Durvalumab plus tremelimumab for the treatment of patients with progressive, refractory advanced thyroid carcinoma: the phase II GETNE-DUTHY trial

Domain: biology
Published: 2026-04-04
Editorial outcome: minor_revision

Abstract
Single-agent PD-1 blockade demonstrated promising efficacy in advanced thyroid cancer. The phase II, single-arm, multi-cohort GETNE-DUTHY trial (clinicaltrials.gov NCT03753919, EudraCT 2018-001066-42) aimed to determine whether dual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can improve the clinical outcomes in advanced thyroid cancer. Three parallel cohorts including patients with differentiated thyroid carcinoma (Cohort 1, n=37), medullary thyroid carcinoma (Cohort 2, n=30), and anaplastic thyroid carcinoma (Cohort 3, n=12) were recruited. Cohort 1 and 2 included patients following progression to previous standard systemic therapy and in Cohort 3 were recruited regardless of previous therapy. The primary endpoint was 6-month progression-free survival rate for Cohort 1 and 2 and 6-month overall survival rate for Cohort 3. Secondary endpoints included objective response rate, progression-free survival, overall survival, and safety. The 6-month progression-free survival rates were 32.4% (95% confidence interval [CI]: 20.4–51.6) (Cohort 1) and 40.8% (95% CI: 26.3–63.6) (Cohort 2); 6-month overall survival rate was 65.6% (95% CI: 43.2–99.8) (Cohort 3). The overall response rates were 8%, 10%, and 33% for Cohort 1, 2, and 3, respectively. No additional safety signals observed. Durvalumab plus tremelimumab treatment in patients with anaplastic thyroid carcinoma met the primary endpoint of this study, showing encouraging survival outcomes.

Introduction
Thyroid cancer is the most common endocrine malignancy1 and is characterised by significant histological, clinical, and biological heterogeneity. The histological subtypes of thyroid cancer range from differentiated thyroid carcinoma (DTC), which has a relatively favorable prognosis, to anaplastic thyroid carcinoma (ATC), an aggressive subtype associated with a poor prognosis and a median overall survival (OS) of less than one year.2–4

Multikinase inhibitors (MKIs) have been established as standard therapies for various histological subtypes of thyroid cancer, with agents such as sorafenib, lenvatinib, and cabozantinib used for the treatment of DTC5–7 and vandetanib and cabozantinib used for treating medullary thyroid carcinoma (MTC).8,9 However, therapeutic options for patients with DTC who exhibit disease progression on MKIs remain limited.10,11 Regarding MTC, the recent approval of the selective RET inhibitor selpercatinib for the treatment of RET-mutant tumours and tumour-agnostic NTRK inhibitors (e.g. larotrectinib and entrectinib) for the treatment of non-medullary thyroid cancers with NTRK fusions has transformed the management of advanced disease. However, treatment options for patients who show disease progression while on these agents remain limited.12,13

Programmed death ligand 1 (PD-L1) inhibitor monotherapy improves the OS of patients with different types of advanced cancers, demonstrating a manageable safety profile in clinical trials.14–17 However, few studies have evaluated the efficacy of immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies, in the treatment of thyroid cancers.18,19 As the efficacy of ICIs for the treatment of moderately immunogenic tumours is modest, dual targeting of PD-1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has emerged as an enhanced therapeutic strategy for other cancers.20,21 Previous studies on durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) for the treatment of neuroendocrine neoplasms yielded modest but clinically meaningful survival outcomes in a subset of patients with poorly differentiated carcinomas, along with a manageable safety profile.22 These findings provide a biologically grounded rationale for evaluating the efficacy and safety of dual checkpoint inhibition therapy in patients with advanced thyroid carcinomas, a population with limited therapeutic options and share molecular vulnerabilities.

In this work, we evaluate the efficacy and safety of dual immune checkpoint inhibition using the combination of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) in patients with advanced thyroid carcinomas. The study meets its primary endpoint in the cohort of patients with ATC, showing encouraging efficacy in these patients, whereas the clinical benefit is limited in patients with DTC and MTC. Our results support that ICI may play a role in the treatment of patients with the aggressive ATC disease and suggest limited value in patients with DTC and MTC.

Results
Patient characteristics
Between April 2019 and October 2023, 88 patients were screened, of whom 79 were included in the study. Of these, 37 had DTC, 30 had MTC, and 12 had ATC (Fig. 1). The MTC cohort was closed prematurely because of slow accrual. All enrolled patients received at least one dose of the study treatment and were included in the full analysis set for efficacy and safety analyses. The baseline demographic and disease characteristics of all patients and the detailed history of systemic therapy for each cohort are summarised in Table 1. In patients with ATC, 33.3% of them were treated with local radiotherapy prior to inclusion. The median patient age was 66 years (range, 32–88 years), and 53.2% of the patients were female. Considering the eligibility criteria, patients in the ATC cohort could be treatment-naïve.

Efficacy
Outcomes varied across histological subtypes during a median follow-up period of 14.0 months (range, 0.2–61.2). The 6-month PFS rates and median PFS were 32.4% (95% CI: 20.4–51.6) and 3.7 months (95% CI: 2.7–6.5) for patients with DTC; 40.9% (95% CI: 26.3–63.6) and 5.3 months (95% CI: 2.8–23.2) for patients with MTC; and 33.3% (95% CI: 15-74.2) and 3.6 months (95% CI: 2.2-NR) for patients with ATC (Fig. 2a). The 6-month OS rate and median OS were 65.6% (95% CI: 43.2–99.8) and 13.8 months (95% CI: 5.7–NR), respectively, for patients with ATC (Fig. 2b). The 18-months PFS rates were 6.0% (95% CI: 1.6-22.6), 26.5% (95% CI: 13.6-51.6), 8.3% (95% CI: 1.3-54.4) for DTC, MTC and ATC, respectively. The PFS and OS outcomes for the three cohorts are presented in Table 2 and Supplementary Tables 1 and 2.

In the DTC cohort, patients with ECOG PS of 0 and 1 had median PFS of 8.2 months (95% CI: 2.8–NR) and 2.8 months (95% CI: 2.6–5.5) and median OS of 32.8 months (95% CI: 12.2–NR) and 12.3 months (95% CI: 3.9–28.5), respectively (Supplementary Fig. 1). In the MTC cohort, male patients had a median PFS of 3.0 months (95% CI: 2.8–15.7) and a median OS of 35.1 months (95% CI: 19.5–NR), whereas female patients had a median PFS of 23.2 months (95% CI: 5.3–NR) and a median OS that was not reached. For the ATC cohort, the median OS was 7.5 months (95% CI: 3.1–NR) for males and 20.8 months (95% CI: 13.8–NR) for females.

The ORR for the DTC, MTC, and ATC cohorts were 8%, 10%, and 33%, respectively, with no CR recorded (Fig. 3 and Supplementary Table 3). The response status at 6 and 12 months were 9% and 8% for the entire cohort, 3% and 3% for the DTC cohort, 10% and 10% for the MTC cohort, and 25% and 17% for the ATC cohort, respectively. The ORR in patients with liver metastasis was 8.3% (1/12). The single patient in this group who showed an objective response had papillary thyroid carcinoma. In the DTC cohort, two patients who showed objective responses had papillary tumours, and one had an oncocytic subtype. Median DoR for the DTC, MTC, and ATC cohorts was 19.3 (interquartile range [IQR]=18.7), 28.0 (IQR=13.2), and 5.7 (IQR=14.9) months, respectively.

Nine patients survived for at least four years from treatment initiation (Supplementary Figure 2), and eight were still alive at the time of data cutoff (May 2024). Of these nine patients, three had DTC. All three patients with DTC had liver metastases at the time of study enrolment and a history of radioiodine therapy. Among the long-term survivors with DTC, one patient with follicular histology, who was initially diagnosed with metastatic disease, showed disease progression and was ongoing, the second patient with follicular histology showed disease progression and subsequently died, and the patient with oncocytic histology remained progression-free throughout the study observation period. Four long-term survivors had MTC. Of these, one patient remained progression-free and was ongoing, whereas the other three showed disease progression and were alive at the time of the data cutoff. The two long-term survivors with ATC showed disease progression but were still alive, with survival times of 55.4 and 57.2 months, respectively. Among the long-term survivors who showed disease progression, one patient with ATC did not receive subsequent treatment, whereas the other seven received different treatments, mostly TKIs. The details of all treatment regimens administered to the patients after progression to the study treatment are shown in Supplementary Table 4.

No significant difference in 6-month PFS was observed between patients with and without liver metastasis (34.8% [95% CI, 19.9–80.9] for patients with liver metastasis vs. 39.5% [95% CI, 28.0–55.9] for those without liver metastasis). Similarly, the 6-month OS rates did not differ significantly between the two groups (75.6% [95% CI, 60.3–94.7] vs. 81.1 % [95% CI, 71.1–92.4] for patients with and without liver metastasis, respectively) (Supplementary Fig. 3). Although patients with imAEs had numerically lower hazard ratios (HR) for both PFS and OS, these associations did not reach statistical significance when analysed as time-dependent variables (PFS: HR = 0.75, 95% CI: 0.45–1.25, p=0.273; OS: HR = 0.61, 95% CI: 0.34–1.10, p=0.103).

Among the 10 patients who showed treatment responses, four (40%) were PD-L1 positive (Fig. 3, Supplementary Data 1). Of the ten patients, one with oncocytic carcinoma had MSI and was PD-L1 negative. Among patients with ATC who showed treatment responses, two (50%) were PD-L1 positive and two did not have a sufficient amount of tumour samples to allow for the assessment of PD-L1 status. RET status was locally assessed in 15 patients with MTC (50.0%), of whom 11 (73.3%) had mutations. Data on RET status were available for one patient with MTC who achieved an objective response, and the data showed no RET mutations. In the ATC cohort, data on BRAF status were available for eight (66.7%) patients. Notably, among the four patients who achieved an objective response, only two had available data on BRAF status: one with BRAF wild type and the other with BRAFV600E. BRAK/MEK inhibitors were administered prior to two patients with ATC, one for a duration of one week and another for 11 months. Durvalumab and tremelimumab provided in these two patients a PFS interval of 3 and 10 months after BRAF/MEK inhibitors, respectively.

Safety profile
At the time of the data cutoff, eight patients (10.1%) remained on study treatment. The reasons for treatment discontinuation included disease progression (54 patients [68.4%]), unacceptable toxicity (seven patients [8.9%]), death (six patients [7.6%]), patient’s decision (three patients [3.8%], two of them withdraw the consent), and loss to follow-up (one patient [1.3%]). The median number of treatment cycles administered to all treated patients was five (range: 1–66) for durvalumab and four (range: 1–4) for tremelimumab. Regarding the management of TRAEs, durvalumab treatment was delayed in 12 patients (15.2%), whereas tremelimumab treatment was delayed in seven patients (8.7%). Durvalumab cycles were omitted in four patients (5.1%), whereas tremelimumab cycles were omitted in two patients (2.5%).

A total of 49 patients died. Of these, 39 (79.6%) died due to disease progression and seven (14.3%) due to adverse events unrelated to treatment. The cause of death was unspecified in two (4.1%) patients. One patient died due to dyspnoea; notably, a causal relationship with the study treatment could not be established. The most frequent TRAEs observed in the entire study cohort were dermatological events (44.3% of patients), fatigue (20.3%), diarrhoea (15.2%), and elevated hepatic enzyme levels (11.4%) (Fig. 4 and Supplementary Table 5). All TRAEs were managed with standard supportive measures. The toxicity profiles of the treatments were comparable across cohorts, and no additional safety signals were observed. Grade ≥3 TRAEs occurred in 19.0% of patients, with the most frequent being fatigue (2.5%), encephalitis (2.5%), and arthritis (2.5%). Serious adverse events (SAEs) were experienced by 43 (54.4%) patients, and they mainly included dyspnoea (6.3%), diarrhoea (6.3%), fever (3.8%), and fatigue (3.8%). Grades 1–2 SAEs were experienced by 14 patients (17.7%), 50% of whom may have been related to COVID-19. Grade ≥3 imAEs occurred in six (7.6%) patients (Supplementary Table 6).

Methods
Trial design and patients
This trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol was approved by the competent authority in Spain (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) and the independent ethics committee of Vall d'Hebron University Hospital on 20 February 2019 (Ref. 2019/369). Written informed consent was obtained from all patients prior to their enrolment in the study.

The DUTHY/GETNE T-1812 trial (EudraCT: 2018-001066-42; ClinicalTrials.gov: NCT03753919; published 22 November 2018) was a phase II, single-arm, multi-cohort trial with three parallel cohorts conducted by the Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE) in 15 reference centres in Spain. Patients with confirmed locally advanced or metastatic thyroid carcinoma were recruited into the following three cohorts: patients with DTC (including papillary, follicular, poorly differentiated, and oncocytic tumours) who showed disease progression to systemic therapy with lenvatinib or at least two MKIs, including or not lenvatinib (Cohort 1); patients with MTC who showed disease progression to systemic therapy with vandetanib or at least two MKIs, including or not vandetanib (Cohort 2); and patients with ATC regardless of prior therapy (Cohort 3). Data on the use of cabozantinib for DTC and selpercatinib for MTC were not available at the time of study design. The primary inclusion criteria for this study were as follows: age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, body weight >30 kg, life expectancy >3 months, and adequate organ and bone marrow function. Female patients were required to be postmenopausal or have a negative urinary or serum pregnancy test within 72 h prior to the first dose of the study treatment. The main exclusion criteria were previous treatment with a PD-1, PD-L1, or CTLA-4 inhibitor; history of immunotherapy; immunodeficiency or use of any immunosuppressive medication within 28 days before the first dose of durvalumab/tremelimumab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses not higher than 10 mg/day of prednisone or its equivalent; concurrent use of cancer treatments or investigational products; and a history of allogeneic organ transplantation. A complete list of eligibility criteria is provided in the study protocol.

Procedures
Patients received durvalumab 1500 mg intravenously (IV) every four weeks plus tremelimumab 75 mg IV every four weeks for up to four cycles, followed by durvalumab monotherapy every four weeks until disease progression was confirmed according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, unacceptable toxicity, or withdrawal of consent, whichever occurred first (Supplementary Fig. 4). The dosages were selected using pharmacokinetic models developed with data from a phase 1 study for durvalumab 39, and phase 1 to 3 for tremelimumab 40. The rationale for the selected scheme was provided by previous clinical trials with dual ICI in patients with advanced melanoma and phase 1 trials with durvalumab plus tremelimumab 41. Dose delays (≤12 weeks) or omissions were permitted for the management of toxicity. Dose reduction was not permitted.

Clinical assessments, including a complete physical examination, measurement of vital signs, laboratory tests (blood chemistry, haematology, and thyroid function), and evaluation of ECOG performance status, were performed during the initial screening, every two weeks during treatment with durvalumab plus tremelimumab, and every four weeks during maintenance with durvalumab monotherapy until the end of treatment. All patients provided archival formalin-fixed paraffin-embedded tumour tissue samples. Blood samples for biomarker analysis were collected during screening visits, on day one of the second treatment cycle, and at the end of treatment. Tumour response was assessed using computed tomography or magnetic resonance imaging scans and categorised according to RECIST 1.1. Tumour response was assessed at baseline and every 12 weeks until disease progression or death was confirmed, irrespective of dose delays.

Outcome measures
The primary study endpoint was the 6-month progression-free survival (PFS) rate for the DTC and MTC cohorts and the 6-month OS rate for the ATC cohort. For the DTC and MTC cohorts, the primary endpoint was considered met if a 6-months PFS rate of 45% was achieved. For the ATC cohort, the primary endpoint was considered met if a 6-months OS of 35% was achieved. The 6-month PFS rate was defined as the percentage of patients who remained alive and disease progression-free at six months, whereas the 6-month OS rate was defined as the percentage of patients who remained alive at six months after the start of the study treatment.

The secondary endpoints were overall response rate (ORR), defined as patients who achieved partial response (PR) or complete response (CR); duration of response (DoR), defined as the time from the first PR/CR to disease progression or the last tumour assessment; median PFS, defined as the time from the start of treatment until disease progression or death (patients without events were censored at the last tumour assessment); median OS, defined as the time from the start of treatment until death (patients without events were censored at the last follow-up); response status at six and 12 months after the start of treatment, defined as the percentage of patients who showed treatment response at each timepoint; 18-month PFS rate, defined as the percentage of patients who remained alive and disease progression-free at 18 months; 18-month OS rate, defined as the percentage of patients who remained alive at 18 months after the start of the study treatment; and safety profile. Tumour response was assessed using the RECIST 1.1 and irRECIST 1.1. No significant differences were observed between the two evaluation methods (Supplementary Table 3); therefore, the results reported in this study were evaluated using the RECIST 1.1. The prognostic value of biomarkers was established as an exploratory objective. As liver metastasis has been related to poorer outcomes in patients with solid cancers treated with immunotherapy 35, a post-hoc analysis of the prognostic value of the presence of liver metastases was included.

For safety analysis, all treatment-related adverse events (TRAEs) were coded and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0.

Molecular Assessments
Different exploratory analyses of biomarkers were performed to further categorise patients who responded to treatment. PD-L1 staining was performed using the VENTANA PD-L1 (SP263) assay (Cat. No. 741-4905 / 07419821001; Ventana Medical Systems, Inc. Roche) on the VENTANA BenchMark ULTRA automated staining platform, using the OptiView DAB IHC detection kit (Cat. No. 760-700/06396500001). All immunohistochemically stained sections were reviewed and scored by a board-certified pathologist. PD-L1 expression was assessed using the combined positive score (CPS), with positivity defined as CPS ≥1. CPS was calculated as the number of PD-L1-positive tumor and immune cells divided by the total number of viable tumor cells, multiplied by 100. Central revision of the microsatellite instability (MSI) phenotype using immunohistochemistry (IHC) was performed for patients who showed an objective response according to the following ESMO recommendations: loss of nuclear expression of at least one of the following proteins: MLH1 (Roche, cat n°: 760-5091), MSH6 (Roche, cat n°: 760-5092), PMS2 (Roche, cat n°: 760-5094), and MSH2 (Roche, cat n°: 760-5093). BRAFV600 was locally assessed at each site using next-generation sequencing (NGS), IHC, real-time PCR, or the Idylla BRAF Mutation Test. The RET M918T mutation in patients with MTC and RET fusions in patients with DTC were assessed locally using NGS.

Statistical Analysis
Simon’s two-stage design (Minimax) was used for sample size estimation in this study.42 Considering the information in previous studies,6 the null hypothesis assumed a 6-month PFS rate of 25% for the DTC and MTC cohorts based on historical data, whereas the target for the experimental therapy was a 45% rate. Calculations using a one-sided ɑ of 5% and 80% power showed that 36 patients per cohort were required. Per Simon’s criteria, progression to the second stage required ≥5 of the first 17 patients per cohort to be progression-free at 6 months. A single-stage design was implemented for the ATC cohort. Assuming a historical 6-month OS rate of 5% and an anticipated improvement to 35% (one-sided ɑ=5%, power=80%), 12 patients were needed and ≥3 patients alive at 6 months to declare the study positive.

Efficacy and safety analyses were conducted using the full analysis set, which included all patients. The response rates were calculated as the percentage of patients who achieved a response and their 95% CI was estimated using the Clopper–Pearson method. PFS and OS were estimated using the Kaplan–Meier method and Cox proportional model, and comparisons were tested using log-rank tests (Mantel-Cox). The 18-month PFS rate was defined as the percentage of patients who remained alive and disease progression-free at 18 months, whereas the 18-month OS rate was defined as the percentage of patients who remained alive at 18 months after the start of the study treatment. Patients without event at the data cutoff point were censored at the last tumour assessment for PFS and at the last follow-up for OS analysis. Although the protocol planned the estimation of primary endpoints using binomial calculations, some tumor assessments and survival follow ups were performed within +/- 1 month from the 6 month expected time point due to changes in scheduled visits per patient or site availability, or different clinical courses of the disease, so the sponsor decided that Kaplan Meier estimated would give a more accurate estimation at 6 months. Binomial calculations are listed in Supplementary table 7. The presence of immune-mediated adverse events (imAEs) was introduced as a time-dependent variable in a Cox proportional model to analyse the relationship between imAEs and PFS. Primary statistical tests were one-tailed and other statistical tests used for efficacy and safety analyses were two-tailed, and results with p-values <0.05 were considered significant. Data were collected through the MFAR eCRF system. All statistical analyses were performed using R (version 3.6.3 [2020-02-29]; The R Foundation for Statistical Computing, Vienna, Austria).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This is a very interesting phase II, single-arm, multi-cohort trial was conducted to 70 determine whether dual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can improve the clinical outcomes in advanced thyroid cancer. The results of this trial are specifically meaningful to the ATC cohort of patients particularly the BRAF wild type ones for who no meaningful drugs are available. I have provided specific questions in the attached edited version of manuscript but the main points to focus on are:\n1. The methods state that 18 month PFS would be reported for ATC but the results is missing that. Honestly, having methods above results is preferred mainly because one can refer results to methods and make sure the questions asked in the methods are answered. however, i did see that this format is the journal preference.\n2. The reference 22 is incorrect- they did not use ICI with DT. Please consider replacing with Hamidi S, Iyer PC, Dadu R, Gule-Monroe MK, Maniakas A, Zafereo ME, Wang JR, Busaidy NL, Cabanillas ME. Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAFV600E-Mutated Anaplastic Thyroid Carcinoma. Thyroid. 2024 Mar;34(3):336-346. doi: 10.1089/thy.2023.0573. Epub 2024 Feb 13. PMID: 38226606.\n3. They mention patients with the BRAF mutation were included in the study. It would be nice to know in the discussion- how long were these patients on BRAF directed therapy before they were started on Durvalumab and tremelimumab.\n4. They focused on outcomes in patients with liver mets. Have they seen a difference in outcomes in patients with brain mets veruss those without?\n5. They mentioned patients with DTC and MTC that progressed. what treatments were they transitioned to once they were off study?\n6. Also they included PFS data for DTC and MTC- given the meaningful end point of OS with ATC, and the fact that their 18 months PFS was supposed to be studied per methods- they should report the ATC patients PFS esp if it was less than 18 months.\n7. Line 455- states\"baseline levels of key biomarkers in tumour 455 tissue and blood samples were correlated with efficacy outcomes\" - what and how was this done- what biomarkers were used and these have not been described in results- please mention these.\n8. Line 484 states: \"Assuming a historical 6- month OS rate of 5% and an anticipated improvement to 35% (one-sided .=5%, 485 power=80%), 12 patients were needed.\" - what reference was used to show an improvement to 35%- please cite this", "reviewer_2": "This phase II, single-arm trial evaluated whether dual PD-L1/CTLA-4 blockade with durvalumab and tremelimumab could improve clinical outcomes in advanced thyroid cancers. Patients with DTC (n = 37) and MTC (n = 30) and progressive metastatic disease under prior standard systemic therapy were included, along with 12 ATC patients enrolled regardless of previous therapy.\nGiven the extremely poor prognosis of ATC and the limited efficacy of currently available systemic treatments, the outcomes observed in the ATC cohort are particularly encouraging, with a 6-month OS rate of 65.6% and an overall response rate of 33%. However, efficacy in the DTC and MTC cohorts was modest, with 6-month PFS rates of 38.8% and 35.1%, respectively.\nAs few studies have assessed the efficacy of immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies, in thyroid cancers, this trial is of particular interest. An OS of 13.8 months and an 18-month survival rate of 46.9% highlight a clinically meaningful benefit of ICIs on overall survival in patients with ATC. The efficacy of the study treatment in the DTC and MTC cohorts remained modest, with 6-month PFS rates of 38.8% and 35.1%, respectively, as appropriately acknowledged in the discussion section.\n\nMajor Comments\n• ATC patients were included regardless of BRAF status and prior therapy. As the ATA guidelines recommend: “In BRAFV600E-mutated stage IVC and unresectable stage IVB ATC patients who decline radiation therapy, initiation of BRAF/MEK inhibitors (dabrafenib plus trametinib) is recommended over other systemic therapies if available.” Please specify the BRAF status of the ATC patients included. For BRAFV600E-mutated ATC cases, justify management outside the scope of ATA recommendations.\n• Specify the progression interval before inclusion for the DTC and MTC cohorts.\n• The authors stated: “Durvalumab plus tremelimumab treatment in patients with ATC met the primary endpoint of this study, showing encouraging survival outcomes.” Please clarify in the Methods section what “meeting the primary endpoint” precisely means.\n\nMinor Comments\n• “Patients received durvalumab 1500 mg intravenously (IV) every four weeks plus tremelimumab 75 mg IV every four weeks for up to four cycles, followed by durvalumab monotherapy every four weeks.” Please justify the choice of these dosages and regimen.\n• Are any pharmacokinetic or pharmacodynamic data available?\n• Among patients who died during the study, the cause of death was not specified for 6 of 49 cases (12%). This proportion appears high for a prospective study involving close follow-up of patients with advanced cancer.\n• Limited information is provided regarding tumor mutational burden, CPS scores, or TPS scores. Are these data available?\n• Few data are presented on molecular alterations in the included cancers. Consider adding a table (possibly as supplementary material) listing key genetic drivers identified across cancer types (e.g., BRAF, RAS mutations, gene fusions, etc.). Please also specify the type of genetic testing performed (presumably NGS?).\n• The authors mention RET fusions in MTC. As this event is exceptionally rare in MTC, please confirm whether any MTC cases harbored a RET fusion and specify the fusion type identified.\n• Consider adding the following clarification in the Methods section: “Patients with locally advanced or metastatic ATC were included regardless of prior therapy.”\n• Was there a centralized pathological review of tumor samples?\n• From what percentage of a poorly differentiated component was a cancer classified as “poorly differentiated”?\n• If correctly understood, two of the ten ATC patients underwent total thyroidectomy prior to inclusion. Histologically, were these tumors fully undifferentiated, or did they contain an undifferentiated component within a poorly or well-differentiated carcinoma?\n• Can the authors provide MTC grading according to the publication J Clin Oncol. 2021 Nov 3;40(1):96–104. doi:10.1200/JCO.21.01329?\n• The authors stated: “Previous studies on durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) for the treatment of neuroendocrine neoplasms yielded modest but clinically meaningful survival outcomes in a subset of patients with poorly differentiated carcinomas, along with a manageable safety profile.20,21” Reference 21 does not appear to concern neuroendocrine tumors.\n• The captions of Figure 3 regarding RET, PD-L1, BRAF, and MSI status are misaligned.\n• The authors stated: “The combination of an anti-PD-1 agent with BRAF/MEK inhibitors or other MKIs yields objective responses in patients with ATC, often with a manageable safety profile.22,25” Reference 22 does not seem to support this statement.\n• The authors stated: “In this study, durvalumab plus tremelimumab showed modest efficacy in the MTC cohort, with survival outcomes inferior to those previously reported for MKIs.8,9,31.” However, in reference 31, all MTC patients were treated with selpercatinib as first-line therapy, and in references 8 and 9, 61% and 78% of patients, respectively, received vandetanib or cabozantinib as first-line therapy. Please provide bibliographic references of therapeutic trials conducted in pre-treated MTC patients, as in your study, for an appropriate comparison, as far as possible.\n• In Table 1, check the percentages (e.g., for well-differentiated/poorly differentiated/unknown categories, and for ATC where totals exceed 100% [100 + 8.3%]; for MTC, 26.3 + 5.3 + 76.7 > 100%).\n• Clarify in Table 1 whether “previous surgery” refers to total thyroidectomy or another type of surgical intervention.\n• Consider including the median duration of response in Table 2 to provide a concise overview of key efficacy results.\n• Did any ATC patients receive neck irradiation prior to inclusion?", "reviewer_3": "This is the statistical review for a single-arm trial with 3 cohorts (DTC/MTC/ATC) aiming to demonstrate efficacy based on 6-months PFS/OS rates. Only for the ATC cohort, the primary endpoint was successfully demonstrated. The MTC arm stopped recruitment prematurely.\nThere are several aspects in the description of methods and presentation of results that need to be addressed.\nThere is a discrepancy between how the trial was planned and how the primary endpoint is reported. The original sample size estimation was based on Simon’s two stage design for binomial endpoints for DTC/MTC arms, and as single stage design for ATC with binomial endpoint, using 6-months PFS (DTC/MTC) and 6-months OS (ATC) rates. Primary endpoints are reported based on KM estimates, i.e. for time-to-event endpoints accounting for censoring. While I agree with using KM estimates, this discrepancy should be pointed out.\nPlease provide not only the percentage but also the absolute number of patients with PD/Death for the primary endpoints for all cohorts, including the number of censored patients.\nPlease provide a reference for the assumption of a 6-month OS rate of 5% for the ATC arm. I could not find those in the manuscript or study protocol.\nPlease include the number of pts needed to be alive after 6 months out of 12 patients for the single stage design in cohort 3 according to the sample size planning.\nThe primary endpoint is planned for a one-sided alpha of 5%, so the statement ‘All statistical tests used for efficacy and safety analyses were two-tailed and results with p-values <0.05 were considered significant’ is not correct.\nRECIST/ Suppl table 1: According to the study protocol, RECIST 1.1 will be used for response assessment. I think, this should be the reason why the primary endpoints are reported based on RECIST, not the strong agreement with irRECIST 1.1.\nIn the discussion, the authors state ‘exploratory biomarker analyses were performed to identify potential predictors of the response. These results suggest that emerging biomarkers, including PD-L1 expression and MSI status, may help refine patient selection.’ Apart from the annotation shown in figure 3 I could not find any analysis on these data, or any analysis supporting this statement. In fact, biomarker is rather scarce and not done for the majority of patients.\nAgreement analysis. A significant kappa > 0 is not the same as ‘No significant differences were observed between the two evaluation methods’. Please rephrase this.\nThe Clopper-Pearson method for CIs is not adequate for censored data.\nPlease specify the date of data cut-off for the analysis.\nResults on time-dependent analysis of imAEs (line 182/183): Please correct, it is the occurrence of imAEs and not the endpoint PFS/OS which is analysed as time-dependent factor.\nFigure 3a/b waterfall plots: numbers do not add up, it should be 32 DTC patients etc but it is less."}, "author_response": "Reviewer 1: This is a very interesting phase II, single-arm, multi-cohort trial was conducted to 70 determine whether dual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can improve the clinical outcomes in advanced thyroid cancer.\nThe results of this trial are specifically meaningful to the ATC cohort of patients\nparticularly the BRAF wild type ones for who no meaningful drugs are available.\nAuthors’ response: The authors want to sincerely thank reviewer 1 for the time\nand dedication invested in reviewing our manuscript. We deeply value your\ncomments and especially appreciate your recognition of the study's interest\nand the clinical relevance of the results obtained, particularly for the cohort of\npatients with BRAF wild-type anaplastic thyroid carcinoma (ATC), who\ncurrently lack effective therapeutic options and performed quite well in this\nstudy. Your comments motivate us to continue research in this area with the\ngoal of offering meaningful therapeutic alternatives for this patient\npopulation with unmet medical needs.\nPlease accept our warmest regards and, once again, our thanks for your\nvaluable contribution.\nReviewer 1: I have provided specific questions in the attached edited version of\nmanuscript but the main points to focus on are:\n1. The methods state that 18 month PFS would be reported for ATC but the\nresults is missing that. Honestly, having methods above results is preferred\nmainly because one can refer results to methods and make sure the\nquestions asked in the methods are answered. However, I did see that this\nformat is the journal preference.\nAuthors’ response: The 18-month rate for PFS and OS are placed in Table 2. This\ntable summarizes the main efficacy endpoints of our study. Following your\nrequest further information is given in the main text. Thank you so much.\nReviewer 1:\n2. The reference 22 is incorrect- they did not use ICI with DT. Please consider\nreplacing with Hamidi S, Iyer PC, Dadu R, Gule-Monroe MK, Maniakas A,\nZafereo ME, Wang JR, Busaidy NL, Cabanillas ME. Checkpoint Inhibition in\nAddition to Dabrafenib/Trametinib for BRAFV600E-Mutated Anaplastic\nThyroid Carcinoma. Thyroid. 2024 Mar;34(3):336-346. doi:\n10.1089/thy.2023.0573. Epub 2024 Feb 13. PMID: 38226606.\nAuthors’ response: Thank you for your comment and for providing this\nvaluable citation. The reference has been replaced.\nReviewer 1:\n3. They mention patients with the BRAF mutation were included in the study.\nIt would be nice to know in the discussion- how long were these patients on\nBRAF directed therapy before they were started on Durvalumab and\ntremelimumab.\nAuthors’ response: We agree that this information would be interesting.\nAmong the 6 patients with known BRAF mutated status, two received\ndabrafenib plus trametinib for a week and 11 months. Some information has\nbeen added following your request to results and discussion sections:\nBRAK/MEK inhibitors were administered prior to two patients with ATC, one for a\nduration of one week and another for 11 months. Durvalumab and tremelimumab\nprovided in these two patients a PFS interval of 3 and 10 months after BRAF/MEK\ninhibitors, respectively.\nThe two patients with ATC who received prior BRAF/MEK inhibitors showed\npromising PFS with durvalumab and tremelimumab, suggesting ICI is yet a\nvaluable option after failure of TKIs in these patients.\nReviewer 1:\n4. They focused on outcomes in patients with liver mets. Have they seen a\ndifference in outcomes in patients with brain mets versus those without?\nAuthors’ response: Brain metastases are always of interest and are related\nwith worse prognosis. However, taking into account the bad prognosis of the\npatients with ATC and the patients with DTC and MTC who progressed to 2\nprior systemic treatments, and the inclusion criteria of a life expectancy >3\nmonths, patients with brain metastasis were probably excluded. Additionally,\nbrain metastases are not so common among patients with thyroid cancers.\nOnly one patient, with follicular subtype, had a target or non target lesion\nlocated in the brain.\nFor the study of immune checkpoint inhibitors, liver metastases are of interest\nbecause the liver mostly has a “cold” immune microenvironment that limits\nthe expected effect of ICI through the increased immune surveillance. The\nhigher rate of CD8+ regulatory lymphocytes in the liver help to reduce the\npotential immune-mediated antitumoral response evoked by ICIs .\nReviewer 1:\n5. They mentioned patients with DTC and MTC that progressed. what\ntreatments were they transitioned to once they were off study?\nAuthors’ response: These patients were followed until study closure and all the\nsubsequent treatments are listed on Supplementary Table 2:\nDTC MTC ATC\nn=3 n=4 n=2\nBlinded clinical trial 1 (33%) 1 (25%) -\nCabozantinib 1 (33%) 1 (25%) -\nLenvatinib 2 (67%) - -\nSelpercatinib - 2 (50%) -\nCarboplatin - - 1 (50%)\nTaxol 1 (33%) - 1 (50%)\nGemcitabine - - 1 (50%)\nPegylated liposomal doxorubicin - - 1 (50%)\nRadiotherapy 1 (33%) - -\nNo subsequent treatment - - 1 (50%)\nTo make more clear the availability of this information, we modified the\nfollowing sentence:\nThe details of all treatment regimens administered to the patients after\nprogression to the study treatment are shown in Supplementary Table 4.\nReviewer 1:\n6. Also they included PFS data for DTC and MTC- given the meaningful end\npoint of OS with ATC, and the fact that their 18 months PFS was supposed\nto be studied per methods- they should report the ATC patients PFS esp if it\nwas less than 18 months.\nAuthors’ response: We agree that the PFS for patients with ATC should be\nreported. The median PFS for patients with ATC is placed in Table 2 and,\nfollowing your suggestion, is given in the main text.\nReviewer 1:\n7. Line 455- states\"baseline levels of key biomarkers in tumour 455 tissue and\nblood samples were correlated with efficacy outcomes\" - what and how was\nthis done- what biomarkers were used and these have not been described\nin results- please mention these.\nAuthors’ response: Thank you for your comment. We acknowledge that this\nsentence is too vague. We deleted the phrase because it is unnecessary, we\nexplained the exploratory analyses in the section “Molecular Assessments”.\nWe included correlative analysis of PD-L1 expression, presence of MSI and RET\nfusions with the efficacy outcomes. Results are reported within the\nmanuscript.\nReviewer 1:\n8. Line 484 states: \"Assuming a historical 6- month OS rate of 5% and an\nanticipated improvement to 35% (one-sided .=5%, 485 power=80%), 12\npatients were needed.\" - what reference was used to show an improvement\nto 35%- please cite this.\nAuthors’ response: This is extrapolated from the standard treatment practice.\nClassical studies with chemotherapy reported dismal OS, with 6-months OS\nrates of approximately 5% 1-2. We may agree that an improvement to 35%\nwould be considered clinically meaningful as ⅓ of patients will increase their\nlife expectancy regarding other standard options and more in such a\npretreated population. Spartalizumab showed an OS rate of 40% at one year\nin ATCs 3.\nRefs:\n1. Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R. A randomized trial\nof doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid\ncarcinoma. Cancer. November 1, 1985;56(9):2155–2160.\n2. Sosa JA, Elisei R, Jarzab B, Balkissoon J, Lu S-P, Bal C, et al. Randomized safety and\nefficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic\nthyroid carcinoma. Thyroid Off J Am Thyroid Assoc. February 2014;24(2):232–240.\n3. Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin C-C, Ramlau R, et al. PD-1 Blockade\nin Anaplastic Thyroid Carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. August 10,\n2020;38(23):2620–2627.\nReviewer 1. Questions from the attached document:\nThe following questions are comments placed on the document attached\nreviewer_1_attachment_1760599799_41.\nReviewer 1 (lines 105-107): please cite references- spartalizumab study, keynote for\nsingle agent pembrolizumab.\nAuthors’ response: Thank you for your suggestion. These two references have\nbeen included:\n1. Oh, D.-Y. et al. Efficacy and safety of pembrolizumab monotherapy in patients with\nadvanced thyroid cancer in the phase 2 KEYNOTE-158 study. Cancer 129, 1195–1204\n(2023).\n2. Capdevila, J. et al. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol 38,\n2620–2627 (2020).\nReviewer 1 (line 121): the methods section is missing\nAuthors’ response: as per Nature journal guidelines, the methods are placed\nafter the discussion.\nReviewer 1 (line 132): what were the eligibility criteria? Why was the PFS for ATC\nnot studied or mentioned in methods or results?\nAuthors’ response: Eligibility criteria are mentioned in the Methods section.\nWe focused on overall survival for the ATC cohort. However, the PFS for ATC\nwas also reported in Table 2:\nDTC MTC ATC\nOutcomes\nn= 37 n = 30 n = 12\nMedian PFS; months (95% CI) 3.7 (2.7-6.5) 5.3 (2.8-23.2) 3.6 (2.2-NR)\n6-month PFS rate; % (95% CI) 32.4 (20.4-51.6) 40.9 (26.3-63.6) 33.3 (15.0-74.2)\n18-month PFS rate; % (95% CI) 6.0 (1.6-22.6) 26.5 (13.6-51.6) 8.3 (1.3-54.4)\nMedian OS; months (95% CI) 13.8 (9.4-32.8) 35.5 (30.1-NR) 13.8 (5.7-NR)\n6-month OS rate; % (95% CI) 70.3 (56.7-86.7) 96.6 (90.1-100) 65.6 (43.2-99.8)\n18-month OS rate; % (95% CI) 41.5 (28.0-61.4) 78.8 (65.3-97.5) 46.9 (25.0-87.9)\nReviewer 1 (line 139): the methods states that 18 month PFS were to be reported\nbut its not mentioned here\nAuthors’ response: We reported in the text the main endpoints. The 18-month\nrate for PFS and OS are placed in Table 2 because we believe that is more\nhelpful for the readers to find all endpoints summarized in a single place.\nReviewer 1 (line 163): what treatment was offered when they progressed?\nAuthors’ response: The subsequent treatments are listed in Supplementary\nTable 2. To make more clear the availability of this information, we modified\nthe following sentence:\nThe details of all treatment regimens administered to the patients after\nprogression to the study treatment are shown in Supplementary Table 2.\nReviewer 1 (line 176): why liver metastases were the focus here? Why not brain\nmets?\nAuthors’ response: Despite brain metastases being always of interest, they\nwere present only in one patient. Liver metastases are a known factor that\ncan reduce the efficacy of ICIs, making it of special interest to study.\nReviewer 1 (line 195): Did they receive BRAF directed therapy before getting on\nthis? how long were they on BRAF therapy\nAuthors’ response: We agree that this information would be interesting.\nFurther information has been added. No responses were reported among\npatients receiving previous BRAF/MEK inhibitors\nReviewer 1 (line 200): at what point in their trial did they withdraw consent. Was\ndata censored to the date of withdrawal?\nAuthors’ response: Reviewing the data, we noticed that the reason for the end\nof treatment was the patient's decision. One patient was followed until study\nclosure and the other two withdrew their consent. This data has been clarified\nin the manuscript:\nThe reasons for treatment discontinuation included disease progression (54\npatients [68.4%]), unacceptable toxicity (seven patients [8.9%]), death (six patients\n[7.6%]), patient’s decision withdrawal of consent (three patients [3.8%], two of them\nwithdraw the consent), and loss to follow-up (one patient [1.3%]).\nFor the patients who withdrew their consent, the data was censored to the\ndate of withdrawal. One patient decided to finish the treatment before the\nsecond cycle and the two others at cycle 10 and 20 with durvalumab.\nReviewer 1: please cite hamidit et al. checkpoint inhibitor combined with anti-PD1.\nref 22 is incorrect- they didn’t use ICI\nAuthors’ response: Thank you for your comment and for providing this\nvaluable citation. The reference has been replaced.\nReviewer 1 (line 268): why?\nAuthors’ response: Due to the better efficacy shown with dual ICI over single\nICI in several solid tumours, dual ICI were substituting single ICI treatments.\nHowever, our results do not support the addition of the second ICI suggesting\nthat single therapeutic strategies may provide similar efficacy with lower\ntoxicity and economic cost.\nReviewer 1 (line 370): this needs to be moved above the results.\nAuthors’ response: Per guidelines, the journals belonging to the Nature family\nput the Methods section after Discussion.\nReviewer 1 (line 428): why not ATC?\nAuthors’ response: For DTC and MTC there were previous investigations\nproviding rationale for the use of PFS. However, in patients with ATC, due to\nthe aggressive nature of the disease, with no standard therapy showing\nbenefit, and an expected OS of 3-4 months, 6-month OS rate could provide\nbetter evidence of a potential benefit.\nReviewer 1 (line 442): this is not reported in results\nAuthors’ response: The 18-month rate for PFS and OS are placed in Table 2 and\nnow added within the main text in the results section of the manuscript. Table\n2 summarizes the main efficacy endpoints of our study.\nReviewer 1 (line 455): what were the biomarkers?\nAuthors’ response: Thank you for your comment. We acknowledge that this\nsentence is too vague. We deleted the sentence because we explained the\nexploratory analyses in the section “Molecular Assessments”.\nReviewer 1 (line 485): please cite reference\nAuthors’ response: As explained, based on previous experience with anti PD-1\nand the benchmark studies with chemotherapy reporting dismal OS rates, we\nconsider that an increase in 30% would be of clinical relevance.\nReviewer 2: This phase II, single-arm trial evaluated whether dual PD-L1/CTLA-4\nblockade with durvalumab and tremelimumab could improve clinical outcomes in\nadvanced thyroid cancers. Patients with DTC (n = 37) and MTC (n = 30) and\nprogressive metastatic disease under prior standard systemic therapy were\nincluded, along with 12 ATC patients enrolled regardless of previous therapy.\nGiven the extremely poor prognosis of ATC and the limited efficacy of currently\navailable systemic treatments, the outcomes observed in the ATC cohort are\nparticularly encouraging, with a 6-month OS rate of 65.6% and an overall response\nrate of 33%. However, efficacy in the DTC and MTC cohorts was modest, with 6-\nmonth PFS rates of 38.8% and 35.1%, respectively.\nAs few studies have assessed the efficacy of immune checkpoint inhibitors (ICIs),\nsuch as anti-PD-1 antibodies, in thyroid cancers, this trial is of particular interest. An\nOS of 13.8 months and an 18-month survival rate of 46.9% highlight a clinically\nmeaningful benefit of ICIs on overall survival in patients with ATC. The efficacy of\nthe study treatment in the DTC and MTC cohorts remained modest, with 6-month\nPFS rates of 38.8% and 35.1%, respectively, as appropriately acknowledged in the\ndiscussion section.\nAuthors’ response: The authors sincerely appreciate your valuable comments\nand feedback on our manuscript. We are pleased to learn that you find this\nphase II study of the combination of dual PD-L1/CTLA-4 blockade with\ndurvalumab and tremelimumab in advanced thyroid cancers of interest.\nWe fully agree that the results observed in the anaplastic thyroid carcinoma\n(ATC) cohort are encouraging, given the extremely poor prognosis of this\nentity and the limited therapeutic options available. The 6-month overall\nsurvival (OS) rate of 65.6% and the objective response rate of 33% suggest a\npotentially significant clinical benefit in this subgroup of patients. We\nappreciate your also highlighting the 18-month survival rate of 46.9%, which\nwe believe reinforces the clinical relevance of this treatment in ATC.\nRegarding the differentiated (DTC) and medullary carcinoma (MTC) cohorts,\nwe share your assessment that efficacy was more modest, as clearly noted in\nour discussion. Nevertheless, we believe these findings are still informative,\nconsidering that the included patients had progressive metastatic disease\nunder prior standard systemic therapy, representing a complex clinical\nscenario with unmet medical need. Furthermore, the fact that this study\nincludes a relatively representative number of patients with DTC and MTC\ntreated with ICIs in a prospective setting contributes to the currently limited\nbody of evidence in this field.\nOne of the central motivations of this study was precisely to explore the\npotential benefit of immunotherapy in thyroid cancer subtypes that have\nbeen little investigated so far. Although the results in DTC and MTC do not\nreach the magnitude observed in ATC, we believe they provide relevant\ninformation on the clinical efficacy of this therapeutic strategy, which may\nguide future research, including the development of combined strategies or\nmore personalized approaches.\nWe once again appreciate your constructive comments, which have allowed\nus to reach more deeply on the interpretation of our results and their\nrelevance in the current clinical context.\nReviewer 2: Major Comments\n ATC patients were included regardless of BRAF status and prior therapy. As\nthe ATA guidelines recommend: “In BRAFV600E-mutated stage IVC and\nunresectable stage IVB ATC patients who decline radiation therapy,\ninitiation of BRAF/MEK inhibitors (dabrafenib plus trametinib) is\nrecommended over other systemic therapies if available.”\nPlease specify the BRAF status of the ATC patients included. For\nBRAFV600E-mutated ATC cases, justify management outside the scope of\nATA recommendations.\nAuthors’ response: Our study was designed following the guidelines and\nregulations applicable in Spain. The use of BRAF/MEK inhibitors in ATCs is\ncurrently not approved either by the European Medicines Agency or the\nSpanish Agency of Medicines and Medical Devices. This situation highlights\nthe importance of our study in this orphan population. Additionally, BRAF\nmutation status was not assessed routinely in patients with advanced thyroid\ncarcinomas. This information is only available in a few cases, as shown in\nFigure 3.\nReviewer 2:\n Specify the progression interval before inclusion for the DTC and MTC\ncohorts.\nAuthors’ response: The median progression interval before inclusion has been\nadded to the Table 1:\nDTC MTC ATC GETNE-DUTHY\nCharacteristics\nn= 37 n = 30 n = 12 n = 79\nTime from last progression prior study inclusion\nMedian; months (95% CI) 0.8 (0.7-1.1) 0.9 (0.5-1.3) 0.8 (NA) 0.8 (0.7-1.1)\nReviewer 2:\n The authors stated: “Durvalumab plus tremelimumab treatment in patients\nwith ATC met the primary endpoint of this study, showing encouraging\nsurvival outcomes.”\nPlease clarify in the Methods section what “meeting the primary endpoint”\nprecisely means.\nAuthors’ response: Thank you for your suggestion, we agree that this\nclarification would improve the understanding of our results. We added the\nfollowing fragment to our text:\nFor the DTC and MTC cohorts, the primary endpoint was considered met if a 6-\nmonths PFS rate of 45% was achieved. For the ATC cohort, the primary endpoint\nwas considered met if a 6-months OS of 35% was achieved.\nReviewer 2: Minor Comments\n “Patients received durvalumab 1500 mg intravenously (IV) every four weeks\nplus tremelimumab 75 mg IV every four weeks for up to four cycles, followed\nby durvalumab monotherapy every four weeks.”\nPlease justify the choice of these dosages and regimen.\nAuthors’ response: Thank you for your suggestion. We added this information\nin Methods:\nThe dosages were selected using pharmacokinetic models developed with data\nfrom a phase 1 study for durvalumab 1, and phase 1 to 3 for tremelimumab 2. The\nrationale for the selected scheme was provided by previous clinical trials with dual\nICI in patients with advanced melanoma and phase 1 trials with durvalumab plus\ntremelimumab 3.\n1. Baverel PG, Dubois VFS, Jin CY, et al: Population Pharmacokinetics of Durvalumab\nin Cancer Patients and Association With Longitudinal Biomarkers of Disease Status.\nClin Pharmacol Ther 103:631–642, 2018\n2. Wang E, Kang D, Bae K-S, et al: Population pharmacokinetic and pharmacodynamic\nanalysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol\n54:1108–1116, 2014\n3. Antonia S, Goldberg SB, Balmanoukian A, et al: Safety and antitumour activity of\ndurvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase\n1b study. Lancet Oncol 17:299–308, 2016\nReviewer 2:\n Are any pharmacokinetic or pharmacodynamic data available?\nAuthors’ response: No pharmacokinetic analysis was conducted in our study.\nThe Pharmacokinetics of durvalumab and tremelimumab was already\ncharacterized in previous studies and is available in the Investigator Brochure.\nPKs is a classical endpoint for phase I trials and this was not in the scope of\nthis phase II study. You may also count with further information in the\nfollowing references:\n Baverel PG, Dubois VFS, Jin CY, et al: Population Pharmacokinetics of Durvalumab\nin Cancer Patients and Association With Longitudinal Biomarkers of Disease Status.\nClin Pharmacol Ther 103:631–642, 2018\n Wang E, Kang D, Bae K-S, et al: Population pharmacokinetic and pharmacodynamic\nanalysis of tremelimumab in patients with metastatic melanoma. J Clin Pharmacol\n54:1108–1116, 2014\nThe study analysed the presence of several biomarkers (PD-L1 Positivity, MSI\nand presence of RET genetic alterations) and correlated them with efficacy\nendpoints. This was an exploratory objective. The genetic alterations are\nshown in Figure 3.\nWe showed some results but due to the small number and the limited number\nof samples analyzed the interpretability of these exploratory endpoints had\nlow impact. This has been shown as a constraint of the study in the discussion:\nFourth, patients who showed treatment response were included in the biomarker\nanalyses; therefore, the possibility of post-hoc selection bias cannot be completely\nexcluded. However, these analyses were exploratory, and the results were\ninterpreted cautiously.\nReviewer 2:\n Among patients who died during the study, the cause of death was not\nspecified for 6 of 49 cases (12%). This proportion appears high for a\nprospective study involving close follow-up of patients with advanced\ncancer.\nAuthors’ response: Thank you for your comment. We revised the causes of\nexitus with the participant centers. Three of them died due to disease\nprogression and other due to an adverse event not related to treatment. The\nother two patients died at home and unfortunately were lost to follow-up. The\nCOVID-19 pandemic possibly difficulted a complete follow-up of these\npatients. This information has been updated in the manuscript.\nReviewer 2:\n Limited information is provided regarding tumor mutational burden, CPS\nscores, or TPS scores. Are these data available?\nAuthors’ response: The data available is limited. We introduced the\ninformation as Supplementary table 3 and already discussed this as a limiting\nfactor in the discussion. This was an investigator-initiated study and the\nbudget for translational research was very limited, precluding the extensive\nmolecular profiling of all patients.\nReviewer 2:\n Few data are presented on molecular alterations in the included cancers.\nConsider adding a table (possibly as supplementary material) listing key\ngenetic drivers identified across cancer types (e.g., BRAF, RAS mutations,\ngene fusions, etc.). Please also specify the type of genetic testing performed\n(presumably NGS?).\nAuthors’ response: Please, consult the new table added as a Supplementary\nTable 3. The techniques used are also disclosed in the methods section,\nmolecular analysis subsection.\nReviewer 2:\n The authors mention RET fusions in MTC. As this event is exceptionally rare\nin MTC, please confirm whether any MTC cases harbored a RET fusion and\nspecify the fusion type identified.\nAuthors’ response: Thank you for your comment.In patients with DTC only RET\nfusions were detected, while in patients with MTC there were detected only\nRET mutations. No RET fusions are detected in MTCs, only in DTCs. RET\nmutations occur in an elevated percentage of patients with MTC (above 50%),\nspecially in advanced disease in which some studies reported a prevalence of\nthe mutation of up to 80%. These RET mutations were detected in eleven\n(73.3%) patients with MTCs. RET inhibitors such as selpercatinib and\npralsetinib are viable treatment options for these patients. The available\ninformation has been added to Supplementary Table 5. The manuscript has\nbeen revised and the following texts have been corrected for more clarity:\nIn Efficacy Results:\nRET status was locally assessed in 15 patients with MTC (50.0%), of whom 11 (73.3%)\nhad mutations or fusions. Data on RET status were available for one patient with\nMTC who achieved an objective response, and the data showed no RET mutations\nor fusions.\nIn Material and Methods:\nThe RET M918T mutation in patients with MTC and RET fusions in patients with DTC\nwere assessed locally using NGS.\nReviewer 2:\n Consider adding the following clarification in the Methods section: “Patients\nwith locally advanced or metastatic ATC were included regardless of prior\ntherapy.”\nAuthors’ response: Following your suggestion, the cohort definitions were\nmodified for more clarity:\nPatients with confirmed locally advanced or metastatic thyroid carcinoma were\nrecruited into the following three cohorts: [...], and patients with ATC regardless of\nprior therapy whether they previously underwent therapy or not (Cohort 3).\nReviewer 2:\n Was there a centralized pathological review of tumor samples?\nAuthors’ response: The diagnostic and pathological review was assessed\nlocally by the investigators. The reason to not perform the central review was\nbudget constraints. Only a few exploratory analyses were planned. We\nacknowledge that a central review would have increased the validity of our\nstudy but it should be remarked that all study centers were reference hospitals\nin Spain with highly qualified pathologist and multidisciplinary collaborative\nteams for the diagnosis and management of the patients.\nReviewer 2:\n From what percentage of a poorly differentiated component was a cancer\nclassified as “poorly differentiated”?\nAuthors’ response: The pathological review was locally performed by\nexperienced pathologists from reference centers following the current clinical\nguidelines for the differential diagnosis of thyroid cancer. It was confirmed\nwith the centers that poorly differentiated cancer was a variant of DTC.\nReviewer 2:\n If correctly understood, two of the ten ATC patients underwent total\nthyroidectomy prior to inclusion. Histologically, were these tumors fully\nundifferentiated, or did they contain an undifferentiated component within\na poorly or well-differentiated carcinoma?\nAuthors’ response: Two of the ten patients with ATC underwent thyroidectomy\nbefore study inclusion. The surgery outcome was R0 for one and R2 for the\nother. All patients with ATC were undifferentiated according to the\npathological diagnosis from the reference center.\nReviewer 2:\n Can the authors provide MTC grading according to the publication J Clin\nOncol. 2021 Nov 3;40(1):96–104. doi:10.1200/JCO.21.01329?\nAuthors’ response: Thank you for providing us with this interesting\npublication. The sponsor agrees that reporting mitotic rate of Ki-67 might have\nbeen of interest. Nevertheless, at the time of study conception and conduction,\nthe Ki-67 implementation was not established in MTC. There is no centralized\nsample revision and, therefore, this data cannot be obtained.\nReviewer 2:\n The authors stated: “Previous studies on durvalumab (anti-PD-L1) and\ntremelimumab (anti-CTLA-4) for the treatment of neuroendocrine\nneoplasms yielded modest but clinically meaningful survival outcomes in a\nsubset of patients with poorly differentiated carcinomas, along with a\nmanageable safety profile.20,21”\nReference 21 does not appear to concern neuroendocrine tumors.\nAuthors’ response: Thank you for the comment. The reference 21 was\nincorrectly added and has been deleted.\nReviewer 2:\n The captions of Figure 3 regarding RET, PD-L1, BRAF, and MSI status are\nmisaligned.\nAuthors’ response: Thank you for your observation. The figure has been\nreplaced with a new one with the captions correctly aligned.\nReviewer 2:\n The authors stated: “The combination of an anti-PD-1 agent with BRAF/MEK\ninhibitors or other MKIs yields objective responses in patients with ATC,\noften with a manageable safety profile.22,25”\nReference 22 does not seem to support this statement.\nAuthors’ response: The reference 22 has been replaced by the following one:\nHamidi, S. et al. Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for\nBRAFV600E-Mutated Anaplastic Thyroid Carcinoma. Thyroid 34, 336–346 (2024).\nReviewer 2:\n The authors stated: “In this study, durvalumab plus tremelimumab showed\nmodest efficacy in the MTC cohort, with survival outcomes inferior to those\npreviously reported for MKIs.8,9,31.” However, in reference 31, all MTC patients\nwere treated with selpercatinib as first-line therapy, and in references 8 and\n9, 61% and 78% of patients, respectively, received vandetanib or cabozantinib\nas first-line therapy. Please provide bibliographic references of therapeutic\ntrials conducted in pre-treated MTC patients, as in your study, for an\nappropriate comparison, as far as possible.\nAuthors’ response: Thank you for your comment. The references have been\nrevised and replaced by the appropriate ones. In the new references, efficacy\noutcomes for pre-treated MTC patients who received selpercatinib,\ncabozantinib, vandetanib and pralsetinib are provided:\n1. Kreissl, M. C. et al. Efficacy and Safety of Vandetanib in Progressive and\nSymptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial. J\nClin Oncol 38, 2773–2781 (2020).\n2. Cabanillas ME, de Souza JA, Geyer S, Wirth LJ, Menefee ME, Liu SV, et al.\nCabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor-\nRefractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II\nInternational Thyroid Oncology Group Trial. J Clin Oncol Off J Am Soc Clin Oncol.\nOctober 10, 2017;35(29):3315–3321.\n3. Subbiah V, Hu MI, Mansfield AS, Taylor MH, Schuler M, Zhu VW, et al. Pralsetinib in\nPatients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered\nThyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study. Thyroid\nOff J Am Thyroid Assoc. January 2024;34(1):26–40.\n4. Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, et al. Efficacy of\nSelpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. August 26,\n2020;383(9):825–835.\nReviewer 2:\n In Table 1, check the percentages (e.g., for well-differentiated/poorly differentiated/unknown categories, and for ATC where totals exceed 100% [100 + 8.3%]; for MTC, 26.3 + 5.3 + 76.7 > 100%).\nAuthors’ response: Apologies for this error. Table 1 has been revised.\nReviewer 2:\n Clarify in Table 1 whether “previous surgery” refers to total thyroidectomy or\nanother type of surgical intervention.\nAuthors’ response: Previous surgery includes partial or total thyroidectomy,\nbut also a few cases of laryngectomy and chordectomy. This information has\nbeen included in Table 1.\nReviewer 2:\n Consider including the median duration of response in Table 2 to provide a\nconcise overview of key efficacy results.\nAuthors’ response: Following your suggestion, the median duration of\nresponse has been added to Table 2.\nReviewer 2:\n Did any ATC patients receive neck irradiation prior to inclusion?\nAuthors’ response: Four patients with ATC received neck irradiation prior to\ninclusion. This information has been included in the text as follows:\nIn patients with ATC, 33.3% of them were treated with local radiotherapy prior to\ninclusion.\nReviewer 3: This is the statistical review for a single-arm trial with 3 cohorts\n(DTC/MTC/ATC) aiming to demonstrate efficacy based on 6-months PFS/OS rates.\nOnly for the ATC cohort, the primary endpoint was successfully demonstrated.\nThe MTC arm stopped recruitment prematurely.\nThere are several aspects in the description of methods and presentation of results\nthat need to be addressed.\nThere is a discrepancy between how the trial was planned and how the primary\nendpoint is reported. The original sample size estimation was based on Simon’s\ntwo stage design for binomial endpoints for DTC/MTC arms, and as single stage\ndesign for ATC with binomial endpoint, using 6-months PFS (DTC/MTC) and 6-\nmonths OS (ATC) rates.\nPrimary endpoints are reported based on KM estimates, i.e. for time-to-event\nendpoints accounting for censoring. While I agree with using KM estimates,\nthis discrepancy should be pointed out.\nAuthors’ response: Thank you very much for your thoughtful and detailed\nreview of the statistical aspects of the trial. The sponsor really appreciates\nyour valuable feedback, that has contributed to improve the quality and\naccuracy of this study.\nWe appreciate your observation regarding the discrepancy between the\noriginally planned analysis and the way the primary endpoints are reported.\nWhile the analysis was indeed performed using Kaplan-Meier (KM) estimates\nto appropriately account for censoring in the time-to-event data, we\nacknowledge that this represents a deviation from the initial binomial\nframework described in the design. The use of Kaplan-Meier method is widely\naccepted to address survival rates at several timepoints and it is more\nconsistent when tumor assessments for all patients are not exactly performed\nwithin the estimated endpoints, which was the case. Some CT-scans were\nperformed within a time window from the 6 months, so the sponsor decided\nthat Kaplan-Meier estimates would give a more accurate estimation. All\npatients were assessed within +/-1 month after 6 months of treatment\ninitiation, so this limitation has a really low impact when considering Kaplan-\nMeier estimates. The sponsor agrees that this methodological change should\nbe clearly explained and justified in the manuscript to ensure transparency\nand consistency. The methods section has been reviewed to explicitly describe\nthis point, clarify the rationale for reporting KM estimates, and discuss any\nimplications for the interpretation of the findings:\nAlthough the protocol planned the estimation of primary endpoints using\nbinomial calculations, some tumor assessments and survival follow ups were\nperformed within +/- 1 month from the 6 month expected time point due to\nchanges in scheduled visits per patient or site availability, or different clinical\ncourses of the disease, so the sponsor decided that Kaplan Meier estimated would\ngive a more accurate estimation at 6 months. Binomial calculations are listed in\nSupplementary table 8.\nReviewer 3: Please provide not only the percentage but also the absolute number\nof patients with PD/Death for the primary endpoints for all cohorts, including the\nnumber of censored patients.\nAuthors’ response: Thank you for your suggestion. The information has been\nadded as Supplementary Tables 1 and 2.\nReviewer 3: Please provide a reference for the assumption of a 6-month OS rate of\n5% for the ATC arm. I could not find those in the manuscript or study protocol.\nAuthors’ response: This is extrapolated from the standard treatment practice.\nFollowing your request, the Sponsor has added a reference to benchmark\nstudies for the use of chemotherapy that classically is used for ATCs, despite\nit should be considered that these studies were performed exclusively in the\nfirst treatment line setting whereas our study allowed the inclusion of patients\nafter progression to standard treatment options. Pretreated patients tend to\nhave worse prognosis than treatment naive. This was taken into account for\nstudy design and OS rate assumptions. In our cohort, 42% of patients were\npretreated with two prior treatment lines, which is correlated with dismal\noutcomes.\nReference:\nShimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R. A randomized trial of\ndoxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid\ncarcinoma. Cancer. November 1, 1985;56(9):2155–2160.\nReviewer 3: Please include the number of pts needed to be alive after 6 months\nout of 12 patients for the single stage design in cohort 3 according to the sample\nsize planning.\nAuthors’ response: Following your request the number of patients required to\nreject null hypothesis is added in the statistical methods section:\nAssuming a historical 6-month OS rate of 5% and an anticipated improvement to\n35% (one-sided ɑ=5%, power=80%), 12 patients were needed and ≥3 patients alive\nat 6 months to declare the study positive.\nReviewer 3: The primary endpoint is planned for a one-sided alpha of 5%, so the\nstatement ‘All statistical tests used for efficacy and safety analyses were two-tailed\nand results with p-values <0.05 were considered significant’ is not correct.\nAuthors’ response: Thank you so much for noticing. It is true that the primary\nendpoint tests were one-sided. The statistical methods section has been\namended:\nPrimary statistical tests were one-tailed and other statistical tests used for efficacy\nand safety analyses were two-tailed, and results with p-values <0.05 were\nconsidered significant.\nReviewer 3: RECIST/ Suppl table 1: According to the study protocol, RECIST 1.1 will\nbe used for response assessment. I think this should be the reason why the primary\nendpoints are reported based on RECIST, not the strong agreement with irRECIST\n1.1.\nAuthors’ response: The study was designed by 2019/2020 when\nimmunotherapy use in thyroid cancers was scarce.\nRECIST 1.1, which was at that time more commonly used for the oncologists,\nwas taken as the primary endpoint. That was the main reason to choose\nRECIST as primary criteria over irRECIST. However, the investigators assessed\nCT scans by both criteria to check consistency of the results. Our analysis\nindicates that RECIST and irRECIST were very concordant. We believe the use\nof irRECIST and the check of consistency between both criteria strengthened\nour results and increased validity.\nReviewer 3: In the discussion, the authors state ‘exploratory biomarker analyses\nwere performed to identify potential predictors of the response. These results\nsuggest that emerging biomarkers, including PD-L1 expression and MSI status,\nmay help refine patient selection.’ Apart from the annotation shown in figure 3 I\ncould not find any analysis on these data, or any analysis supporting this statement.\nIn fact, biomarker is rather scarce and not done for the majority of patients.\nAuthors’ response: The discussion also states that these exploratory analyses\nfaced several constraints and limitations, mainly due to budget limitations\nwhich precluded the analysis of all samples. Additionally some patient\nsamples could not be collected or the material was insufficient. The discussion\nstates:\nThis study had several limitations. First, PD-L1 status was not systematically\nassessed in all patients; thus, we could not reach definitive conclusions regarding\nits predictive value. Future studies are needed to comprehensively evaluate the\nmolecular biomarkers of response to ICIs in patients with thyroid cancer,\nparticularly those with ATC.\nThe molecular results are reported in Figure 3 and were very exploratory due\nto the limitations. According to your observation, we also tempered the\nsentence commented here so it is very clear that our results could not reach\nto solid conclusions but rather point towards the need of additional\ntranslational research in this context:\nNotably, exploratory biomarker analyses were performed with a subset of patients\nto identify potential predictors of the response. These exploratory preliminar\nresults suggest that emerging biomarkers, including PD-L1 expression and MSI\nstatus, may help refine patient selection, despite further research will be needed.\nReviewer 3: Agreement analysis. A significant kappa > 0 is not the same as ‘No\nsignificant differences were observed between the two evaluation methods’.\nPlease rephrase this.\nAuthors’ response: Following your request, this sentence has been amended\nfor further clarity. Thanks:\nCohen’s kappa test to assess the agreement among RECIST and irRECIST. A p-\nvalue below 0.05 indicates that the agreement among RECIST and irRECIST is\nstatistically significant and indicates that the concordance between both is real\nand trustable.\nReviewer 3: The Clopper-Pearson method for CIs is not adequate for censored\ndata.\nAuthors’ response: This is a mistake while confectioning the statistical section.\nClopper-Pearson is used to calculate 95% CIs of ORR, which has no censored\ndata. The statistical section has been amended for correctness:\nThe ORR were reported as percentage and their 95% CI was estimated using the\nClopper–Pearson method. PFS and OS were estimated using the Kaplan–Meier\nmethod and Cox proportional model, and comparisons were tested using log-\nrank tests\nReviewer 3: Please specify the date of data cut-off for the analysis.\nAuthors’ response: Data cut off was May 2024. Following your request data cut\noff is specified at first appearance in the manuscript:\nNine patients survived for at least four years from treatment initiation\n(Supplementary Figure 2), and eight were still alive at the time of data cutoff (May\n2024).\nReviewer 3: Results on time-dependent analysis of imAEs (line 182/183): Please\ncorrect, it is the occurrence of imAEs and not the endpoint PFS/OS which is\nanalysed as time-dependent factor.\nAuthors’ response: The sentence has been modified according to your\nsuggestions for further clarity:\nAlthough patients with imAEs had numerically lower hazard ratios (HR) for both\nPFS and OS, these associations did not reach statistical significance when PFS\nand OS were analysed as time-dependent variables\nReviewer 3: Figure 3a/b waterfall plots: numbers do not add up, it should be 32\nDTC patients etc but it is less.\nAuthors’ response: For the waterfall plots, patients without target lesions,\nwithout measurable diameters or with best overall response equal to “UK” or\n“NE” were excluded. Excluding these patients, the numbers represented in\nFigure 3 are correct. Moreover, there were 30 patients with DTC, not 32."}, {"round": 2, "reviewer_comments": {"reviewer_1": "This is a phase II, single-arm, multi-cohort trial was conducted determine whether dual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can improve the clinical outcomes in advanced thyroid cancer.\nThis is a much needed, invaluable study for advanced thyroid cancer and makes a tremendous contribution to what we have as treatment options for some of the aggressive thyroid cancers.\nThank you for clarifying the comments and suggestions. Given that a third of patients had received radiation before the drug combination, did you see any difference in survival of those who received radiation to neck before durval and treme combo versus who did not? Did any of these undergo surgery due to tumor shrinkage?\nAlso one of the comments by author is that they didnt see any benefit of adding a second ICI over single agent. I dont think this is necessarily true as better results were seen from an OS standpoint with ipilimumab and nivolumab.\nOverall, the paper looks ready for publication if they could add a comment of if there was any difference in survival in between those who received radiation to neck versus not.", "reviewer_3": "All my points have been addressed by the authors.\nOne minor issue: In the new suppl. tables 1 and 2, the table head should probably read 'estimated cumulative survival rate' instead of 'estimated cumulative survival ratio'"}, "author_response": "Reviewer #1 (Remarks to the Author)\nThis is a phase II, single-arm, multi-cohort trial was conducted determine whether\ndual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can\nimprove the clinical outcomes in advanced thyroid cancer.\nThis is a much needed, invaluable study for advanced thyroid cancer and makes a\ntremendous contribution to what we have as treatment options for some of the\naggressive thyroid cancers.\nThank you for clarifying the comments and suggestions. Given that a third of\npatients had received radiation before the drug combination, did you see any\ndifference in survival of those who received radiation to neck before durval and\ntreme combo versus who did not? Did any of these undergo surgery due to tumor\nshrinkage?\nAuthors’ response: One-third of the patients with ATC (four patients) received\nradiotherapy prior to study inclusion. Of these, three did not undergo surgery,\nand one underwent surgery before receiving radiotherapy. Given the low\nnumber of patients with ATC (12 patients), the possibility to obtain significant\nconclusions from subgroup analysis were limited. Moreover, the two patients\nwith longer survivorship did not receive previous radiotherapy, which could\nbias statistical tests interpretations. We identified in the Swimmer plot\n(Supplementary Figure 2) the patients who received prior radiotherapy, to give\nsome information about the survival of patients with ATC who received and\nnot previous radiotherapy.\nReviewer #1: Also one of the comments by author is that they didn't see any\nbenefit of adding a second ICI over single agent. I dont think this is necessarily true\nas better results were seen from an OS standpoint with ipilimumab and nivolumab.\nAuthors’ response: Thank you for your comments. Compared to the median OS\nin patients with DTC in our study, Sehgal et al. (2024) reported a higher median\nOS (24.6 vs. 13.8 months) with nivolumab plus ipilimumab therapy. However,\nOh et al. (2023) reported a median OS of 34.5 months in patients with DTC\ntreated with pembrolizumab in monotherapy. The variability of the results\nobtained in the different trials reflects the underlying heterogeneity of the\npatients included in small thyroid trials, limiting the conclusions regarding the\nbenefit of dual ICI versus monotherapy. We have modified the manuscript text\naccordingly.\nThus, with the data available, thea benefit of addingtion of anti-CTLA-4 to anti-\nPD-1 treatment cannot be confirmed or discardeddoes not have a clear benefit.\nReferences:\nSehgal K, Pappa T, Shin KY, et al. Dual Immune Checkpoint Inhibition in Patients With\nAggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial. JAMA Oncol.\n2024;10(12):1663-1671. doi:10.1001/jamaoncol.2024.4019\nOh DY, Algazi A, Capdevila J, et al. Efficacy and safety of pembrolizumab monotherapy in\npatients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study. Cancer.\n2023;129(8):1195-1204. doi:10.1002/cncr.34657\nReviewer #1: Overall, the paper looks ready for publication if they could add a\ncomment of if there was any difference in survival in between those who received\nradiation to neck versus not.\nAuthors’ response: Thank you for your revision. Regarding the survival of\npatients who received radiation and considering the low number of patients\nwith ATC, we identified them in the Swimmer plot (Supplementary Figure 2),\nto give some information about the survival of patients with ATC who received\nand not previous radiotherapy.\nReviewer #3 (Remarks to the Author)\nAll my points have been addressed by the authors.\nOne minor issue: In the new suppl. tables 1 and 2, the table head should probably\nread 'estimated cumulative survival rate' instead of 'estimated cumulative survival\nratio'\nAuthors’ response: Thank you for your previous suggestions. They were helpful\nin improving the quality of our manuscript. Following your suggestion, we\nchanged “ratio” by “rate” in Supplementary Tables 1 and 2."}]

Decision letter