Abstract
Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9–3.5) and median OS was 3.1 months (95% CI; 0.6–5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.
Introduction
Anaplastic thyroid cancer (ATC) is a rare aggressive thyroid malignancy, with a median overall survival (OS) rate of only 5 months and a 1-year survival rate <20% (Smallridge et al. 2012). In the absence of initial distant metastases, an intensive multimodal-therapy, combining chemotherapy and external beam radiation, results in a median OS close to 2 years and a 1-year survival rate of 46–68% (De Crevoisier et al. 2004, Prasongsook et al. 2017). On the other hand, advanced disease with distant metastasis showed the worse prognosis, with a 1-year survival odds of 8.2% (Smallridge et al. 2012). The main breakthrough of the last three decades in the treatment of ATC is the use of a dabrafenib–trametinib combination in tumors harboring a somatic BRAFV600E mutation (Cabanillas et al. 2016, Iyer et al. 2018). The response rate reported in a phase II study on 16 patients is 69% with an estimated length of tumor response longer than 12 months (Subbiah et al. 2018). These results led to the approval of this drug combination in the United States. Unfortunately, the evidence of somatic BRAF mutations is variable in clinical practice. In fact, according to United States surveys, up to 50% of ATC patients harbors a somatic BRAF mutation (Begum et al. 2004, Landa et al. 2016, Chen et al. 2018, Pozdeyev et al. 2018), and less than 20% within Europe, for unknown reasons yet (Gauchotte et al. 2011, Bonhomme et al. 2017, Romei et al. 2018). The other targetable somatic mutations in ATC consist in ALK fusions and point mutations, NTRK and RET/PTC fusions (Guerra et al. 2013, Bonhomme et al. 2017, Okamura et al. 2018). In the presence of one of these abnormalities targeted treatment may produce spectacular tumor responses, as a consequence these molecular alterations should be routinely screened, but each of these abnormalities is found in less than 4% of the cases (Guerra et al. 2013, Bonhomme et al. 2017, Okamura et al. 2018).
In the absence of any targetable mutation, which is the case in up to 84% of ATC diagnosed in France, the main treatment option remains a combination of chemotherapy (doxorubicin/platin or paclitaxel/platin) and external beam radiation therapy (EBRT) (De Crevoisier et al. 2004). This allows temporary local tumor control, but rarely of distant metastases. Immunotherapy is under evaluation with interesting results (Wirth et al. 2018). Notably, a recent phase II trial with spartalizumab showed promising and durable results in advanced ATC, with an overall response rate of 19% and also three cases of complete response, regardless of BRAF gene molecular status (Capdevila et al. 2020). If early phase clinical trials are not available, patients and clinicians have little choice for second- and third-line treatments.
Lenvatinib is a multi-target antiangiogenetic broad-spectrum tyrosine kinase inhibitor (TKI). It proved its efficacy and tolerability in the phase III SELECT study on radioactive iodine refractory (RAIR) differentiated thyroid cancer (DTC) patients showing a progression free survival (PFS) of 18.3 months vs 3.6 with placebo (Schlumberger et al. 2015). From this perspective, lenvatinib was used as possible rescue therapy for progressive ATC, in the absence of molecular targets (Cabanillas et al. 2016, Iyer et al. 2018). Initial results in a phase II study on 17 Japanese ATC patients were promising with an objective response rate of 24%, a disease control rate of 94%, a median PFS of 7.4 months (95% CI: 1.7–12.9) and a median OS of 10.6 months (Tahara et al. 2017, Takahashi et al. 2019). Case reports of off-label treatment have also been reported with controversial results in terms of efficacy (Iñiguez-Ariza et al. 2017, Oishi et al. 2017, Yamazaki et al. 2017, Iwasaki et al. 2018, Iyer et al. 2018, Koyama et al. 2018, Ohkubo et al. 2018, Kanazawa & Kammori 2019). One of the drawbacks of the use of anti-vascular endothelial growth factor (VEGF) drugs in ATC is the risk of fatal bleeding in case of tumor invasion of the upper aerodigestive tract or predisposing conditions, such as previous high-doses external beam radiotherapy (Lamartina et al. 2016), which are frequent situations in ATC; this risk might be limited with the use of initial reduced daily doses (Locati et al. 2019). Despite this difficulty, a prospective multicentric phase II trial on the use of lenvatinib in ATC was set up (EudraCT 2015-001929-17). Enrollment was prematurely interrupted for an absence of efficacy and recent results show a PFS of 2.6 months and an OS of 3.2 months (Wirth et al. 2020).
In the absence of any alternative, and following the Japanese phase II study results, off-labelled lenvatinib was prescribed in France in ATC patients, who were not eligible in clinical trials.
The objective of this national, retrospective, multicenter study performed within the frame of the French refractory thyroid cancer network (Tumeurs de la THYroïde REFractaires, TUTHYREF) is to describe the efficacy and the toxicity profile of off-label use of lenvatinib in metastatic ATC.
Patients and methods
Inclusion criteria
A consecutive series of ATC patients, treated off-label with lenvatinib between January 1, 2015 and December 31, 2019, from five centers of the TUTHYREF network (Gustave Roussy, Villejuif; Institut Bergonié, Bordeaux; University Hospital of Lille, Lille; Oncology University Institute-IUCT-Oncopole, Toulouse; University Hospital of Brest, Brest) was analyzed. Inclusion criteria were: age >18 years; ATC histological diagnosis; Eastern Cooperative Oncology Group performance status (ECOG) ≤3; available documentation of the patient’s clinical history; minimal life expectancy of one month. All previous treatments lines were recorded, with special regard to chemotherapy (i.e. platin ± taxol schemes; platin ± adriamicin schemes), neck/mediastinum external beam radiation, and other possible treatments (radioactive iodine therapy, immunotherapy, or other targeted therapy).
At the time of diagnosis, each center gained patients’ medical consent to anonymous utilization of all clinical, histological and radiological data for research purpose. Pathological diagnosis was obtained from surgical or biopsy specimens that were reviewed by expert pathologists of the TUTHYREF network. ATC were classified according to the histology of the primary tumor as pure ATC, that is tumors composed only by an undifferentiated proliferation and mixed ATC, defined as anaplastic proliferation with foci of differentiated thyroid cancer (DTC) or poorly differentiated thyroid cancer (PDTC) of any extent. Patients who experienced an anaplastic transformation during the long-term follow-up of a differentiated or poorly differentiated thyroid cancer of follicular cell origin were excluded from this study.
Patients were treated and followed according to international guidelines and local practices discussed within local or national multidisciplinary boards. Treatment starting lenvatinib dose could be 24 mg (full dose) or lower, adapted according to the patient’s status and comorbidities.
Data on each patient were retrospectively reviewed. Tumors were classified according to the 2017 pTNM staging 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Treatment efficacy was assessed clinically, with physical examination, at least every month and by imaging with CT scans performed approximately every 2 months. PET with 18-fluoro-D-glucose (18FDG‐PET/CT) and MRI were performed in selected cases. A retrospective central review assessment of the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 evaluation (Eisenhauer et al. 2009) was performed by a senior radiologist. In case of progression, no confirmatory CT scan was performed 1 month later. Complete clinical response was defined as complete relief of tumor symptomatology. Serum thyroglobulin (Tg) level was recorded, if available, and was considered detectable when >0.2 ng/mL. Adverse events were classified according to Common terminology criteria for adverse events (CTCAE) version 5.0 (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
Next-generation-sequencing (NGS) analysis was performed in some tumor samples locally in the different centers, in search of (K-H-N) RAS, BRAF, KIT, PIK3CA, PTEN, TP53 gene mutations, RET, ALK and NTRK rearrangements. The assessments were achieved with different techniques (CE-IVD Sentosa®SQ NSCLC Panel (Vela Diagnostics) kit, Ion Ampliseq Cancer Panel V2 kit, QiampDNA FFPE tissue Kit (Qiagen) or OncomineTM).
Statistical analysis
We realized descriptive analysis by using means, medians, standard deviations for continuous variables and numbers and percentages for qualitative parameters. OS and PFS were estimated using the Kaplan–Meier method. The PFS was defined as the period of treatment, where no disease progression was observed. The OS was defined as the duration between the date of initiation of treatment to death from any cause or to the date of the last follow-up. Survival curves comparison between groups of patients was realized using the log-rank test. Best morphological response was evaluated with an intention to treat analysis. Genetic alterations have been summarized with an OncorPrint plot (Cerami et al. 2012, Gao et al. 2013). The statistic software used was IBM SPSS Statistic version 24.
Results
We analyzed files of 26 ATC patients who received lenvatinib treatment between 2015 and 2019. Three patients were excluded from the analysis: one case for treatment within a clinical trial, and two cases because of the occurrence of ATC transformation found in a distant metastasis biopsied during lenvatinib treatment of a radioactive iodine refractory DTC. Twenty-three patients were therefore included in the present study, 9 women (39%) and 14 men (61%), with a mean age of 64 years (range: 36–78) (Table 1). All patients presented with a rapid swelling of the thyroid gland.
Patient characteristics.
| Characteristics | Patients (n = 23) | Percentage (%) or range |
|---|---|---|
| Gender | ||
| Male/female | 14/9 | 60.9/39.1 |
| Mean age at diagnosis | 64.1 ± 11.1 | |
| Median age at diagnosis | 67.8 | range 36–78 |
| ECOG at baseline | ||
| 0 | 10 | 43.5 |
| 1 | 9 | 39.1 |
| 2 | 4 | 17.4 |
| STAGE at diagnosis | ||
| IVA | 2 | 8.7 |
| IVB | 4 | 17.4 |
| IVC | 17 | 73.9 |
| Histological diagnosis | ||
| Thyroidectomy | 10 | 43.5 |
| Diagnostic lobectomy | 3 | 13.0 |
| Surgical biopsy | 10 | 43.5 |
| Surgical QoR | ||
| R0 | 0 | 0 |
| R1 | 3 | 13.0 |
| R2 | 7 | 30.4 |
| Tracheotomy | ||
| Yes | 4 | 17.4 |
| No | 19 | 82.6 |
| Histology | ||
| Pure ATC | 15 | 65.2 |
| Mixed ATC | 8 | 34.8 |
| Metastatic sites at lenvatinib initiation | ||
| Lung | 21 | 91.3 |
| Chest/abdominal lymph nodes | 12 | 52.2 |
| Bones | 9 | 39.1 |
| Liver | 5 | 21.7 |
| Brain | 4 | 17.4 |
| Othersa | 3 | 13.0 |
aMuscles, subcutaneous tissue or adrenal gland.
ATC, anaplastic thyroid cancer; QoR, Quality of resection.
Pathologic diagnosis was performed on subtotal/total thyroidectomy or lobectomy specimens in 13 cases, and on biopsy specimens in 10 cases. Pathology consisted in pure anaplastic thyroid carcinoma in 15 cases (65%) and mixed ATC carcinoma in 8 cases (35%) (Table 2). Among mixed ATC patients, four of them showed DTC contingent (three cases of classical papillary thyroid cancer and one case of tall cell variant of papillary thyroid cancer); the remaining four showed PDTC contingent. Histological reports of mixed ATC/DTC did not quantify the relative percentage of one component over the other, with the exception of one case that had 5% of tall cell DTC variant and 95% of ATC.
Patient characteristics according to type of histology.
| Mixed ATC | Pure ATC | |
|---|---|---|
| Total cases | 8 | 15 |
| Differentiated component | ||
| DTCa | 4/8 | – |
| PDTC | 4/8 | – |
| Gender | F (3); M (5) | F (6); M (9) |
| Mean age at diagnosis | 58.6 ± 14.7 | 67.1 ± 7.6 |
| ECOG at baseline | ||
| 0 | 3 | 7 |
| 1 | 4 | 5 |
| 2 | 1 | 3 |
| Stage IV A-B-C | A (1), B (1), C (6) | A (1), B (3), C (11) |
| Lenvatinib third line or more | 5 of 8 cases | 6 of 15 cases |
| Partial response | 2 cases | – |
| Treatment duration | 5.4 ± 3.6 months (range 1–11) | 2.1 ± 2.4months (range 0.1–10.1) |
| Biopsy of distant metastasis | 3 cases | 1 case |
| Available molecular status | 7 cases | 12 cases |
aDTC, three cases of papillary thyroid carcinoma and one case of tall cell variant of papillary thyroid carcinoma.
ATC, anaplastic thyroid cancer; DTC, differentiated thyroid cancer; PDTC, poorly differentiated thyroid cancer.
Four of the 23 patients (17%) had a biopsy of a distant metastasis during the course of the disease. The mean interval of time between the initial ATC diagnosis and the biopsy of this distant metastasis was 44 months (range: 5.2–99.3). Pathology of the metastatic site was PDTC in all cases, and not ATC, while the initial histology was mixed ATC (with PDTC contingent) for three case and pure ATC for one case. At the time of initial diagnosis, patients were stage IVA in two cases (9%), stage IVB in four cases (17%) and stage IVC in 17 cases (74%).
Tumor somatic alterations were analyzed in 19 cases (83%) and are reported in Fig. 1. The search for BRAFV600E mutation was performed in all 19 patients and resulted negative in 18 cases and inconclusive in 1 case; ALK rearrangement was searched in 15 patients, with 1 positive, 1 inconclusive and 13 negative cases; NTRK rearrangement was searched in 7 patients, with 1 positive and 6 negative cases. Other gene mutations or no-targetable molecular alterations have not been regularly screened in our cohort, and for instance TP53 somatic mutation was screened in only seven cases and found in five patients.
OncoPrint Plot for representation of molecular status for analyzed samples. Molecular details: TP53 mutations in 5 patients, 3 mixed ATC and 2 pure ATC (1 case of exon 8 c.818G>A; 1 case of exon 7 c.734G>A; 1 case of exon 9 c.994-1G>C; 1 case of exon 7 c.710T>A; 1 case of exon 11 c.853_859delinsTAGGAAA); RAS mutations in 5 patients, 2 mixed ATC and 3 pure ATC (4 cases of NRAS Q61K; 1 case of HRAS G12V); ALK rearrangement, 1 mixed ATC (1 case of translocation 2p23); PTEN rearrangement, 1 pure ATC (1 case of DZANK1/PTEN t(20,10)(p11.23,q23.31)); EGFR mutation, 1 mixed ATC (1 case of exon 20 p.V769M); NTRK rearrangement, 1 mixed ATC (1 case of t(12,15)(p13.2,q25.3)); RB1 mutation, 1 mixed ATC (1 case of exon 6 c.607+1G>T). A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0106.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
OncoPrint Plot for representation of molecular status for analyzed samples. Molecular details: TP53 mutations in 5 patients, 3 mixed ATC and 2 pure ATC (1 case of exon 8 c.818G>A; 1 case of exon 7 c.734G>A; 1 case of exon 9 c.994-1G>C; 1 case of exon 7 c.710T>A; 1 case of exon 11 c.853_859delinsTAGGAAA); RAS mutations in 5 patients, 2 mixed ATC and 3 pure ATC (4 cases of NRAS Q61K; 1 case of HRAS G12V); ALK rearrangement, 1 mixed ATC (1 case of translocation 2p23); PTEN rearrangement, 1 pure ATC (1 case of DZANK1/PTEN t(20,10)(p11.23,q23.31)); EGFR mutation, 1 mixed ATC (1 case of exon 20 p.V769M); NTRK rearrangement, 1 mixed ATC (1 case of t(12,15)(p13.2,q25.3)); RB1 mutation, 1 mixed ATC (1 case of exon 6 c.607+1G>T). A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0106.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
OncoPrint Plot for representation of molecular status for analyzed samples. Molecular details: TP53 mutations in 5 patients, 3 mixed ATC and 2 pure ATC (1 case of exon 8 c.818G>A; 1 case of exon 7 c.734G>A; 1 case of exon 9 c.994-1G>C; 1 case of exon 7 c.710T>A; 1 case of exon 11 c.853_859delinsTAGGAAA); RAS mutations in 5 patients, 2 mixed ATC and 3 pure ATC (4 cases of NRAS Q61K; 1 case of HRAS G12V); ALK rearrangement, 1 mixed ATC (1 case of translocation 2p23); PTEN rearrangement, 1 pure ATC (1 case of DZANK1/PTEN t(20,10)(p11.23,q23.31)); EGFR mutation, 1 mixed ATC (1 case of exon 20 p.V769M); NTRK rearrangement, 1 mixed ATC (1 case of t(12,15)(p13.2,q25.3)); RB1 mutation, 1 mixed ATC (1 case of exon 6 c.607+1G>T). A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0106.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Lenvatinib treatment
Lenvatinib was given as first line treatment in 1 case (4%), as second line treatment in 11 cases (48%), as third line treatment in 5 cases (22%), as fourth line treatment in 1 case (4%), as fifth line in 2 cases (9%), as sixth line treatment in 2 cases (9%), and finally as ninth line in 1 case (4%). All previous treatment lines until lenvatinib initiation are shown in Table 3.
Types of chemotherapies and duration of treatment for each therapeutic line until lenvatinib initiation.
| Patients | 1st line | Months | 2nd line | Months | 3rd line | Months | 4th line | Months | 5th line | Months | 6th line | Months | 7th line | Months | 8th line | Months | 9th line | Months | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | Car-Tax | 3 | L | 4 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| 2 | M | Car-Tax | 2 | L | <6 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| 3 | M | Iode131 | 1 | Cis-Adr | 6 | Gemz | 3 | Car-Tax | 5 | Gemo | 16 | Sut | 8 | Paz | 3 | Ever | 12 | L | <11 |
| 4 | Cis-Adr | 5 | L | 10 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 5 | M | Cis-Adr | 4 | Car-Tax | 1 | Iode131 | 1 | Paz | 17 | L | 5 | – | – | – | – | – | – | – | – |
| 6 | Pla | 2 | Cis-Adr | 3 | L | 1 | – | – | – | – | – | – | – | – | – | – | – | – | |
| 7 | Cis-Adr | 7 | Car-Tax | 1 | L | <1 | – | – | – | – | – | – | – | – | – | – | – | – | |
| 8 | M | Cis-Adr | 6 | Car-Tax | 3 | Other* | 26 | Cri | 6 | Imm | 16 | L | 11 | – | – | – | – | – | – |
| 9 | Cis-Adr | 2 | Car-Eto | 1 | L | <3 | – | – | – | – | – | – | – | – | – | – | – | – | |
| 10 | Pla | 2 | L | 2 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 11 | Unknown | 3 | Gemo | 3 | Iode131 | 1 | Sor | 4 | L | 4 | – | – | – | – | – | – | – | – | |
| 12 | M | Cis-Adr | 4 | L | <2 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| 13 a | L | <3 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 14 | Cis-Adr | 6 | L | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 15 | Cis-Adr | 4 | L | <5 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 16 | Cis-Adr | 4 | L | <2 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 17 | M | Cis-Adr | 4 | Car-Tax | 1 | L | <3 | – | – | – | – | – | – | – | – | – | – | – | – |
| 18 | Cis-Adr | 1 | L | 2 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 19 | M | Cis-Adr | 1 | Car-Adr | 4 | Car-Tax | 2 | L | <7 | – | – | – | – | – | – | – | – | – | – |
| 20 | Cis-Adr | 6 | Car-Tax | 18 | Gemo | 8 | Tax | 11 | Iode131 | 1 | L | <3 | – | – | – | – | – | – | |
| 21 | Adr | 2 | L | <2 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 22 | Car-Tax | 5 | L | <1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 23 | Cis-Adr | 11 | Car-Tax | 1 | L | 3 | – | – | – | – | – | – | – | – | – | – | – | – |
aOne patient did not receive any chemotherapies before lenvatinib, * Angiopoietin-VEGF inhibitor.
Car-Adr, Carboplatin-Adriamicin; Car-Eto, Carboplatin-Etoposide; Car-Tax, Carboplatin-Taxol; Cis-Adr, Cisplatin-Adriamicin; Cri, Crizotinib; Ever, Everolimus; Gemo, Gemox (gemcitabine-oxaliplatin); Gemz, Gemzar (gemcitabine); Imm, immunotherapy with antiPD01; Paz, Pazopanib; Pla, Platin; Sor, Sorafenib; Sut, Sunitinib; Tax, Taxol; L, Lenvatinib; M, mixed ATC.
Looking at treatment line distribution according to pure vs mixed ATC, we confirmed that in most cases, lenvatinib was adopted as 2nd line choice, regardless of histology details: 53% (8/15) of pure ATC patients and 37% (3/8) of mixed ATC ones. However, in the remaining five mixed tumors lenvatinib was variably administrated later on in therapeutic history (from the 3rd to the 9th therapeutic line), as shown in Table 3. This means that mixed ATC underwent more therapeutic lines before lenvatinib initiation (Table 3).
With respect to previous treatments, 22 patients (96%) had one line of cytotoxic chemotherapy before lenvatinib initiation and 17 (74%) underwent neck and mediastinum external beam radiation therapy. The most frequent chemotherapy scheme was cisplatin (120 mg/m2) plus adriamycin (60 mg/m2), realized as first-line therapy in 14 cases (61%) and second-line in 3 cases (13%) (De Crevoisier et al. 2004). Four patients (17%) did receive radioactive iodine (RAI); among them, two cases had mixed ATC and two pure ATC histology and the treatment was performed before the referral to TuThyRef centers.
At the time of lenvatinib initiation, all patients had distant metastases that were located in the lungs in 21 cases (91%), in chest/abdominal lymph nodes in 12 cases (52%), in bones in nine cases (39%), in liver in five cases (22%), in brain in four cases (17%) and in other sites in three cases (13%) (muscle, adrenal and s.c. tissue).
Comorbidities at baseline were identified in 12 cases (52%): ten patients (43%) were treated for hypertension, six patients (26%) had other cardiovascular comorbidities, three patients (13%) had a history of another cancer that was treated several years earlier, and four patients (17%) had a tracheostomy.
Four patients (17%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and the other 19 (83%) had an ECOG performance status of 0 or 1.
Baseline CT scans disclosed upper respiratory airway invasion in 7 cases (30%) and vascular invasion in 11 cases (48%).
Initial symptoms at the time of lenvatinib initiation included dysphonia in ten cases (43%), dysphagia in six cases (26%) and neck pain in four cases (17%).
Median time between the date of ATC diagnosis and lenvatinib initiation was 9.3 months (range: <1–87). The starting dose was 24 mg in 13 patients (57%), 20 mg in 7 patients (30%), 14 mg in 2 patients (9%) and 12 mg in 1 patient (4%). The reasons leading to initiate treatment with a lower dose were comorbidities in six patients (26%), alteration of ECOG status in two (9%), and clinicians’ preference in the other two patients (9%). Dose reduction and transitory discontinuation of lenvatinib was necessary for adverse events in 39 and 43% of cases, respectively, after a median period of 1.2 month (range 0.3–9.8). Median duration of lenvatinib treatment was 2.7 ± 3.2 (range: <1–11) months. Duration of treatment was ≤ 3 months in 14 cases (61%), between 3 and 6 months in five cases (22%) and >6 months in four cases (17%). Among the 14 patients with the shortest treatment duration, four subjects drop out lenvatinib very soon, with a duration therapy ≤1 month in four cases. All of them had pure ATC histotype and died because of disease progression during lenvatinib treatment or soon after its discontinuation.
Causes of lenvatinib discontinuation were confirmed tumor progression in 14 cases (61%) and clinical disease progression till death in four cases (17%), severe adverse events in four cases (17%) (including three grade five drug-related adverse events and one sepsis), and change for another target therapy in one case (4%) (Fig. 2).
Duration of lenvatinib therapy (days) and cause of discontinuation. Note: Bar represents each patient with the particular of treatment days at the end. AE, adverse event; Other TP, other therapy.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Duration of lenvatinib therapy (days) and cause of discontinuation. Note: Bar represents each patient with the particular of treatment days at the end. AE, adverse event; Other TP, other therapy.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Duration of lenvatinib therapy (days) and cause of discontinuation. Note: Bar represents each patient with the particular of treatment days at the end. AE, adverse event; Other TP, other therapy.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Serum Tg level was measured in seven patients. There was no detectable anti-Tg antibody. We found detectable Tg in five cases with a median value at baseline of 139 ng/mL (range 16–9041). Among the five patients with a detectable Tg level, Tg level decrease by more than 50% in four cases (17%), and decrease by 24% in one case (4%) during lenvatinib treatment. Median Tg value, at the time of best tumor response (morphologic nadir) was 84 ng/mL (range: 6–1044).
Efficacy
A clinical improvement in dysphonia, dysphagia or neck pain was observed in seven cases (30%) with a complete clinical response in five cases (22%). These assessments have been performed according to clinical judgement. Four had a pure ATC histology and one a mixed subtype.
There was no complete tumor RECIST response. For 16 out of 23 patients (70%) we were able to perform the a central RECIST review of CT scans. Among them, the best RECIST response was a partial response (PR) in two (9%) cases, stable disease (SD) in seven (30%) cases, progressive disease (PD) in seven (30%) cases. Central RECIST review was not performed in seven patients, five (22%) of them however experienced a clinical progression, one (4%) patient withdrew treatment for serious AE, and one (4%) patient switched for a clinical trial. Among the five patients with clinical progression not confirmed by imaging, four patients had rapid clinical progression and death occurred less than 2 months after initiation of treatment; the remaining patient was treated with lenvatinib for 324 days and he was classified as stable disease from local radiological reports during that period, but we did not have the radiological frames for the central RECIST review.
Both PR occurred in patients with mixed tumor: one mixed ATC/DTC and one mixed ATC/PDTC. The former patient harbors a RAS mutation and the other an ALK rearrangement. Among the seven patients with SD (two with a mixed tumor), a TP53 mutation was found in two cases (9%), and a RAS mutation in one case (4%).
Median time to best morphological response was three months (range: 0.4‐12.7). Durations of PR were 2.3 (mixed ATC/DTC patient) and 11.1 months (mixed ATC/PDTC patient), respectively and median duration of SD was 4.1 (range: 1.7–10.1) months.
As mentioned above, central retrospective imaging evaluation was available for 16 (70%) patients who were included in the PFS analysis. Progression free survival was 2.7 (±0.4) months (95% CI; range 1.9–3.5).
OS analysis was performed for all the patients of the cohort. The median OS since lenvatinib initiation was 3.1 months (±1.2) (95% CI; 0.6–5.5), while the median OS since ATC diagnosis was 14.6 months (±4.9) (95% CI; 4.9–24.2). After a median follow-up of 3.0 months (range: 0.4–15.7), 16 patients died. Cause of death was tumor progression in 12 cases (12/16: 75%), severe AE in three cases (3/16: 19%) and other causes in one case (1/16: 6%). We found no statistically significant difference in survival curves according to median age, sex, BMI, starting lenvatinib dose and clinical features, such as ECOG performance status, co-morbidity or median blood pressure.
According to initial histology, the median OS was 2.7 months (CI95%: 1.5–3.8) for pure ATC, that is significantly shorter than a median OS of 6.3 months (95% CI: 0.0–12.7) (P = 0.026) for mixed ATC. Moreover, if the patient with initial pure ATC histology, who was re-biopsed as PDTC, was included in the group of mixed tumors, the median OS was of 10.3 ± 6.0 months (95% CI; 0.0–22.1) compared with a median OS of 2.4 ± 0.6 months (95% CI; 1.1–3.6) for pure ATCs (P = 0.0001) (Fig. 3).
Overall survival according to histology from lenvatinib initiation Panel A according to initial histology; Panel B grouping the patient with pure ATC on primary tumor and PDTC in distant metastasis biopsy with mixed ATC.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Overall survival according to histology from lenvatinib initiation Panel A according to initial histology; Panel B grouping the patient with pure ATC on primary tumor and PDTC in distant metastasis biopsy with mixed ATC.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Overall survival according to histology from lenvatinib initiation Panel A according to initial histology; Panel B grouping the patient with pure ATC on primary tumor and PDTC in distant metastasis biopsy with mixed ATC.
Citation: Endocrine-Related Cancer 28, 1; 10.1530/ERC-20-0106
Safety
At least one AE of any grade was identified in 18 patients (78%) and grade 3–4 AE were seen in eight patients (35%) (Table 4). The most common all-grade toxicities were: hypertension and asthenia (44% each), anorexia (22%), thrombocytopenia (13%), diarrhea (13%) and dyspnea (13%). Lenvatinib was temporary interrupted for AEs in 10 patients (43%), for a mean period of 10 days (range 5–23).
Adverse effects.
| Toxicity | Total | Grade 1 and 2 | Grade 3 and 4 | Grade 5 | ||||
|---|---|---|---|---|---|---|---|---|
| No | % | No | % | No | % | No | % | |
| At least 1 toxicity | 18 | 78.3 | 7 | 30.4 | 8 | 34.8 | 3 | 13.0 |
| Hypertension | 10 | 43.5 | 7 | 30.4 | 3 | 13.0 | 0 | 0 |
| Asthenia | 10 | 43.5 | 7 | 30.4 | 3 | 13.0 | 0 | 0 |
| Anorexia | 5 | 21.7 | 4 | 17.4 | 1 | 4.3 | 0 | 0 |
| Diarrhea | 3 | 13.0 | 2 | 8.7 | 1 | 4.3 | 0 | 0 |
| Dyspnea | 3 | 13.0 | 3 | 13.0 | 0 | 0 | 0 | 0 |
| Thrombocytopenia | 3 | 13.0 | 3 | 13.0 | 0 | 0 | 0 | 0 |
| Hypothyroidism | 2 | 8.7 | 2 | 8.7 | 0 | 0 | 0 | 0 |
| Hemoptysis | 2 | 8.7 | 0 | 0 | 0 | 0 | 2 | 8.7 |
| Hypocalcemia | 1 | 4.3 | 0 | 0 | 1 | 4.3 | 0 | 0 |
| Leucopenia | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Dysphonia | 1 | 4.3 | 0 | 0 | 1 | 4.3 | 0 | 0 |
| Hepatic cytolysis | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Epistaxis | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Fainting | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Hand-foot syndrome | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Hypokalemia | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Pneumothorax | 1 | 4.3 | 0 | 0 | 0 | 0 | 1 | 4.3 |
| Bleeding other | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Oropharyngeal pain | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Vomiting | 1 | 4.3 | 1 | 4.3 | 0 | 0 | 0 | 0 |
| Fistula | 1 | 4.3 | 0 | 0 | 1 | 4.3 | 0 | 0 |
| Infection | 1 | 4.3 | 0 | 0 | 1 | 4.3 | 0 | 0 |
AE leading to dose decrease (39% of the patients) or temporary drug discontinuation (43% of the patients) were asthenia, anorexia, thrombocytopenia, dyspnea and syncope.
Severe grade 5 AE, leading to death, occurred in three cases (13%), and consisted in hemoptysis in two cases and pneumothorax in one case. In cases of fatal bleeding, the only risk factor found in patients’ history was previous neck irradiation, while no other predisposing conditions were evidenced, notably no vascular (arterial or venous), upper digestive or airway invasion, nor a history of previous bleeding. With respect to patient suffering from pneumothorax, we did not find any predisposing factor (i.e. emphysematous disease), prior to lenvatinib initiation; in this case, central RECIST revision showed stable disease as best response. At the time of fatal AEs, the three patients had already reduced lenvatinib doses because of previous AEs, and no one was taking full dose: one patient with hemoptysis and the patient with pneumothorax were under 20 mg (instead of initial 24 mg) of lenvatinib, while the other patient with hemoptysis was under 10 mg (instead of initial 20 mg) of lenvatinib.
Discussion
Our study shows a median PFS of less than 3 months in 23 lenvatinib treated ATC patients with significant toxicity in nearly a half of the patients, including three cases of lethal AE. A statistically significant longer OS was observed in mixed ATC compared with pure ATC patients. PR was obtained in only two patients with mixed ATC.
The efficacy of lenvatinib in ATC is controversial. Supported by the Japanese phase II outcomes (Tahara et al. 2017, Takahashi et al. 2019), lenvatinib was approved for ATC treatment in Japan. In recent years, several other Japanese studies experimented lenvatinib effectiveness: one small case-series on five patients reported an objective response rate (ORR) of 60% (Koyama et al. 2018); a report on seven patients, showed an ORR of 43% and a disease control rate (DCR) of 57% (Yamazaki et al. 2017); a study on 23 patients (Iwasaki et al. 2018) reported an ORR of 17.4% and a DCR of 43.5%. However, for most of these studies, a modest median OS of less than 6 months and a median time-to-progression less than 3 months were observed (Iwasaki et al. 2018, Koyama et al. 2018), and among patients with tumor response a high AEs rate was found (Iwasaki et al. 2018). A very recent Japanese study confirmed lenvatinib superiority compared to a palliative treatments approach, albeit with a median OS of only 4.2 months (Iwasaki et al. 2020). Moreover, occasional case-reports showed some efficacy (Oishi et al. 2017, Ohkubo et al. 2018, Kanazawa & Kammori 2019). Besides the Japanese experience, results on American patients are less encouraging, consistent with the results of our study: a small case-series on three ATC patients showed only transitory effects, with high toxicity rate (Iñiguez-Ariza et al. 2017), and another study on ten patients showed a morphological control (SD+PR) in 70%, but with a PFS of only 2.7 months (Iyer et al. 2018). Finally, the recent results from a further multicentric phase II exploring the effectiveness of lenvatinib in ATC patients, fully confirmed our unsatisfying experience, since the study was interrupted for inefficacy and showed a PFS of 2.6 months and an OS of 3.2 months (Wirth et al. 2020).
Concerning our case-series, we have to acknowledge several limitations. The retrospective design of the study limits the strength of the results and precludes any firm conclusion on lenvatinib efficacy. The sample size is relatively small but consistent with that of other literature reports, given the rarity and the aggressiveness of ATC. Patients population often underwent former heavy treatments lines, before lenvatinib initiation, and that may have influenced lenvatinib therapeutic outcome. Finally, the treatment protocol was not homogeneous and represents a real-world experience of several tertiary referral centers for thyroid disease in France in a context of limited therapeutic resources.
The ATC population studied was heterogeneous, with some patients being long-survivors of ATC despite the presence of distant metastases, and lenvatinib given as a third or further treatment line. This unusually long survival may be explained, once again, by the presence of mixed ATC tumors that showed better outcomes than pure ATC. Moreover, mixed ATC had received several lines of treatment and a better tumor response during lenvatinib treatment (2 PR). As mentioned above, it is noteworthy that the fact of undergoing several therapies may have influenced the outcomes of following treatments lines, including lenvatinib, but at the same time, this is the expression of a somehow milder disease behavior, which let patients benefit and tolerate more therapeutic options.
The two PR patients showed a peculiar clinical history: one disclosed a short response duration, but the other one exhibited a response for more than 9 months. The former started lenvatinib as third line therapy after two traditional chemotherapy protocols, while the latter received it as the sixth line, after receiving two traditional chemotherapy lines, two targeted therapy lines both within the framework of a trial (one with an angiopoietin-inhibitor and another with crizotinib, oriented by an ALK rearrangement detection), and finally an immunotherapy protocol with an anti-PD1 drug with a prolonged response for 16 months. During his history, the longer responder also benefited from a biopsy of a distant metastasis, which confirmed the disease progression on the PDTC contingent.
Thus, while the shorter responder showed a course of disease more consistent with an ATC, the longer responder definitely showed an exceptional history of disease, and despite the presence of an anaplastic component in the thyroid gland (confirmed by two independent pathologists), discloses an evolution more similar to that observed in PDTC. This patient also had detectable Tg levels, with a sharp reduction during lenvatinib treatment.
Moreover, three other patients had a biopsy of distant metastases, consistent with PDTC and not ATC. This fact highlights that when we are faced with long-term ATC survivors with distant metastases, the hypothesis of a mixed tumor should be raised. Therefore, this should lead to a histological re-challenge by distant metastasis biopsy, associated to serum Tg determination, even in case of pure ATC type. In fact, new histological and molecular information may enhance our knowledge about disease’s behavior and guide the further therapeutic choices.
We found an important rate of AEs of all grades, consistent with those observed in PDTC trials (Schlumberger et al. 2015) and in real life experiences (Berdelou et al. 2018, Locati et al. 2019). Nonetheless, an important rate of severe AEs was observed including three events resulting in patients’ death. Severe hemorrhages (as massive hemoptysis) occurred in patients who did not bleed prior to lenvatinib treatment; in these cases, we found no evidence of airway invasion, while a previous high-dose neck irradiation was performed for both, which is a recognized risk factor of bleeding during anti-angiogenetic tyrosine kinase treatment (Lamartina et al. 2017). The other severe AE was a spontaneous pneumothorax, that led to death. Although a rare complication, pneumothorax onset during lenvatinib treatment for thyroid cancer has already been described (Berdelou et al. 2018, Yamazaki et al. 2018), that can be fatal.
In conclusion, the efficacy of lenvatinib in ATC patients proved to be limited in our retrospective cohort of heavily pretreated ATC patients. Other authors experienced greater therapeutic benefits, even if in different ATC population settings. However, the recent results from a prospective phase II are consistent with our experience (Wirth et al. 2020). Future trials, exploring the combination between lenvatinib and immunotherapy, might provide new evidences in favor of lenvatinib use for ATC (Wirth et al. 2020).
Concerning the present study, we observed some benefits in selected cases, where a more differentiated component or an ongoing differentiation emerged during natural history. This consideration leads us to recognize ATC as a broad spectrum of disease, generally aggressive, but with ranging shades of lethality. Based on this variability, we could orient our choices, moving beyond a prefixed diagnosis and re-challenging with new histological and molecular tests for a possible evolving disease.
Declaration of interest
Nathalie Roudaut: sponsorship at conferences by EISAI and advisory as medical expert at professional meetings for EISAI. Martin Schlumberger: sponsorship at conferences by AstraZeneca, Bayer, Eisai, Ipsen, and Sanofi Genzyme and received grants for research from Bayer, Eisai, Exelixis–IPSEN, and Sanofi Genzyme. Sophie Leboulleux: advisory role for Sanofi Genzyme, EISAI, Loxo, and Bayer and received grants for research from Sanofi Genzyme, Novartis and Bayer. The other authors disclosed no potential conflicts of interest for this study.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Ethics statement
This study was approved by Gustave Roussy Ethics Committee. This study was realized according to the Declaration of Helsinki and in agreement with ethical standards.
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