TKIs) in patients with radioiodine refractory differentiated thyroid cancer (RR-DTC). Additionally, to compare: i) ORR and PFS among patients treated with lenvatinib and sorafenib; ii) ORR and PFS among patients receiving lenvatinib as first-line vs. second-line and; iii) adverse effects (AEs) observed in patients treated with these medications.

Methods

Retrospective analysis of RR-DTC adult patients treated with TKIs at the Division of Endocrinology, University of Buenos Aires (March 2011-November 2023).

Results

Among 43 patients included in the study, 32 received sorafenib (30 as first-line and 2 as second-line), while 29 received lenvatinib (12 as first-line and 17 as second-line). The median PFS and OS for the entire cohort were 32.7 and 39.0 months, respectively. Lenvatinib demonstrated a significantly higher ORR compared to sorafenib (37.9% vs. 9.4%, p = 0.008). However, both drugs exhibited similar median PFS (23.2 vs. 16.0 months, p = 0.419). No significant difference was observed in ORR and PFS between patients receiving first-line vs. second-line lenvatinib. Sorafenib-treated patients experienced higher rates of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018), whereas lenvatinib-treated patients had higher rates of proteinuria (31% vs. 0%, p < 0.001) and grade 3 hypertension (31% vs. 9%, p = 0.034).

Conclusion

TKIs demonstrated efficacy and tolerability comparable to real-world data in RR-DTC. PFS was not statistically different between sorafenib and lenvatinib. Our study will help guide physicians in making informed decisions regarding treatment sequencing with TKIs in these patients.

Differentiated thyroid cancer

tyrosine kinase inhibitors

sorafenib

lenvatinib

progression-free survival

adverse events

Up to 15% of differentiated thyroid cancer (DTC) patients exhibit an aggressive disease, resulting in the development of distant metastases [1]. Approximately two-thirds of these patients do not respond to radioactive iodine (RAI) treatment which leads to an overall poor prognosis, with a median survival rate ranging from approximately 3 to 6 years and a 10-year survival rate of only 10% [2].

Over the past decade, there have been concerted efforts to enhance survival rates through the implementation of local treatments and the utilization of tyrosine kinase inhibitors (TKIs). Sorafenib and lenvatinib were the first two TKIs approved for their use in locally advanced or metastatic radioiodine refractory (RR) DTC and are both available as first line treatments for this condition [3, 4]. Additionally, cabozantinib was approved in 2021 by the Food and Drug Administration (FDA) as second- or third-line treatment for these patients [5].

Larotrectinib and entrectinib, selective inhibitors targeting NTRK alterations, as well as selpercatinib and pralsetinib, inhibitors of RET alterations, have received FDA approval for the treatment of any solid tumor harboring these specific driver mutations [6–10]. Also, the combination of dabrafenib and trametinib (BRAF and MEK inhibitors, respectively) was granted accelerated approval by the Food and Drug Administration for the treatment of adult and pediatric patients ≥ 6 years of age with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options [11, 12]. These selective therapies have shown promising results in terms of effectiveness and tolerance [13].

Although TKIs have shown clinical benefit and an improvement in progression-free survival (PFS) in randomized control trials and real-world studies, their effectiveness lasts for a limited period of time and additional lines of treatments are needed to maintain a tumoral response. Therefore, in clinical practice, PFS and overall survival (OS) are of great importance. In line with this idea, while lenvatinib seems to be a more potent drug in terms of tumoral response, it is not clear if using it as a first-line treatment over sorafenib will be more beneficial in terms of PFS and OS rates.

In the present study, our objectives were, firstly, to assess the objective response rates (ORR), median PFS and OS of TKI treatment in a group of patients with RR-DTC. Secondly, to compare the ORR and median PFS among patients under lenvatinib and sorafenib, and among patients with first-line vs. second-line lenvatinib. Additionally, we aimed to compare the adverse effects profile of patients receiving these medications.

Study design

A retrospective analysis of all adults (≥ 18 years old) patients with a diagnosis of RR-DTC treated with TKIs between March 2011 and November 2023 at the Division of Endocrinology, University of Buenos Aires (Argentina) was performed. RR disease was defined as RAI non-avid lesions, progressive lesions despite radioiodine avidity during treatment, and/or cumulative RAI activity > 600–800 mCi [2]. The decision to initiate systemic therapy was made by a multidisciplinary team, taking into consideration tumor progression, tumor-related symptoms, size and location of tumors, and patient comorbidities. In Argentina, sorafenib has been used off-label since 2011 until its approval for the National Administration of Drugs, Food and Medical Devices (ANMAT) in 2015.

Lenvatinib became available in Argentina through compassionate use starting in 2017, with official approval following in 2018. While primarily utilized as first-line therapy, some health insurance services restrict its authorization until after disease progression on sorafenib.

Otherwise, in patients with slowly progressive metastatic disease and cardiovascular comorbidities our team discuss with the patient the best choice of treatment.

Clinical endpoints

Computed tomography scans of the neck, thorax, and/or abdomen were performed depending on the localization of the metastatic disease, to assess changes in the diameters of target lesions before and after the treatment with TKIs. RECIST criteria (version 1.1) was used to evaluate tumor responses. We determined the presence of complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) at 3, 6, 12, 18, and then every 6 months after the initiation of treatment with the TKI, unless unexpected increase of thyroglobulin which usually prompts rapid image evaluation. Tumor response was defined as CR when there was disappearance of all target lesions, PR when the sum of the diameters of target lesions decreased by ≥ 30%, PD when an increase of 20% in the sum of the diameters of the target lesions was observed and SD when none of the other criteria were met. Objective response rate (ORR) was defined as complete response (CR) plus PR and disease control rate as CR + PR + SD. Duration of response (DOR) was defined as the time from onset of response (CR, PR, or SD) to progression or death due to any reason. The time of progression prior to TKI treatment was the period of time within the patient had documented progression until the decision to start the TKI. In patients without progressive disease (for example, in patients with high tumor burden or potentially symptomatic disease), the time of progression prior to TKI treatment was 0 (zero).

Adverse effects (AEs) were evaluated by using Common Terminology Criteria (CTAE) for Adverse Events version 5.0. All our patients under TKI therapy were in contact by phone with one of our medical doctors to facilitate real-time discussions of toxicities that might require rapid interventions. Follow-up visits including a physical examination, ECG/QTc, and laboratory testing (including blood cell count, liver and renal function, electrolyte levels, TSH, and proteinuria) were performed initially every 15 days and then monthly, with personalized assessments depending on alterations. Patients received 400 mg sorafenib twice daily and lenvatinib 24 mg daily as the starting dose. In some cases, lower doses were prescribed due to prior serious adverse effects with TKIs or due to the risk of local complications arising from an abrupt reduction in unresectable lesions affecting vital structures.

Genomic interrogation was assessed with Oncomine FocusTM® or Foundation One®CDx platforms.

Statistical analysis

Quantitative data were described as median and interquartile range. Categorical variables were expressed in number and percentage and 95% confidence limits for continuous data were presented where appropriate. We defined PFS as the time from TKI initiation until disease progression or death. OS was defined as the percentage of patients who were alive after they had been treated with TKI therapy. PFS and OS were estimated using the Kaplan–Meier curve. The comparison of tumoral responses between sorafenib and lenvatinib, as well as between first-line and second-line lenvatinib, was conducted using the chi-square or Fisher’s exact test, as appropriate. Additionally, the frequency of adverse events (AEs) was assessed using the same statistical methods. Median duration of TKI treatment and median DoR between groups were compared using the Mann-Whitney U test. The comparison of PFS between both groups was performed using the long-rank test.

Patients’ general characteristics

Between March 2011 and November 2023, a total of 43 patients initiated therapy with TKIs. Table 1 provides detailed information on the general characteristics of the cohort. Among these patients, 32 received sorafenib (30 receiving as first-line treatment and 2 as second-line treatment), while 29 patients received lenvatinib (12 as first-line and 17 as second-line treatment). Additionally, five patients were treated with pazopanib, with one patient receiving it as first-line, another as second-line, and three patients as third-line therapy. One patient who experienced disease progression while on sorafenib subsequently received lenvatinib, followed by cabozantinib as third-line treatment. Furthermore, a patient harboring an ETV6-NTRK3 fusion received larotrectinib as third-line therapy, and subsequently, selitrectinib (fourth-line treatment) was administered following the identification of an on-target mutation in the TRK kinase domain.

Table 1

General characteristics of the 43 patients included in the study.
Mean age at diagnosis (years)	53.2 ± 13.0
Mean age at TKI therapy initiation (years)	58.7 ± 11.1
Female sex (%)	26 (60.5%)
Histology
Papillary	28 (65.1%)
Follicular	9 (20.9%)
Oncocytic	6 (14.0%)
Metastatic lesions
Lungs	31 (72.1%)
Neck and mediastinum	26 (60.5%)
Bone	17 (39.5%)
Others	5 (11.6%)
ECOG PS
0	25 (58.1%)
1	17 (39.5%)
2	1 (2.3%)
Median cumulative RAI dose (mCi)	300 (150–600)
Time of progression prior to TKI therapy (months)	8 (3–13)
ECOG PS: Eastern Cooperative Oncology Group Performance Status, RAI: Radioactive iodine, TKI: tyrosine kinase inhibitor. Quantitative variables are expressed in number and percentage, qualitative variables with normal distribution are expressed in mean ± standard deviation and qualitative variables without normal distribution are expressed in median and interquartile range.

Tumoral responses, progression-free survival, and overall survival in the total cohort

After a median treatment duration of 14.7 months (range: 5–70), five (11.6%) patients achieved a CR, 9 (20.9%) had a PR, 18 (41.9%) experienced SD, and seven (16.3%) had PD. Tumoral response assessment was not feasible in four patients due to a treatment duration of less than 3 months without documented progression. Figure 1 shows the tumoral responses by drug, encompassing 61 treatments with measurable response (in 2 patients with sorafenib and 6 patients with Lenvatinib tumoral response could not be assessed yet and did not demonstrate clinical progression). Tumor shrinkage was observed in 72% of these treatments. The median duration of objective response among patients achieving CR, PR, or SD in the total cohort was 20 months (95% CI: 12.5–27.4).

For the entire cohort, the median progression-free survival (PFS) was 32.7 months (95% CI: 27.6–37.8), and the median overall survival (OS) was 39.0 months (95% CI: 32.1–45.9) (Fig. 2).

Among those patients treated with pazopanib, three (60%) experienced SD, while the remaining patients exhibited progressive disease PD. One patient who progressed while on sorafenib and subsequently received lenvatinib as second-line therapy achieved SD for 33 months upon receiving cabozantinib as third-line treatment.

Anecdotally, in the case of the patient harboring an ETV6-NTRK3 fusion, larotrectinib was administered as third-line therapy, resulting in an initial CR followed by progression of disease at 12 months. Subsequently, selitrectinib was initiated as fourth-line treatment after the identification of an on-target mutation in the TRK kinase domain. Unfortunately, the patient eventually succumbed to pulmonary PD.

Furthermore, four patients with unresectable local disease received neoadjuvant treatment. Among them, one patient received sorafenib as first-line therapy, achieving SD followed by progression at 25 months. Upon switching to lenvatinib as second-line treatment, this patient maintained SD for 41 months. The remaining patients received lenvatinib, with two achieving stable disease and one achieving a complete response at six months of treatment. Remarkably, the patient who achieved a CR underwent surgery 10 months after starting lenvatinib, achieving an R1 resection margin. Lenvatinib was continued in this patient due to pulmonary metastatic disease.

Comparison between sorafenib and lenvatinib

No statistical differences were observed in baseline characteristics between patients treated with sorafenib and lenvatinib (Table 2).

Table 2

Comparison of general characteristics and efficacy between sorafenib and lenvatinib groups
	Sorafenib (n = 32)	Lenvatinib (n = 29)	p
General characteristics
Mean age at diagnosis (years)	52.0 ± 13.3	54.3 ± 11.2	0.477 ^a
Mean age at TKI therapy initiation (years)	58.4 ± 11.4	59.3 ± 10.1	0.735 ^a
Female sex (%)	19 (59.4%)	16 (55.2%)	0.740 ^b
Histology
Papillary	20 (62.5%)	19 (65.5%)	0.899 ^b
Follicular	7 (21.9%)	5 (17.2%)
Oncocytic	5 (15.6%)	5 (17.2%)
Metastatic lesions
Lungs	23 (71.9%)	18 (62.1%)	0.415 ^b
Neck and mediastinum	21 (65.6%)	18 (62.1%)	0.773 ^b
Bone	12 (37.5%)	11 (37.9%)	0.972 ^b
Others	4 (12.5%)	5 (17.2%)	0.724 ^c
ECOG PS
0	19 (59.4%)	17 (58.6%)	0.617 ^b
1	12 (37.5%)	12 (41.4%)
2	1 (3.1%)	-
Median cumulative RAI dose (mCi)	300 (150–600)	250 (150–566)	0.735 ^d
Median time of progression prior to TKI therapy (months)	8.5 (5-16.2)	7.5 (1.5–12)	0.337 ^d
Median duration of treatment (months)	12.2 (5-21.3)	8.4 (3.6–22.4)	0.348 ^d
Efficacy outcomes
Complete response	-	4 (13.8%)	0.007^b
Partial response	3 (9.4%)	7 (24.1%)
Stable disease	20 (62.5%)	7 (24.1%)
Progressive disease	7 (21.9%)	5 (17.2%)
NE	2 (6.3%)	6 (20.7%)
Objective response rate (CR + PR)	3 (9.4%)	11 (37.9%)	0.008^b
Disease control rate (CR + PR + SD)	23 (71.9%)	18 (62.1%)	0.415^b
Median duration of response (CR + PR + SD) (months)	12.0 (95% CI: 9.2–24.4)	10.8 (95% CI: 9.2–24.3)	0.906^d
ECOG PS: Eastern Cooperative Oncology Group Performance Status, RAI: Radioactive iodine, TKI: tyrosine kinase inhibitor, NE: non-evaluable, CR: complete response, PR: partial response, SD: stable disease. ^a Student's t-test, ^b Chi-squared test, ^c Fisher's exact test, ^d Mann-Whitney U test.

Among patients treated with sorafenib, the best tumoral responses included PR in three (9.4%) patients and SD in 20 (62.5%) patients. Conversely, patients receiving lenvatinib demonstrated a higher ORR, with four patients (13.8%) achieving CR, seven (24.1%) achieving PR, and seven (24.1%) experiencing SD. The ORR was significantly greater in patients receiving lenvatinib compared to sorafenib (37.9% vs. 9.4%, p = 0.008) (Table 2).

No statistical differences were found in the median DoR between patients treated with lenvatinib and sorafenib (10.8 vs. 12.0 months, p = 0.906) (Table 2). Similarly, median PFS did not significantly differ between patients receiving lenvatinib and sorafenib (22.2 months, 95% CI: 9.6–34.8; vs. 15.0 months, 95%CI: 10.4–19.6; p = 0.104) (Fig. 3).

Comparison between first-line vs second-line lenvatinib treatment

No significant differences were observed between patients who received lenvatinib as first-line versus second-line therapy in terms of ORR and PFS rates. The median PFS was 22.2 months (95% CI: 0-44.5) in patients treated with lenvatinib as second-line therapy and was not reached in patients who received it as first-line therapy. At 12 months, the PFS rate was 63% in patients with second-line lenvatinib compared to 70% in patients with first-line lenvatinib (p = 0.507) (Table 3).

Table 3

Comparison of the efficacy between first-line and second or third-line therapy with Lenvatinib
	First-line lenvatinib (n = 12)	Second-line lenvatinib (n = 17)	p
Complete response	2 (16.7%)	2 (11.8%)	0.848^a
Partial response	3 (25.0%)	3 (17.6%)
Stable disease	2 (16.7%)	6 (35.3%)
Progressive disease	2 (16.7%)	3 (17.6%)
NE	3 (25.0%)	3 (17.6%)
Objective response (CR + PR)	5 (41.7%)	5 (29.4%)	0.694^a
Progression-free survival	70% at 12 months	63% at 12 months	0.507^b
Median duration of treatment	5.1 (3.4–11.5)	13.7 (3.6–32.1)	0.092^c
NE, non-evaluable, CR: complete response, PR: partial response. ^aChi-squared test ^b Long-rank test ^c Mann-Whitney U test

Adverse events

Nearly all patients treated with sorafenib and lenvatinib experienced at least one AE, as summarized in Table 4.

Table 4

Comparison in the occurrence of common (≥ 5%) adverse events between sorafenib and lenvatinib
	Any grade			Grade 3 or 4
Adverse event	Sorafenib (n = 32)	Lenvatinib (n = 29)	p	Sorafenib (n = 32)	Lenvatinib (n = 29)	p
Any treatment related event	31 (96.9%)	29 (100%)	1.000^a	18 (56.2%)	19 (65.5%)	0.459 ^b
Hand-foot syndrome	22 (68.7%)	12 (41.4%)	0.032^b	7 (21.9%)	4 (13.8%)	0.412 ^b
Hypertension	19 (59.4%)	21 (72.4%)	0.284 ^b	3 (9.4%)	9 (31.0%)	0.034 ^b
Asthenia	15 (46.9%)	13 (44.8%)	0.873 ^b	3 (9.4%)	2 (6.9%)	1.000 ^a
Diarrhea	15 (46.9%)	12 (41.4%)	0.666 ^b	3 (9.4%)	-	0.245 ^a
Weight loss	8 (25.0%)	4 (13.8%)	0.271 ^b	-	1 (3.4%)	0.475 ^a
Alopecia	8 (25.0%)	1 (3.4%)	0.018 ^b	-	-
Thyrotropin increase	6 (18.7%)	6 (20.7%)	0.849 ^b	-	-
Stomatitis	4 (12.5%)	7 (24.1%)	0.238 ^b	-	-
Heart failure	3 (9.4%)	1 (3.4%)	0.614 ^a	2 (6.2%)	-	0.497 ^a
Proteinuria	-	9 (31.0%)	˂0.001 ^b	-	3 (10.3%)	0.101 ^a
Dose reduction	19 (59.4%)	14 (48.3%)	0.385 ^b
Temporary withdrawal	16 (50.0%)	16 (55.2%)	0.686 ^b
Definitive withdrawal	3 (9.4%)	1 (3.4%)	0.614 ^a
^a Fisher’s exact test ^bChi-square test

All patients were typically prescribed 400 mg sorafenib twice daily as the starting dose, with one exception receiving 400 mg daily. The most frequent AE with sorafenib was the hand-foot skin syndrome (69%), followed by hypertension (59%), diarrhea (47%), and asthenia (47%). Hand-foot skin syndrome was also the most common serious (grade 3 or 4) AE (22%).

Twelve (41%) patients initiated lenvatinib at a full dosage of 24 mg daily, while others started at lower doses (10–14 mg daily) due to prior serious adverse effects with sorafenib such as heart failure or due to the presence of an unresectable tumor near vital structures and to avoid the potential for local complications. The most common AE with lenvatinib was hypertension (72%) followed by asthenia (45%), hand-foot skin syndrome (41%) and diarrhea (41%). Hypertension was the most common serious AE (31%).

Patients who received sorafenib presented a higher frequency of hand-foot skin syndrome (69 vs. 41%, p = 0.032) and alopecia (25 vs 3%, p = 0.018) compared to those treated with lenvatinib. Conversely, proteinuria was more common in patients with lenvatinib (31 vs 0%, p˂0.001). Although the frequency of hypertension was not significantly different between the lenvatinib and the sorafenib and groups (72 vs 59%, p = 0.284), the occurrence of grade 3 or 4 hypertension was significantly higher in patients receiving lenvatinib (31 vs 9%, p = 0.034).

The frequency of any adverse event, serious AEs, dose reductions, temporary and definitive withdrawals did not significantly differ between patients treated with sorafenib and lenvatinib (Table 5). Definitive withdrawal was necessary in three (9%) patients receiving sorafenib, due to heart failure in two cases and coagulopathy in one. One patient developed squamous cell carcinomas (SCCs) of the skin after sorafenib treatment, which were surgically removed without recurrence. Only one patient (3%) receiving lenvatinib required definitive withdrawal due to nephrotic-range proteinuria, while no secondary malignancies were detected in patients treated with lenvatinib.

In this retrospective study we updated our results with the use of TKIs for thyroid cancer treatment after 10 years of experience [14]. Considering all lines of treatment, 32% of patients from our cohort achieved an OR, and the PFS and OS rates were 32 and 39 months, respectively. Our results coincide with other institutional experiences [15–25] and this real-world data serve to guide the discussions within the medical team and with the patients regarding the initiation of systemic therapy in RR-DTC.

In our cohort, patients who received sorafenib demonstrated an ORR of 9%. This aligns with findings from other real-world studies, which have reported ORRs ranging from 11–25% [14–17], as well as with results from the DECISION trial, where patients exhibited a PR of 12% without any CRs [3]. In contrast, our group of patients treated with lenvatinib exhibited a lower ORR compared to what was reported in the SELECT phase III study and in non-trial settings (ranging from 33–69%) [4, 18–25]. One plausible explanation for this difference could be that more than half of our patient cohort received lenvatinib after progressing on first-line sorafenib. Indeed, studies with a higher proportion of TKI-naïve patients have reported higher ORRs (62%-64%) [18, 19], whereas those including more non-naïve TKI patients reported ORRs similar to ours (ranging from 31–38%) [21, 23–25]. Additionally, observational studies tend to enroll patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, more comorbidities, and patients who did not start treatment at full dose [18–25]. Indeed, a previous analysis from our cohort revealed that in a subgroup of patients meeting the SELECT trial inclusion criteria, the PR with lenvatinib increased from 36% in the total cohort to 50% [26].

In line with the aforementioned findings, it was anticipated that the ORR in our cohort would be significantly higher in the lenvatinib group compared to the sorafenib group (37.9% vs. 9.4%, p = 0.008). Although no prospective randomized comparative analysis between sorafenib and lenvatinib has been published, a few retrospective studies have aimed to compare these two tyrosine kinase inhibitors (TKIs) [27, 28]. Ito et al. demonstrated a superior ORR in patients treated with lenvatinib compared to those receiving sorafenib (65% vs. 22%, p = 0.015) in a cohort of 18 and 21 patients, respectively [27]. Subsequently, Kim et al., in a larger multicenter retrospective cohort study, also reported a higher ORR in the lenvatinib group (59% vs. 24%, p < 0.001) [28]

The median progression-free survival (PFS) observed with sorafenib (15 months) and lenvatinib (22 months) in our study aligns closely with findings reported in both clinical trials and real-world studies [3, 4, 14–25]. In the DECISION trial, the median PFS following sorafenib treatment was reported as 10.8 months [3], while observational cohorts reported a range from 8 to 22 months [14–17]. Similarly, the median PFS in the SELECT trial was 18.3 months [4], with real-world studies reporting a range of 10 to 18 months [18–25]. Although lenvatinib appears to demonstrate superior PFS compared to sorafenib, our analysis did not reach statistical significance. In contrast to our findings, the retrospective study by Kim et al. demonstrated a significantly longer PFS with lenvatinib compared to sorafenib after adjusting for multiple confounding factors (35 vs. 13 months, p = 0.001) [28]. One potential explanation for the disparity between our results and theirs is that our study included a higher proportion of patients who received second-line lenvatinib. Notably, in the SELECT trial, patients with prior TKI exposure exhibited lower PFS rates compared to TKI-naïve patients (15 months) [4]. However, our analysis did not find a significant difference when comparing first- and second-line lenvatinib. Furthermore, while we did not adjust for variables between groups due to sample size limitations, the duration of treatment and time to progression prior to TKI initiation were similar between patients treated with lenvatinib and sorafenib.

The adverse event (AE) profiles of sorafenib and lenvatinib observed in our study were consistent with findings from clinical trials and other retrospective cohorts [3, 4, 14–25]. Both tyrosine kinase inhibitors (TKIs) exhibited high percentages of AEs (97% with sorafenib and 100% with lenvatinib) and serious AEs (56% with sorafenib and 65% with lenvatinib), with no statistical difference observed between the groups. Furthermore, both TKIs demonstrated similar frequencies of dose reductions, interruptions, and withdrawals. However, patients treated with sorafenib showed higher frequencies of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018) compared to those receiving lenvatinib. Conversely, the frequency of proteinuria was 31% in patients receiving lenvatinib compared to 0% in those receiving sorafenib (p < 0.001). These findings are consistent with other studies comparing the adverse event profiles of sorafenib and lenvatinib in differentiated thyroid cancer (DTC) patients [27–29].

Of note, although the frequency of hypertension was not significantly different between the lenvatinib and the sorafenib and groups (72 vs. 59%, p = 0.284), the occurrence of grade 3 or 4 hypertension was significantly higher in patients receiving lenvatinib (31 vs 9%, p = 0.034). Unlike our study, Asian studies found that patients treated with lenvatinib exhibited a higher incidence of all-grades hypertension compared to those treated with sorafenib [27–29]. This difference may be attributed to the relatively high incidence of hypertension reported in Asian cohorts (78%-95%) compared to Caucasians, which is associated with lower body mass [27–29]. Indeed, the frequency of hypertension in our cohort (73%) was similar to that reported in the SELECT trial (68%).

Our study has several limitations that warrant consideration. Firstly, being a retrospective study, it inherently carries a selection bias, potentially influencing the generalizability of our findings. Furthermore, although efforts were made to mitigate confounding factors, the sorafenib and lenvatinib treatment groups were not directly comparable due to the retrospective nature of the study. Despite similarities in median treatment duration and time of progression prior to TKI initiation between the two groups, residual confounding cannot be entirely ruled out. Additionally, the sample size in our study is relatively small compared to other institutional experiences [17, 19, 23], which may limit the statistical power and generalizability of our results. However, it's worth noting that our study represents the largest single-center experience with TKIs in Latin America, contributing valuable insights into the management of thyroid cancer in this region.

In conclusion, our study demonstrated that tumoral responses and PFS with TKIs in RR-DTC were similar to other real-world data. While lenvatinib exhibited a higher ORR compared to sorafenib, there is no significant difference in terms of PFS or DoR between the two drugs. The incidence of hand-foot skin syndrome and alopecia was observed to be higher among patients receiving sorafenib, whereas proteinuria was more common in those treated with lenvatinib. These results underscore the importance of considering both efficacy and tolerability profiles when selecting the appropriate TKI therapy for individual patients. By providing valuable insights into the real-world outcomes of TKI treatments, our study may assist clinicians in making informed decisions regarding treatment sequencing and optimizing patient care.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of interest

F.P. is PI for Bayer, Exelixis, and Novartis, and speaker and consultant for Bayer and Raffo. The rest of the authors have no conflicts of interests to declare.

Author Contributions

F.J. contributed to the data analysis, visualization, interpretation of the results, and wrote the article. S.C. contributed to the data collection, data curation and review of the manuscript. E.A, contributed to the data collection and reviewed the article and F.P contributed to the conception and design of the study, interpretation of the data, editing and reviewing of the article. All authors read and approved the final version of the manuscript.

Ethics approval

The study was approved by institutional review board.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Davies L, Morris LG, Haymart M, Chen AY, Goldenberg D, Morris J, Ogilvie JB, Terris DJ, Netterville J, Wong RJ, Randolph G; AACE Endocrine Surgery Scientific Committee. American Association Of Clinical Endocrinologists And American College Of Endocrinology Disease State Clinical Review: The Increasing Incidence Of Thyroid Cancer. Endocr Pract. 2015;21(6):686–96. doi: 10.4158/EP14466.DSCR. PMID: 26135963; PMCID: PMC4923940.
Schlumberger M, Brose M, Elisei R, Leboulleux S, Luster M, Pitoia F, Pacini F. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2014;2(5):356–8. doi: 10.1016/S2213-8587(13)70215-8. Epub 2014 Jan 30. PMID: 24795243.
Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Peña C, Molnár I, Schlumberger MJ; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–28. doi: 10.1016/S0140-6736(14)60421-9. Epub 2014 Apr 24. PMID: 24768112; PMCID: PMC4366116.
Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621 – 30. doi: 10.1056/NEJMoa1406470. PMID: 25671254
Brose MS, Robinson B, Sherman SI, Krajewska J, Lin CC, Vaisman F, Hoff AO, Hitre E, Bowles DW, Hernando J, Faoro L, Banerjee K, Oliver JW, Keam B, Capdevila J. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126–1138. doi: 10.1016/S1470-2045(21)00332-6. Epub 2021 Jul 5. PMID: 34237250
Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, Mascarenhas L, Geoerger B, Dowlati A, Pappo AS, Bielack S, Doz F, McDermott R, Patel JD, Schilder RJ, Tahara M, Pfister SM, Witt O, Ladanyi M, Rudzinski ER, Nanda S, Childs BH, Laetsch TW, Hyman DM, Drilon A. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531–540. doi: 10.1016/S1470-2045(19)30856-3. Epub 2020 Feb 24. PMID: 32105622; PMCID: PMC7497841.
Waguespack SG, Drilon A, Lin JJ, Brose MS, McDermott R, Almubarak M, Bauman J, Casanova M, Krishnamurthy A, Kummar S, Leyvraz S, Oh DY, Park K, Sohal D, Sherman E, Norenberg R, Silvertown JD, Brega N, Hong DS, Cabanillas ME. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022;186(6):631–643. doi: 10.1530/EJE-21-1259. PMID: 35333737; PMCID: PMC9066591.
Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D, Besse B, Chawla SP, Bazhenova L, Krauss JC, Chae YK, Barve M, Garrido-Laguna I, Liu SV, Conkling P, John T, Fakih M, Sigal D, Loong HH, Buchschacher GL Jr, Garrido P, Nieva J, Steuer C, Overbeck TR, Bowles DW, Fox E, Riehl T, Chow-Maneval E, Simmons B, Cui N, Johnson A, Eng S, Wilson TR, Demetri GD; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020;21(2):271–282. doi: 10.1016/S1470-2045(19)30691-6. Epub 2019 Dec 11. Erratum in: Lancet Oncol. 2020;21(2): e70. Erratum in: Lancet Oncol. 2020;21(7): e341. Erratum in: Lancet Oncol. 2020;21(8): e372. Erratum in: Lancet Oncol. 2021;22(10): e428. PMID: 31838007; PMCID: PMC7461630.
Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, Worden F, Brose M, Patel J, Leboulleux S, Godbert Y, Barlesi F, Morris JC, Owonikoko TK, Tan DSW, Gautschi O, Weiss J, de la Fouchardière C, Burkard ME, Laskin J, Taylor MH, Kroiss M, Medioni J, Goldman JW, Bauer TM, Levy B, Zhu VW, Lakhani N, Moreno V, Ebata K, Nguyen M, Heirich D, Zhu EY, Huang X, Yang L, Kherani J, Rothenberg SM, Drilon A, Subbiah V, Shah MH, Cabanillas ME. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 2020;383(9):825–835. doi: 10.1056/NEJMoa2005651. PMID: 32846061.
Subbiah V, Hu MI, Wirth LJ, Schuler M, Mansfield AS, Curigliano G, Brose MS, Zhu VW, Leboulleux S, Bowles DW, Baik CS, Adkins D, Keam B, Matos I, Garralda E, Gainor JF, Lopes G, Lin CC, Godbert Y, Sarker D, Miller SG, Clifford C, Zhang H, Turner CD, Taylor MH. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021;9(8):491–501. doi: 10.1016/S2213-8587(21)00120-0. Epub 2021 Jun 9. Erratum in: Lancet Diabetes Endocrinol. 2021;9(10):
e4
. PMID: 34118198.
Busaidy NL, Konda B, Wei L, Wirth LJ, Devine C, Daniels GA, DeSouza JA, Poi M, Seligson ND, Cabanillas ME, Sipos JA, Ringel MD, Eisfeld AK, Timmers C, Shah MH. Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Thyroid. 2022;32(10):1184–1192. doi: 10.1089/thy.2022.0115. Epub 2022 Jul 5. PMID: 35658604; PMCID: PMC9595631.
FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Jun 22, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid.
Pitoia F, Jerkovich F, Trimboli P, Smulever A. New approaches for patients with advanced radioiodine-refractory thyroid cancer. World J Clin Oncol. 2022;13(1):9–27. doi: 10.5306/wjco. v13.i1.9. PMID: 35116229; PMCID: PMC8790300.
Jerkovich F, García Falcone MG, Pitoia F. The experience of an Endocrinology Division on the use of tyrosine multikinase inhibitor therapy in patients with radioiodine-resistant differentiated thyroid cancer. Endocrine. 2019;64(3):632–638.
Treistman N, Nobre GM, Tramontin MY, da Silva GMW, Herchenhorn D, de Lima Araujo LH, de Andrade FA, Corbo R, Bulzico D, Vaisman F. Prognostic factors in patients with advanced differentiated thyroid cancer treated with multikinase inhibitors - a single Brazilian center experience. Arch Endocrinol Metab. 2021;65(4):411–420. doi: 10.20945/2359-3997000000364. Epub 2021 Apr 29. PMID: 33939907; PMCID: PMC10522180.
Gallo M, Michelon F, Castiglione A, Felicetti F, Viansone AA, Nervo A, Zichi C, Ciccone G, Piovesan A, Arvat E. Sorafenib treatment of radioiodine-refractory advanced thyroid cancer in daily clinical practice: a cohort study from a single center. Endocrine. 2015;49(3):726–34. doi: 10.1007/s12020-014-0481-x. Epub 2014 Nov 21. PMID: 25414068.
Kim M, Kim TH, Shin DY, Lim DJ, Kim EY, Kim WB, Chung JH, Shong YK, Kim BH, Kim WG; Korean Thyroid Cancer Study Group (KTCSG). Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study. Thyroid. 2018;28(3):340–348. doi: 10.1089/thy.2017.0356. Epub 2018 Feb 16. Erratum in: Thyroid. 2018;28(5):686. PMID: 29350109; PMCID: PMC6225595.
Sugino K, Nagahama M, Kitagawa W, Ohkuwa K, Uruno T, Matsuzu K, Suzuki A, Masaki C, Akaishi J, Hames KY, Tomoda C, Ogimi Y, Ito K. Clinical factors related to the efficacy of tyrosine kinase inhibitor therapy in radioactive iodine refractory recurrent differentiated thyroid cancer patients. Endocr J. 2018;65(3):299–306. doi: 10.1507/endocrj. EJ17-0365. Epub 2017 Dec 21. PMID: 29269689.
Masaki C, Sugino K, Saito N, Akaishi J, Hames KY, Tomoda C, Suzuki A, Matsuzu K, Uruno T, Ohkuwa K, Kitagawa W, Nagahama M, Ito K. Efficacy and Limitations of Lenvatinib Therapy for Radioiodine-Refractory Differentiated Thyroid Cancer: Real-World Experiences. Thyroid. 2020;30(2):214–221. doi: 10.1089/thy.2019.0221. Epub 2020 Jan 23. PMID: 31854270
Hamidi S, Boucher A, Lemieux B, Rondeau G, Lebœuf R, Ste-Marie LG, Le XK, Mircescu H. Lenvatinib Therapy for Advanced Thyroid Cancer: Real-Life Data on Safety, Efficacy, and Some Rare Side Effects. J Endocr Soc. 2022;6(6): bvac048. doi: 10.1210/jendso/bvac048. PMID: 35475024; PMCID: PMC9032633.
Berdelou A, Borget I, Godbert Y, Nguyen T, Garcia ME, Chougnet CN, Ferru A, Buffet C, Chabre O, Huillard O, Leboulleux S, Schlumberger M. Lenvatinib for the Treatment of Radioiodine-Refractory Thyroid Cancer in Real-Life Practice. Thyroid. 2018;28(1):72–78. doi: 10.1089/thy.2017.0205. Epub 2017 Nov 27. PMID: 29048237.
Jasim S, Iniguez-Ariza NM, Hilger CR, Chintakuntlawar AV, Ryder MM, Morris JC 3rd, Bible KC. Optimizing lenvatinib therapy in patients with metastatic radioactive iodine-resistant differentiated thyroid cancers. Endocr Pract. 2017;23(10):1254–1261. doi: 10.4158/EP171822.OR. Epub 2017 Aug 17. PMID: 28816536.
Locati LD, Piovesan A, Durante C, Bregni M, Castagna MG, Zovato S, Giusti M, Ibrahim T, Puxeddu E, Fedele G, Pellegriti G, Rinaldi G, Giuffrida D, Verderame F, Bertolini F, Bergamini C, Nervo A, Grani G, Rizzati S, Morelli S, Puliafito I, Elisei R. Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy. Eur J Cancer. 2019; 118:35–40. doi: 10.1016/j.ejca.2019.05.031. Epub 2019 Jul 9. PMID: 31299580.
Lee EK, Kim SM, Kim BH, Kim MJ, Lim DJ, Kim MH, Shin DY, Kang HC, Ahn BC, Kim SW, Ahn HY, Park YJ. Lesion-Based Evaluation Predicts Treatment Response to Lenvatinib for Radioactive Iodine-Refractory Differentiated Thyroid Cancer: A Korean Multicenter Retrospective Study. Thyroid. 2019;29(12):1811–1819. doi: 10.1089/thy.2019.0022. Epub 2019 Oct 1. PMID: 31482759.
Aydemirli MD, Kapiteijn E, Ferrier KRM, Ottevanger PB, Links TP, van der Horst-Schrivers ANA, Broekman KE, Groenwold RHH, Zwaveling J. Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data. Eur J Endocrinol. 2020;182(2):131–138. doi: 10.1530/EJE-19-0763. PMID: 31751307.
Jerkovich F, Califano I, Bueno F, Carrera JM, Giglio R, Abelleira E, Pitoia F. Real-life use of lenvatinib in patients with differentiated thyroid cancer: experience from Argentina. Endocrine. 2020;69(1):142–148. doi: 10.1007/s12020-020-02290-9. Epub 2020 Apr 6. PMID: 32253682.
Ito Y, Onoda N, Kudo T, Masuoka H, Higashiyama T, Kihara M, Miya A, Miyauchi A. Sorafenib and Lenvatinib Treatment for Metastasis/Recurrence of Radioactive Iodine-refractory Differentiated Thyroid Carcinoma. In Vivo. 2021 Mar-Apr;35(2):1057–1064. doi: 10.21873/invivo.12350. PMID: 33622902; PMCID: PMC8045109.
Kim M, Jin M, Jeon MJ, Kim EY, Shin DY, Lim DJ, Kim BH, Kang HC, Kim WB, Shong YK, Kim HK, Kim WG. Lenvatinib Compared with Sorafenib as a First-Line Treatment for Radioactive Iodine-Refractory, Progressive, Differentiated Thyroid Carcinoma: Real-World Outcomes in a Multicenter Retrospective Cohort Study. Thyroid. 2023;33(1):91–99. doi: 10.1089/thy.2022.0054. Epub 2022 May 17. PMID: 35443825.
Kim SY, Kim SM, Chang H, Kim BW, Lee YS, Chang HS, Park CS. Safety of Tyrosine Kinase Inhibitors in Patients with Differentiated Thyroid Cancer: Real-World Use of Lenvatinib and Sorafenib in Korea. Front Endocrinol (Lausanne). 2019; 10:384. doi: 10.3389/fendo.2019.00384. PMID: 31244783; PMCID: PMC6581694.

Competing interest reported. F.P. is medical advisor, speaker, and Steering Committee Bayer. Consultancy for Biotoscana and Raffo Laboratories. The rest of the authors have no conflicts of interests to declare.

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Ten Years’ Real-Life Experience on the Use of Multikinase Inhibitors in Patients with Advanced Differentiated Thyroid Cancer

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Tumoral responses, progression-free survival, and overall survival in the total cohort

Comparison between sorafenib and lenvatinib

Comparison between first-line vs second-line lenvatinib treatment

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