Durable response of anaplastic thyroid cancer to pembrolizumab combined with chemotherapy: A case report

ABSTRACT

Anaplastic thyroid cancer is a notoriously aggressive malignancy with a dismal prognosis, typically associated with a median overall survival of less than one year. Therapeutic alternatives are particularly limited for patients without actionable driver mutations. Here, we report a case of BRAF V600E wild-type, PD-L1-positive (tumor proportion score of 80%) anaplastic thyroid cancer with residual/relapsed disease following surgery and subsequent progression on multi-targeted tyrosine kinase inhibitor therapy. The patient was thereafter treated with a combination of pembrolizumab, nab-paclitaxel and carboplatin, resulting in a sustained near-complete response lasting over 30 months, accompanied by a manageable safety profile. The favorable response in this case suggests that further evaluation of this triplet regimen could be considered for anaplastic thyroid cancer, though this remains a speculative premise requiring validation. Further studies are also needed to clarify the underlying mechanisms of this combination and to identify predictive biomarkers for patient selection.

Introduction

Anaplastic thyroid cancer (ATC) is a rare but highly lethal type of thyroid cancer. While it accounts for only 1–2% of all thyroid cancers, ATC contributes to more than half of thyroid cancer-related deaths.¹ Unlike differentiated thyroid cancer (DTC), which has a standardized treatment approach centered on radioiodine therapy with proven efficacy and well-documented adverse effects,² ATC is resistant to radioiodine therapy due to the loss of sodium iodide symporter expression. Although there have been some improvements in survival for the last 2 decades, ATC still has a poor prognosis with a median overall survival (OS) less than 12 months.³ Chemotherapeutic drugs including taxanes, doxorubicin and platinum agents have been used in inoperable ATC but they rarely lead to responses and long-term survival.^4–6 Approximately one-third of ATCs harbor a BRAF V600E mutation. In this subset of patients, the BRAF/MEK targeted combination therapy of dabrafenib and trametinib has been reported to achieve an objective response rate (ORR) of 56% and a median OS of 14.5 months.⁷ For patients who progress on BRAF/MEK targeted therapy or those without a BRAF V600E mutation, antiangiogenic agents have shown modest efficacy.^8,9 Lenvatinib, for instance, is approved for ATC in Japan based on a phase II clinical trial in which it achieved an ORR of 24% and a median OS of 10.6 months in 17 ATC patients.¹⁰ Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is currently undergoing clinical evaluation for ATC. A multicenter phase II study tested the PD-1 inhibitor spartalizumab on 42 ATC patients and showed that a small proportion of patients benefited from ICI monotherapy, with an ORR of 19% and a median OS of 5.9 months.¹¹

Combining chemotherapy with immunotherapy might be able to improve clinical efficacy by synergistically boosting immune response, modifying the immunosuppressive tumor microenvironment (TME), and overcoming resistance, potentially improving patient survival.¹² The NCCN guidelines recommend paclitaxel combined with carboplatin as a first-line regimen for ATC. However, the high risk of hypersensitivity reactions associated with paclitaxel necessitates mandatory high-dose dexamethasone premedication. Corticosteroids exert immunosuppressive effects by inhibiting the production of pro-inflammatory cytokines and eicosanoids, reducing leukocyte migration, and modulating immune cell function through T-cell suppression and M2 macrophage polarization.¹³ Therefore, steroids may potentially compromise the efficacy of immunotherapy when used concurrently.¹⁴ Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free colloidal dispersion composed of 130-nm particles stabilized by human serum albumin, which enables administration of higher drug doses compared to conventional paclitaxel. It is also associated with reduced allergic reactions, less infusion time (30 min), and eliminates the need for dexamethasone premedication.¹⁵ A meta-analysis concludes that nab-paclitaxel improves tumor response and survival outcomes compared to conventional solvent-based taxanes in the first-line treatment of metastatic breast cancer.¹⁶ The efficacy and safety of the combination of pembrolizumab, paclitaxel/nab-paclitaxel and carboplatin have been repeatedly verified in previous clinical trials involving multiple solid tumors including non-small-cell lung cancer,¹⁷ head and neck squamous cell cancer¹⁸ and endometrial cancer.¹⁹ Here, we present a case of metastatic ATC without actionable genetic alterations that progressed on an antiangiogenic agent, and had an ongoing durable response to pembrolizumab, nab-paclitaxel and carboplatin. The structure and presentation of this article are inspired by the work of Kroloff et al. in their case report on ATC.²⁰

Patient presentation

A 56-y-old man presented to another hospital in April 2023 with an enlarging mass on his neck, accompanied by dysphagia and coughing. Thyroid ultrasound showed multiple nodules in both lobes, suggesting nodular goiter with a left lobe adenoma. Cervical CT revealed a mass in the left thyroid lobe, measuring 66 mm × 56 mm × 68 mm. Thyroid function tests (including TSH, FT3 and FT4) were normal. Left thyroidectomy, right partial thyroidectomy and left inferior parathyroid autotransplantation were performed on April 17, 2023, without a preoperative biopsy. Subsequent pathology demonstrated ATC (pT3aN0Mx), but the surgical margin status was not described. PD-L1 expression was high, with a tumor proportion score (TPS) of 80% assessed using the 22C3 pharmDx (Figure 1). Postoperatively, the patient continued to experience recurrent coughing along with weight loss. PET/CT scan on May 5, 2023, revealed a node with FDG-avidity (SUVmax = 10.5) in the left tracheoesophageal groove adjacent to the surgery site, enlarged lymph nodes in the left supraclavicular (SUVmax = 14.7) and mediastinal regions (SUVmax = 7.7), and multiple lesions in both lungs (SUVmax = 8.0). Given the hypermetabolic activities of these lesions, coupled with the patient’s persistent symptoms and the highly aggressive nature of ATC, the diagnosis of recurrent ATC was made. The patient visited our hospital on May 12, 2023. A next generation sequencing (NGS) test was ordered and the patient received one cycle of anlotinib (12 mg daily on a 2-weeks-on/1-week-off schedule), a multi-targeted inhibitor of tyrosine kinase receptors [vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), c-kit] while waiting for the result of NGS, which indicated a low tumor mutation burden (TMB-L, 6.0 Muts/Mb) and was negative for BRAF mutations as well as NTRK and RET fusions. CT scan on May 22, 2023, showed an increase in the size of the left tracheoesophageal groove lesion, mediastinal lymph nodes and bilateral pulmonary lung metastases, with the sum of target lesion diameters increasing by 35.4%, along with new lesions in both lungs, thereby meeting the RECIST (response evaluation criteria in solid tumors) 1.1 criteria²¹ for progressive disease (PD). The patient commenced a combination therapy of pembrolizumab, nab-paclitaxel and carboplatin on May 23, 2023. The treatment details were as follows: pembrolizumab 200 mg on day1, carboplatin AUC 5 on day 1, and nab-paclitaxel 230 mg/m² on day 1, with all drugs administered intravenously once every 3 weeks. During the six cycles of immunochemotherapy, he had rapid, continuous response of all target lesions along with improvement in coughing (Figure 2A,B). After six cycles of combined treatment, the patient continues to receive pembrolizumab maintenance and the lesions continued to shrink. Recent restaging CT of the neck, chest and abdomen demonstrated a near-complete response, with an 80.6% reduction in target lesions per RECIST 1.1 criteria without development of any new metastases (Figure 2C).

Figure 1.

Baseline PD-L1 TPS assessed using the 22C3 pharmDx, calculated as the number of PD‑L1‑stained tumor cells divided by the total number of all tumor cells multiplied by 100%; tumor cells showing partial or complete membrane staining at any intensity are included in the calculation.

Figure 2.

Longest diameters of the target lesions (A) prior to initiation of immunochemotherapy measuring a total of 103mm (May 22, 2023), (B) after 6 cycles of immunochemotherapy measuring a total of 39mm (September 28, 2023), and (C) after 2 years of pembrolizumab measuring a total of 20mm (May 12, 2025).

Consistent with previously reported safety profile, treatment with pembrolizumab and chemotherapy was well tolerated with grade 2 immune-related dermatitis and grade 2 neuropathy caused by nab-paclitaxel. Immune-related dermatitis occurred approximately 16 weeks after pembrolizumab initiation, presenting as maculopapular rash and pruritus on the trunk. The condition was managed with a 4-week tapering course of prednisone starting with 0.5 mg/kg/d and improved gradually over 2 weeks. Peripheral neuropathy developed approximately 6 weeks following nab-paclitaxel treatment, manifesting as numbness with mild pain in both feet, which was managed with oral mecobalamin (0.5 mg three times daily), and the symptoms gradually resolved after discontinuation of nab-paclitaxel. The patient completed 2 y of pembrolizumab treatment in May 2025 and is now under follow-up. The entire treatment history is illustrated in Figure 3.

Figure 3.

Treatment history of this case.

Discussion

Here, we present a case of a patient with driver-gene-negative ATC with a high PD-L1 expression who had residual/relapsed cancer after surgery and metastases in both lungs and multiple lymph nodes. He progressed shortly after 1 cycle of anlotinib, but subsequent treatment with pembrolizumab, nab-paclitaxel and carboplatin combination followed by pembrolizumab maintenance demonstrated sustained therapeutic benefit and great tolerability for more than two and a half years.

According to the latest version of the National Comprehensive Cancer Network (NCCN) guidelines for thyroid carcinoma,²² chemotherapy-based regimens remain the primary therapeutic option for metastatic ATC without actionable genetic alterations. However, these regimens have demonstrated limited efficacy and there is still a huge unmet medical need in ATC. Although ATC is characterized by its highly aggressive biological behavior, accumulating preclinical and clinical evidence has revealed that it is more responsive to ICIs compared to other types of thyroid cancer. This paradoxical therapeutic sensitivity may be attributed to the elevated expression of PD-L1, a well-established predictive biomarker of response to PD-1/PD-L1 inhibitors. Prior studies have reported PD-L1 expression rates ranging from 47% to 81% in ATC specimens, which is significantly higher than in DTC (<10%) and poorly differentiated thyroid cancer (PDTC) (7.7–25%).^23,24 TMB analyses reveal significantly higher TMB in ATC compared to DTC and PDTC, as evidenced by Pozdeyev et al.’s sequencing of 583 DTC and 196 ATC samples revealing greater genetic alterations in ATC,²⁵ Landa et al.’s NGS of 117 thyroid tumors (33 ATCs, 84 PDTCs) showing median mutation burdens of 6 vs. 2 mut/Mb,²⁶ and a cohort study of 113 samples confirming higher TMB in ATC.²⁴ Single-cell RNA sequencing demonstrated that CXCL13+ T lymphocytes were enriched in the TME of ATC and potentially contribute to the formation of early tertiary lymphoid structures. Compared to papillary thyroid cancer (PTC), ATC samples also exhibited a higher level of exhausted T cells, which could be reactivated by ICIs. This unique TME of ATC makes it more sensitive to immunotherapy than other types of thyroid cancer.^27,28 Beyond tumor-intrinsic biomarkers such as PD-L1 expression and TMB, intestinal microecology is emerging as a key extrinsic regulator of anti-tumor immunity and response to ICIs. The gut microbiome can modulate systemic and intratumoral immune states, influencing the efficacy of PD-1/PD-L1 blockade.^29,30 This patient’s durable response despite a low TMB raises the possibility that a favorable gut microbiota composition may have contributed to the observed clinical benefit. Recent reviews highlight specific microbial signatures and metabolites (e.g., short-chain fatty acids) that are directly linked to thyroid cancer pathogenesis and immune modulation.³¹ Future management of ATC could be refined by integrating microbial profiling with traditional biomarkers to better predict responses to immunotherapy. Furthermore, interventions targeting the gut microbiome, such as probiotics or prebiotics, represent a novel adjunctive strategy worthy of exploration to potentially enhance treatment outcomes.³¹

Given the rarity of ATC, prospective evidence on the efficacy and safety of ICIs remains limited. Besides the aforementioned spartalizumab, only pembrolizumab and the combination of nivolumab and ipilimumab have been evaluated in clinical trials for ATC. The phase II ATLEP trial examined pembrolizumab combined with lenvatinib on 27 pretreated metastasized ATCs and achieved an ORR of 51.9%, a median progression-free survival (PFS) of 9.5 months and a median OS of 10.25 months.³² However, it should be noted that this trial has so far been presented only as a conference abstract and has not yet been published in a peer-reviewed journal. The nivolumab/ipilimumab combination was given to 10 ATC patients in a phase II trial, the ORR was 30%, the median PFS was 4.3 months and the median OS had not been reached.³³ Pembrolizumab or nivolumab monotherapy was evaluated in a retrospective study involving 13 ATC patients (12 were treated with pembrolizumab and 1 with nivolumab), with an ORR of 16%, a median PFS of 1.9 months and a median OS of 4.4 months.³⁴ Four retrospective studies, collectively enrolling 40 ATC patients, reported ORRs of 20% to 66% for pembrolizumab plus lenvatinib.^35–38 A phase II study investigating the efficacy and safety of PD-1 inhibitor and anlotinib combined with multimodal radiotherapy in the second-line treatment of recurrent or metastatic ATC is currently ongoing (NCT05659186).

Despite the relative strength of current evidence for the combination of pembrolizumab and lenvatinib in BRAF V600E wild-type ATC, this patient was not eligible for this regimen following rapid progression on anlotinib, since lenvatinib and anlotinib are both anti-angiogenic TKIs and disease progression on one typically precludes the use of the other. Given the markedly elevated PD-L1 TPS and chemotherapy-naïve status, pembrolizumab combined with chemotherapy was pursued in this case, and this regimen has provided the patient with a sustained and well-tolerated response, achieving a PFS exceeding 30 months in this highly aggressive disease. The favorable response in this case suggests that further evaluation of this regimen could be considered for ATC, though this remains a speculative premise requiring validation. Further studies are needed to clarify the underlying mechanisms of this combination and to identify predictive biomarkers for patient selection. It should also be noted that the conclusion regarding the superiority of nab-paclitaxel over conventional paclitaxel is based on studies in non-thyroid cancers and warrants validation in the context of ATC.

Biography

Wen Lin has been working in the field of medical oncology for over 30 years. She works as a medical oncologist at the Cancer Hospital of Shantou University Medical College, in which she is the deputy director of medical oncology department. She primarily focuses on the individualized systemic treatment of multiple solid tumors including thyroid cancer and lung cancer. She serves as the principal investigator for multiple international and domestic multi-center clinical trials.

Funding Statement

This work was supported by the Guangdong Association Study of Thoracic Oncology [N/A].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Ethics approval

This is a case report that does not contain any identifiable patient information.

Patient consent for publication

Consent obtained directly from the patient.