Abstract
Objective
Poorly differentiated thyroid carcinomas (PDTCs) are rare and aggressive head and neck malignancies with a poor prognosis. Systemic treatment for incurable PDTC consists of multi-kinase inhibitors (MKIs) based on extrapolation from the experience with radioiodine refractory differentiated thyroid cancer (DTC). Cabozantinib is an approved second-line MKI therapy for DTC, but there are limited data regarding the safety and efficacy of cabozantinib for PDTC.
Methods
We conducted a single-institution, retrospective analysis of patients with PDTC who received cabozantinib in any line of therapy. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record. Median progression-free survival (PFS) and overall survival (OS) were primary endpoints and estimated using Kaplan–Meier methodology.
Results
Seven patients with PDTC who received cabozantinib were included. 4/7 (57%) patients had a partial response to cabozantinib, while 2/7 (29%) had stable disease (SD) as their best response. The median time on treatment for cabozantinib was 10.53 months. The median PFS from the start of cabozantinib was 12.9 months, and median OS was 14.21 months. Most adverse events to treatment (5/6) were low grade. Two (29%) patients were alive at the date of the last follow-up.
Conclusion
Cabozantinib is an effective and reasonably well-tolerated treatment option for patients with PDTC. Prospective studies are needed to further investigate the role of cabozantinib in the treatment of PDTC, alone and in combination with other agents, including checkpoint inhibitors.
Introduction
Poorly differentiated thyroid carcinomas (PDTCs) are rare head and neck malignancies that account for 2–15% of all thyroid carcinomas (1). PDTC is unique in that it exhibits characteristics intermediate between differentiated thyroid carcinomas (DTCs) and anaplastic thyroid carcinoma (ATC) (2). PDTC is notably aggressive with many patients presenting with airway compromise and up to 85% presenting with or eventually developing distant metastatic disease (3). These cancers are challenging to manage as there is no consensus regarding diagnostic criteria or an explicit management algorithm that standardizes treatment (4, 5). Attempts to identify prognostic factors for these cancers have yielded mixed results with no clear correlation between clinical outcomes and molecular alterations, percentage of PDTC component in the tumor, or associated DTC component (6, 7). Studies focused on PDTC are few in the literature despite being classified as a unique diagnostic entity almost 20 years ago, and thyroid cancer National Comprehensive Cancer Network (NCCN) guidelines do not even include a section on PDTC (8).
While there is no clear consensus on the management of PDTC, in clinical practice, an interdisciplinary approach of surgery, external beam radiation therapy, radioactive iodine (RAI) treatment, and systemic therapies is generally used (9). Systemic treatment of metastatic RAI-refractory (RAIR) PDTC often consists of sorafenib or lenvatinib, which are the multi-kinase inhibitors (MKIs) approved by the Food and Drug Administration (FDA) for the treatment of RAIR-DTC (10). These agents showed significant progression-free survival (PFS) advantage compared to placebo in the DECISION and SELECT trials (10.8 vs 5.8 months with sorafenib and 18.3 vs 3.6 months with lenvatinib, respectively) (11, 12). Both of these studies focused on RAIR-DTC but did include subgroups of patients with PDTC (11.6% (40 pts) in DECISION and 10.7% (28 pts) patients in SELECT), in whom sorafenib showed a nonsignificant PFS improvement over placebo (5.8 months vs 4.43 months) and lenvatinib showed dramatic PFS improvement over placebo (14.8 months vs 2.1 months). Several real-world studies have subsequently supported the safety and efficacy of these frontline MKIs in the treatment of PDTC (13, 14, 15, 16, 17, 18, 19).
Cabozantinib is a standard treatment in the second line for RAIR-DTC. Cabozantinib is an MKI with a broad spectrum of anti-tumor activity with many molecular targets, including VEGFR, AXL, MET, and RET. Cabozantinib use is largely based on extrapolated results for RAIR-DTC previously treated with sorafenib or lenvatinib in the COSMIC-311 trial (20). This study did enroll a small number of patients with PDTC; a recent abstract reported that of the seven patients with PDTC who received cabozantinib on COSMIC-311, all had clinical benefit (3 partial response (PR) and 4 SD), but specific results concerning survival and tolerability were not available (21).
Given the lack of prospective or retrospective data on the safety and efficacy of cabozantinib in PDTC, we performed an observational study to describe our single-institution experience. This study aims to describe outcomes, including new information on survival and toxicity, with cabozantinib in a real-world cohort of PDTC, many of whom had progressed on prior MKI.
Methods
A single-institution study of patients diagnosed with PDTC from January 1, 2010, to January 1, 2022, was performed via query of the University of Pennsylvania Cancer Registry. All patients with a possible diagnosis of PDTC were independently reviewed by two pathologists who specialize in the molecular and immunopathology of thyroid neoplasia. Diagnosis of PDTC was determined by Turin criteria (22). All patients with confirmed PDTC who received cabozantinib at any point during their treatment course were included. Patients on a clinical trial were excluded. Patient demographics, diagnostic imaging, treatment history, toxicities, and clinical outcomes were abstracted from the electronic medical record in accordance with the University of Pennsylvania Institutional Review Board and the Declaration of Helsinki. The disease stage was determined per the American Joint Committee on Cancer (AJCC) eighth edition (23). Treatment responses were assessed by chart review per documentation by individual providers. Adverse events (AEs) were based on provider assessment per chart review and defined per Common Terminology Criteria for Adverse Events (CTCAE) v5 (24).
PFS and overall survival (OS) were the primary endpoints of this study. Median PFS and OS were estimated from the time of initiation of cabozantinib therapy using the Kaplan–Meier methodology and were censored at the date of the last follow-up. PFS and OS were calculated with the Kaplan–Meier method, and groups were compared using the log-rank test, with a significance threshold of P < 0.05. All statistical tests were conducted using R 4.3.2 for Windows.
Results
We identified seven patients with histologically confirmed PDTC who received cabozantinib within the study period. Patient demographic information, disease characteristics, and treatments prior to cabozantinib are reported in Table 1. Median age was 62 years (range, 50–75) and 4/7 (53%) patients were male. All patients were White and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All patients had incurable stage IV disease at the time of cabozantinib initiation, with 4/7 (57.1%) having stage IVC disease. On histological evaluation, 3/7 (43%) patients had >50% PDTC involvement, 2/7 (29%) patients had between 30–50% PDTC involvement, and 2/7 (29%) patients had <30% PDTC involvement. All five patients with a DTC component had concomitant papillary thyroid carcinoma (PTC). Three of these patients (3/5, 60%) had classical PTC, 1/5 had tall cell variant PTC (20%), and 1/5 (20%) had an oncocytic variant. Next-generation sequencing (NGS) was performed on 5/7 (71.4%) patients: 3/5 (60%) had a TP53 mutation and 2/5 (40%) had a TERT mutation. No alterations in BRAF, NTRK1/2/3, or RET, were observed in the study population.
Patient (n = 7) demographics and disease characteristics. Data are presented as n (%).
| Characteristics | Values |
|---|---|
| Median age (range) | 62 (50–75) |
| Sex (%) | |
| Male | 4 (57) |
| Female | 3 (43) |
| Race (%) | |
| White | 7 (100) |
| ECOG (%) | |
| 0 | 5 (71) |
| 1 | 2 (29) |
| Stage at TKI initiation (%) | |
| IVA/IVB | 3 (43) |
| IVC | 4 (57) |
| Distant organ metastases (%) | |
| None | 3 (43) |
| Lung | 3 (43) |
| Bone | 2 (29) |
| Liver | 1 (14) |
| % PDTC involvement (%) | |
| < 30% | 2 (29) |
| 30–50% | 2 (29) |
| > 50% | 3 (43) |
| Molecular alterations observed (%) | |
| NGS not performed | 2 (29) |
| TP53 | 3 (43) |
| TERT | 2 (29) |
| Previous nonsystemic treatments (%) | |
| Radiation | 5 (71) |
| Surgery | 6 (86) |
| RAI | 4 (57.1) |
| First-line systemic therapy (%) | |
| Lenvatinib | 3 (43) |
| Sorafenib | 3 (43) |
| None | 1 (14) |
NGS, next-generation sequencing; PDTC, differentiated thyroid cancer; RAI, radioiodine; TKI, tyrosine kinase inhibitor.
The majority (5/7, 71%) received radiation therapy to the neck (all 33 fractions with a median cumulative thyroid dose of 62 Gy) prior to cabozantinib, and all but one patient (6/7, 86%) had debulking surgery. Three patients (43%) received palliative radiation to sites outside of the neck including the lung and bones. Four patients (57%) received radioactive iodine. Prior to receiving treatment with cabozantinib, all but one patient (86%) was treated with MKIs in the frontline setting (3/7, 43% lenvatinib, 3/7, 43% sorafenib); no patients received immune checkpoint inhibitor (ICI) or cytotoxic chemotherapy. All patients had clinical benefits from frontline MKI, which was continued until the progression of disease (2/6, 33%) or intolerable treatment-related adverse events (TRAE) (4/6, 66%). Median PFS was 11.36 (95% CI: 5.26–20.31 months). On frontline MKI, 2/6 patients had grade 2 TRAE and 4/6 had grade 3 TRAE (Table 2). The median duration of frontline MKI was 342 days (range: 60–855).
Response to treatment and adverse events of TKI therapy. Data are presented as n (%).
| Characteristics | Values |
|---|---|
| Response to frontline TKI | 6 |
| PR | 3 (50) |
| SD | 3 (50) |
| Grade of TRAE to frontline TKI | 6 |
| Grade 2 | 2 (33.3) |
| Grade 3 | 4 (66.7) |
| Frontline TKI TRAE | 6 |
| Hypertension | 2 (33) |
| Dermatologic | 3 (50) |
| Gastrointestinal | 1 (17) |
| Dose of cabozantinib | 7 |
| 60 mg | 3 (43) |
| 80 mg | 1 (14) |
| 140 mg | 3 (43) |
| Response to cabozantinib | 7 |
| PR | 4 (57) |
| SD | 2 (29) |
| PD | 1 (14) |
| Grade of TRAE to cabozantinib | 7 |
| None | 1 (14) |
| Grade 1 | 2 (29) |
| Grade 2 | 2 (29) |
| Grade 3 | 2 (29) |
| Cabozantinib TRAE | 6 |
| Gastrointestinal | 3 (50) |
| Hypertension | 2 (33) |
| Dermatologic | 1 (17) |
TKI, tyrosine kinase inhibitor.
Dosing of cabozantinib was based on provider discretion with most patients receiving either 60 mg (3/7, 43%) or 140 mg (3/7, 43%). After cabozantinib initiation, 4/7 (57%) patients had a partial response and 2/7 (29%) had stable disease. Individual patient treatment courses are depicted in Fig. 1. Most (6/7, 86%) patients experienced TRAEs with cabozantinib, with the majority (5/6, 83%) being grade 1 or 2. The most common TRAEs were diarrhea (50%), hypertension (33%), and rash (17%). Two patients’ required dose reduction, and one patient required treatment discontinuation due to TRAEs. The median time of treatment on cabozantinib was 320 days. Median PFS on cabozantinib was 12.89 months (95% CI: 4.13–19.17 months) (Fig. 2A) and median OS was 14.21 months (95% CI: 4.87–20.12 months) (Fig. 2B). Two patients (29%) were living at the date of last follow-up, although none were still on cabozantinib.
Swimmer plot of seven patients treated with cabozantinib. Six patients were treated with cabozantinib after the failure of first-line targeted therapy. Patient two received cabozantinib as a first-line treatment. Patients (y-axis) are organized by overall survival. Within the swimmer plot, the light blue/green/dark blue bars indicate first-line targeted therapy (Cabozantinib, Lenvatinib, Sorafenib), light blue bar indicates time on cabozantinib, triangles (Δ) indicate time to progression on first-line targeted therapy, and asterisks (*) indicate time to progression on cabozantinib. Overall survival is labeled: x indicates death, o indicates last known follow-up. All patients except for patient four had surgical resection prior to diagnosis.
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0225
Kaplan–Meier curves showing (A) Progression-free survival and (B) Overall survival within the study cohort. A cross represents a data event with a horizontal line representing right censoring and a downward line representing an event.
Citation: European Thyroid Journal 13, 6; 10.1530/ETJ-24-0225
Discussion
In this retrospective study, the first to the authors’ knowledge evaluating cabozantinib for patients with PDTC, patients with PDTC treated with cabozantinib had favorable efficacy outcomes and tolerability. This cohort was comprised of patients with relatively favorable prognosis and treatment-responsive cancers – all seven patients in our series had clinical benefit from frontline MKI therapy with a median PFS of 11.36 months and OS of 22.96 months, far exceeding that reported in a 2022 meta-analysis of ten studies, which described a pooled median PFS of 3.16 months (95% CI: 2.18–5.60), and pooled median OS of 3.16 months (95% CI: 2.17–5.64) (25). Subsequently, on cabozantinib, 57% of our patients had a PR and had a median duration of therapy (DoT) of 320 days, with a median PFS of 12.89 months and median OS of 14.21 months.
The pathological diagnosis of PDTC is among the most challenging in head and neck malignancies due to a lack of clinical consensus regarding diagnostic criteria and the intermediate features PDTC exhibits between DTC and ATC (2, 8). Most patients in this study also exhibited an admixed pathological phenotype between PDTC and PTC. While there is no minimum histologic threshold percentage for the classification of PDTC, this further complicates the clinical decision-making for these cancers and whether they should be treated under a PDTC or DTC paradigm (6, 7). Interestingly, PDTC patients within this cohort exhibited only TP53 and TERT mutations, while no molecular alterations amenable to targeted therapy, including BRAF, NTRK1/2/3, or RET, were observed in the study population. While these results may be skewed in part due to the selection criteria involved in treating these patients with cabozantinib, large-scale studies of NGS for PDTC/ATC have demonstrated that TP53 and TERT are among the most commonly mutated genes in these cancers, with rates as high as 40–60% of cases (26, 27).
Available clinical trial data suggest that, at standard prescribed doses, cabozantinib may have a more favorable side effect profile than lenvatinib, with fewer high-grade AEs and discontinuation of therapy due to toxicity (11, 12, 20). Lenvatinib is often difficult to tolerate at the standard 24 mg dose due to AEs including treatment-related hypertension (56%), fatigue, stomatitis, diarrhea, and palmar-plantar erythrodysesthesia (17, 28). No AE data have been reported on cabozantinib specifically for PDTC, but the most common AEs with cabozantinib in RAIR-DTC were hypertension, diarrhea, fatigue/malaise, and weight loss, which are less frequently dose-limiting (29). In our patient cohort, AEs with cabozantinib were generally low grade, and only one patient required treatment discontinuation.
A unique characteristic of our cohort is the variable dosages of cabozantinib used in the treatment of PDTC. Cabozantinib-S-malate currently exists in two formulations, a high-dose capsule formulation typically taken at a dosage of 140 mg once daily, and a lower-dose tablet taken 60 mg once daily. While neither formulation is approved for the treatment of PDTC, the higher-dosage capsules are typically reserved for the treatment of medullary thyroid cancers based on results from the pivotal phase III EXAM trial (30) while the lower-dose formulation has multiple indications including renal cell carcinoma, hepatocellular carcinoma, and locally advanced or metastatic DTC (31). Phase I data of high-dose cabozantinib did show impressive efficacy for DTC with a response rate of 53%; however, this dosage led to a dose reduction to 60 mg in a majority of patients, with further trials using the reduced dose cabozantinib (32). FDA approval for DTC using this lower-dose formulation was not available until September 17, 2021, and multiple landmark trials, including COSMIC 311 and EXAM, had not yet been finalized during the treatment course of many of the PDTC patients within this study, leading to variable formulations being utilized. While this study lacks the power to determine dose-related efficacy of cabozantinib for PDTC, future studies are needed to determine the dosage that yields the greatest clinical benefit for PDTC patients while weighing the harm of any additional side effects.
Notably, no patients in this cohort received immune checkpoint inhibition, which is becoming an emerging treatment option for ATC/PDTC (32, 33); and none received cytotoxic chemotherapy. The ATLEP trial of pembrolizumab/lenvatinib has shown remarkable outcomes for PDTC, with a partial response rate of 75% in the eight patients included (34). Ongoing trials, including CABATEN, which is investigating the combination of cabozantinib and atezolizumab, will provide more data on the role of combination MKI/ICI therapy for ATC/PDTC. Preliminary results of this trial have shown improved efficacy with cabozantinib plus atezolizumab compared to atezolizumab alone, with moderate efficacy for ATC and a PFS of 4.7 months (35). Unfortunately, information regarding outcomes in the PDTC subgroup is not available.
Limitations of our single-institution study include its small sample size, heterogeneous disease and treatment characteristics, and retrospective design. While it is difficult to draw conclusions from a small case series, real-world data is a valuable tool to study rare aggressive neoplasms such as PDTC, which often are difficult to enroll in prospective studies. Importantly, favorable outcomes in this patient population likely reflect selection for a relatively favorable-prognosis population who lived long enough with robust enough functional status to initiate second-line MKI therapy.
Conclusions
The COSMIC-311 trial showed that cabozantinib following lenvatinib, sorafenib, or both significantly improved PFS over placebo in DTC (29). However, efficacy with cabozantinib is not well understood in patients with PDTC, which has a much more aggressive natural history (19). In our single institution cohort, most patients with PDTC treated with cabozantinib after first-line MKI tolerated treatment relatively well and had durable benefit and favorable survival outcomes compared to typical outcomes for PDTC (36). These results suggest that cabozantinib is safe and effective in PDTC and may represent a viable treatment option for patients that have progressed on or cannot tolerate MKI therapy such as sorafenib or lenvatinib in the frontline. Prospective studies are needed in order to further investigate the role of cabozantinib in the treatment of PDTC, alone and in combination with other agents, including checkpoint inhibitors.
Declaration of interest
LS reports consulting with Regeneron, MJH Sciences, GenMab, Seagen, and Bayer; and institutional research funding from Blueprint Research, Seagen Research, Erasca, Abbvie, Immunocore, and IO Biotech Research outside the submitted work. RC reports advisory roles in Ono Pharmaceutical and Actuate Therapeutics and institutional funding from Innate Pharma, Xencor, AstraZeneca, F-star Biotechnology, Chugai Pharma, and Catargia Ab. All other authors have no conflicts of interest to disclose.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Data availability statement
The data that support the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to the potential to compromise the privacy of patients within the study cohort.
Institutional review board statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Hospital of the University of Pennsylvania, protocol code 854210.
Informed consent statement
The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin due to the nature of the anonymized material contained within this manuscript.
Author contribution statement
OE and LS were involved in the conception of the study. OE, AB, JX were involved in data collection. OE, AB, AH, RC, and LS were involved in preparation of the original manuscript. OE, AB, SC, RC, and LS were involved in revision of the manuscript. OE, AB, and JX were involved in statistical analysis. All authors read and approved the final manuscript.
Acknowledgements
We thank the University of Pennsylvania Cancer Registry for their support and assistance in data curation necessary for the completion of this study. Furthermore, we thank Virginia Livolsi, Zubhair Baloch, and the remainder of the University of Pennsylvania pathology department and the Center for Precision Diagnostics for their assistance in the diagnosis and molecular workup of these cases.
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