PD-1 Blockade in Anaplastic Thyroid Carcinoma original reports Jaume Capdevila, MD, PhD1; Lori J. Wirth, MD2; Thomas Ernst, MD3; Santiago Ponce Aix, MD4; Chia-Chi Lin, MD, PhD5; Rodryg Ramlau, MD, PhD6; Marcus O. Butler, MD7; Jean-Pierre Delord, MD, PhD8; Hans Gelderblom, MD, PhD9; Paolo A. Ascierto, MD10; Angelica Fasolo, MD11; Dagmar Führer, MD, PhD12; Marie Luise Hütter-Krönke, MD13; Patrick M. Forde, MBBCh14; Anna Wrona, MD, PhD15; Armando Santoro, MD16; Peter M. Sadow, MD, PhD2; Sebastian Szpakowski, PhD17; Hongqian Wu, PhD18; Geraldine Bostel, PhD19; Jason Faris, MD17; Scott Cameron, MD, PhD17; Andreea Varga, MD20; and Matthew Taylor, MD21 abstract PURPOSE Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor. METHODS We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1. RESULTS Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n 5 28/40 evaluable), and response rates were higher in PD-L1–positive (8/28; 29%) versus PD-L1–negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 $ 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1–positive population. CONCLUSION To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade. J Clin Oncol 38:2620-2627. © 2020 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION programmed death-ligand 1/2 (PD-L1/L2), have shown Undifferentiated (anaplastic) thyroid carcinoma (ATC) is clinical activity in a broad range of tumor types, par- a rare, aggressive form of thyroid cancer with nearly ticularly in cancers demonstrating PD-L1 expression.9-11 ASSOCIATED 100% disease-specific mortality and no standard ther- Approximately 22%-29% of ATC tumor samples have CONTENT been reported to express PD-L1,12,13 suggesting tar- apeutic approach.1,2 Existing treatment options include See accompanying geting the PD-1/PD-L1 axis may have promise. Indeed, editorial on surgery, radiation, and chemotherapy, used in combi- nation when possible.1 The benefits of aggressive mul- a positive response to combined BRAF and PD-1– page 2603 timodality therapy are typically short lived and survival directed therapy was reported for one patient with Data Supplement benefit is unclear, with a median overall survival (OS) of BRAF-mutant ATC,14 and a small retrospective single- Protocol only 5 months.1-4 Mutations affecting BRAF are found in institution cohort reported on responses in a subset of Author affiliations and support approximately 27%-45%5-7 of ATC, and combination patients with ATC with prior disease progression on information (if therapy with the BRAF inhibitor dabrafenib and the MEK kinase inhibitors with the addition of pembrolizumab.15 applicable) appear inhibitor trametinib was recently approved by the US at the end of this Spartalizumab (PDR001) is a humanized immuno- article. Food and Drug Administration for this subset of patients.8 globulin 4 monoclonal antibody that binds PD-1 with Accepted on March This is the only systemic therapy in the modern era to subnanomolar activity and blocks interaction with PD- 16, 2020 and have shown meaningful activity in ATC, albeit in a subset L1 and PD-L2.16 This first-in-human phase I/II study published at of patients. A critical unmet need remains for effective was designed to investigate the safety and efficacy of ascopubs.org/journal/ therapy for patients with BRAF wild-type disease. spartalizumab in patients with advanced or metastatic jco on May 4, 2020: DOI https://doi.org/10. Drugs targeting the interaction between the pro- solid tumors. Here, we describe the results from the 1200/JCO.19.02727 grammed death-1 (PD-1) receptor and its ligands, phase II part of the study in patients with ATC. 2620 Volume 38, Issue 23 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. PD-1 Blockade in Anaplastic Thyroid Carcinoma METHODS inhibitor in patients with ATC, 10% was selected as the Clinical Study Design and Oversight boundary for moderate efficacy. With an observed ORR of 20% at a sample size of 40, the 90% credible interval This was a phase I/II, international, multicenter, open-label (based on a minimally informative prior b [0.25 to 1]) for the study of spartalizumab in patients with advanced solid true ORR would be (10.8%-30.9%), giving a lower bound tumors (ClinicalTrails.gov identifier: NCT02404441). The greater than the estimated moderate efficacy. data cutoff date was February 1, 2019. Treatment Plan This Novartis-sponsored study was performed in com- pliance with Good Clinical Practice guidelines and in Patients in the phase II ATC treatment group received accordance with the Declaration of Helsinki. The pro- spartalizumab 400 mg, administered intravenously (IV), tocol and all amendments were reviewed and approved once every 4 weeks. Treatment was administered until by an independent ethics committee and/or institutional unacceptable toxicity, progressive disease as per irRC, or review board at each participating site. Written informed patient/physician decision. If more than two consecutive consent was obtained from all patients before the study start. doses were missed because of toxicity, treatment was discontinued. Delays of up to 7 days were permitted; dose Study Objectives modifications were not allowed. The primary objective of the phase I part of the study was Safety and Response Assessments to determine the recommended phase II dose/maximum Regular safety assessments were performed, including tolerated dose for spartalizumab; these findings have been physical examination, ECOG performance status, and reported.16 The primary objective for the phase II part was laboratory parameters. Adverse events (AEs), defined by to estimate the antitumor activity of spartalizumab (overall the National Cancer Institute Common Terminology Cri- response rate [ORR] according to Response Evaluation teria for Adverse Events version 4.03, were assessed at Criteria in Solid Tumors [RECIST] v1.1). Secondary and every visit. exploratory objectives included characterizing the safety Tumor response was evaluated by local investigator’s as- and tolerability of spartalizumab, characterizing the phar- sessment of imaging data using RECIST v1.1 and irRC. macokinetic profile of spartalizumab, further evaluating the Tumor assessments were performed at baseline, and antitumor activity of spartalizumab (ORR according to subsequent assessments were performed every 8 weeks up immune-related response criteria [irRC], progression-free to 40 weeks, then every 12 weeks until disease progression survival [PFS] and OS, duration of response, and disease per irRC, withdrawal of consent, or loss to follow-up. control rate), and assessing the pharmacodynamic effect and potential predictors of efficacy. Pharmacodynamic and Biomarker Analyses At screening, an archival tumor sample and/or a newly Patients obtained pretreatment tumor biopsy was collected from Patients eligible for the phase II part of the study had locally each patient, and an additional tumor biopsy was obtained advanced/metastatic solid tumors; this report describes during treatment. patients with ATC. Central pathology review was performed Biomarker assessments included baseline PD-L1 levels in to confirm the diagnosis but was not required for the start of tumor cells, assessed centrally by immunohistochemistry study treatment. Adult patients with at least one measur- using a diagnostic developed for non–small-cell lung able lesion as determined by RECIST v1.1 and a tumor cancer (Dako PD-L1 IHC 22C3 pharmaDx, performed by amenable to biopsy were enrolled. All patients had an HistoGeneX, Wilrijk, Belgium), baseline CD81 levels assessed Eastern Cooperative Oncology Group (ECOG) performance by immunohistochemistry, expressed as CD81 lymphocyte status of # 1 and provided consent to tumor biopsy at staining as a percentage of the total sample area, and baseline baseline and during treatment. Amendments were made to BRAF status, assessed by Cobas 4800 BRAF V600 the study protocol during recruitment: patients with locally mutation test (performed by HistoGeneX, Wilrijk, Belgium). advanced disease were considered for chemoradiation and/or surgery before entering the study if those therapies Patient samples were also analyzed by next-generation were in the best interest of the patient, disease progression sequencing (Foundation Medicine, Cambridge, Massa- on prior treatment was not required, and patients with chusetts) to assess mutations affecting cancer-related short-term risk for life-threatening complications were not genes and tumor mutation burden,17 and by RNA se- eligible. Other exclusion criteria are described in the study quencing (RNAseq) to evaluate gene expression patterns, protocol (Data Supplement). including interferon gamma (IFNg) signature. Originally, it was planned to enroll approximately 10 pa- Statistical Methods tients with ATC, reflecting the low prevalence of this dis- Detailed statistical methods are summarized in the Data ease. This was then increased to approximately 40 patients. Supplement. ORRs are summarized with accompanying As data are limited on the expected efficacy of a PD-1 95% exact binomial CIs. Associations between ORR and Journal of Clinical Oncology 2621 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Capdevila et al potential biomarkers were assessed using exact Fisher’s including diarrhea, pruritus (five patients each; 12%), tests; Spearman correlation coefficient (95% CI) was es- pruritus generalized (one patient; 2%), rash (two patients; timated for the correlation between efficacy and IFNg 5%; one grade 3), rash macular, increased blood thyroid- signature. Median survival (95% CI) was estimated using stimulating hormone, and hypothyroidism (one patient Kaplan-Meier method. each; 2%). Additional AEs of potential immune-related etiology regardless of relationship to treatment are sum- RESULTS marized in the Data Supplement. Metastasis to the CNS Patient Characteristics and Disposition was the only serious AE suspected to be related to study treatment. This patient was enrolled with no knowledge of During the phase I part of the study, a patient with ATC brain metastases but reported vertigo, vision loss, and treated with spartalizumab 3 mg/kg once every 2 weeks vomiting before study enrollment; inflammation induced by experienced a mixed response, with significant reductions treatment with spartalizumab was proposed by the in- in two target lesions and a best overall response of stable vestigator as a possible mechanism for the serious AE. Dose disease, before developing progressive disease at study interruptions due to AEs occurred in three patients. Dis- Day 222. On the basis of this patient and the associated continuation of study treatment was reported in one patient biomarker data, which identified an increase in CD8 be- who developed grade 4 obstructive airway disorder, not tween the baseline and on-treatment biopsy, a phase II suspected to be related to treatment. A total of 11 patients cohort was opened for patients with ATC. died during the treatment period; deaths were attributed As of February 1, 2019, 42 patients with ATC had been to hemorrhage due to disease (n 5 1) and disease pro- treated with 400 mg spartalizumab IV once every 4 weeks in gression (n 5 10). the phase II part of the study. Patient demographics and baseline characteristics are shown in Table 1. Tumor tissue Efficacy was available for central pathology review for 40 patients As expected for this aggressive disease, the median du- (95%), with 38 patients (90%) confirmed to have ATC. For ration of spartalizumab treatment was short at 8 weeks the two remaining patients, the diagnosis was high-grade (range, 1.7-113.6 weeks). Twenty-four patients discontinued malignant neoplasm with chondroblastic differentiation treatment for progressive disease, eight for death due to study and Hürthle cell carcinoma. Median age was 62.5 years indication, and one for an AE not suspected to be related (range, 46-83 years), and all patients had a performance to treatment. Eleven patients (26%) received treatment of status of 0 or 1. Sixty percent of patients had received prior $ 50 weeks (Fig 1A). Best overall response was evaluated by antineoplastic therapy, with common prior therapies in- both RECIST v1.1 and irRC (Data Supplement). The ORR cluding doxorubicin in 13 (31%), paclitaxel in 12 (29%), according to RECIST v1.1 was 19% (95% CI, 8.6% to 34.1%; and lenvatinib in 4 patients (10%). Seventy-one percent of n 5 8/42), including three patients with a complete response patients also received prior radiotherapy, and 67% had (CR; 7%) and five patients with a partial response (PR; 12%). undergone thyroidectomy/neck dissection. Most patients All responding patients had ATC confirmed by central pa- had metastatic disease at study entry, with lungs (83%) thology review. Duration of response ranged from 16.7 weeks and lymph nodes (48%) as the most common sites of to 1.6 years (ongoing at data cutoff). Median duration metastasis. of response has not yet been reached, and six of eight As of February 1, 2019, treatment was ongoing for 7 pa- responding patients were still receiving treatment with tients (17%); 35 patients (83%) discontinued from the ongoing responses at the data cutoff. By irRC, the ORR study because of progressive disease (57%), death (21%; was 24% (95% CI, 12.1% to 39.5%), including three due to study indication [n 5 8] and shock unrelated to patients with a CR and seven patients with a PR. All pa- study treatment [n 5 1]), AEs (2%), or patient/guardian tients with a confirmed response by RECIST v1.1 or irRC decision (2%). had ATC confirmed by central pathology analysis. Safety and Tolerability The extent of disease reduction and change over time is AEs, regardless of relationship to study treatment, were shown in Fig 1B and the Data Supplement. Of 31 patients reported in 41 patients (98%) and grade 3/4 AEs regardless with evaluable postbaseline sum of target lesions mea- of relationship to study treatment were reported in 29 surements, 13 had some reduction from baseline. Eleven patients (69%; Data Supplement). AEs attributed to study patients were not evaluable for best percentage change treatment were experienced by 19 patients (45%; Table 2). from baseline, because of discontinuation or death before The most frequent were diarrhea, pruritus, fatigue, and first postbaseline assessment (n 5 8) or missing post- pyrexia. Grade 3/4 AEs attributed to study treatment were baseline assessments (n 5 3). reported in four patients (10%): anemia, rash, and me- Median PFS (Data Supplement) was 1.7 months by both tastases to the CNS. Ten patients experienced potential RECIST v1.1 and irRC (95% CI, 1.2 to 1.9 months and 1.2 immune-related AEs of special interest, suspected to be to 2.0 months, respectively). At 1 year, the PFS rate was treatment related. These were mostly grade 1 or 2, 17% and 22% by RECIST v1.1 and irRC, respectively. 2622 © 2020 by American Society of Clinical Oncology Volume 38, Issue 23 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. PD-1 Blockade in Anaplastic Thyroid Carcinoma TABLE 1. Baseline Patient Demographics and Characteristics TABLE 2. Adverse Events (any grade, occurring in $ 3% of patients) Spartalizumab 400 mg Suspected to Be Related to Study Treatment Every 4 Weeks Spartalizumab 400 mg Characteristic (N 5 42) Every 4 Weeks Central pathology review (N 5 42) ATC 38 (90.5) Preferred Term All Grade 3/4 Other 2 (4.8) Total 19 (45.2) 4 (9.5) Missing 2 (4.8) Diarrhea 5 (11.9) 0 Age, years, median (range) 62.5 (46-83) Pruritus 5 (11.9) 0 Sex, male 23 (54.8) Fatigue 3 (7.1) 0 ECOG PS Pyrexia 3 (7.1) 0 0 17 (40.5) Anemia 2 (4.8) 2 (4.8) 1 25 (59.5) Asthenia 2 (4.8) 0 Prior treatment regimens Myalgia 2 (4.8) 0 0 17 (40.5) Rash 2 (4.8) 1 (2.4) 1 20 (47.6) NOTE. Data presented as No. (%). $2 5 (11.9) Prior radiation Medicine testing with a TMB in the intermediate range Yes 30 (71.4) (14 mutations/Mb, the highest TMB in the cohort), had Prior thyroidectomy and/or neck dissection a frameshift mutation in the DNA mismatch repair gene Yes 28 (66.7) MSH6 that contributes to tumor genomic instability.18 Of Metastatic sites at study entry the other five RECIST/irRC responders who had mutational analysis, none had detected mutations affecting mismatch Lung 35 (83.3) repair proteins. Lymph node 20 (47.6) Bone 5 (11.9) Tumor samples were analyzed for baseline PD-L1 ex- pression by immunohistochemistry; data were available for Liver 3 (7.1) 40 patients. The majority (n 5 28/40; 70%) of tumor bi- BRAF V600 mutation by Cobas 4800 opsies were positive for PD-L1 expression ($ 1% positive in Mutant 12 (28.6) tumor cells), and the confirmed RECIST response rate was Nonmutant 26 (61.9) 29% (95% CI, 13.2 to 48.7; n 5 8/28) in patients with PD- Missing 4 (9.5) L1–positive disease. The response rate was highest (ORR, 35%; 95% CI, 14.2 to 61.7) in the subset of patients with NOTE. Data are presented as No. (%) unless otherwise noted. PD-L1 $ 50%; no RECIST responses were observed in Abbreviations: ATC, anaplastic thyroid carcinoma; ECOG PS, Eastern patients with PD-L1 expression , 1% (0/12 patients; Data Cooperative Oncology Group performance status. Supplement). The difference in response rates between PD-L1–positive and –negative groups reached statistical Median OS was 5.9 months (95% CI, 2.4 months to not significance at level 0.1 (Fisher’s exact two-sided test, reached), with 40% of patients alive at 1 year (Fig 1A). P 5 .079). One patient with PD-L1 , 1% had an irRC PR. Biomarker Analyses Survival rates were also higher in patients with baseline tumor samples positive for PD-L1 expression. Although Patient tumor biopsies were analyzed by immunohisto- median PFS remained , 2 months for all PD-L1 subsets, chemistry for baseline (before therapy) expression of PD-L1 1-year PFS rates were notably increased in PD-L1–positive and CD81 lymphocytes, RNA sequencing to characterize patients, with 0%, 20%, and 29%, respectively for PD-L1 gene expression, tumor mutational burden (TMB), and , 1%, 1%-49%, and $ 50%. OS also correlated with PD- mutations affecting genes related to cancer by DNA se- L1 status, with a median OS of 1.6 months in patients with quencing. The outcome of these analyses is summarized PD-L1 , 1%, compared with not yet reached in PD-L1– per patient in the Data Supplement. Commonly mutated positive patients (Fig 2). genes included TP53, TERT, BRAF, PTEN, and CDKN2A/B. TMB was evaluable in 27 patients, and median TMB was Baseline CD8 expression by immunohistochemistry was low at 3.78 mutations/Mb (range, 0-13.87 mutations/Mb). available for 37 patients. Forty-three percent (n 5 16/37) Six of 10 patients with RECIST/irRC responses had TMB of tumors had $ 1% CD81 staining. There was a weak analyses; only two had TMB . 5 mutations/Mb. One re- correlation between CD81 lymphocyte infiltration and PD- sponder, classified as microsatellite stable by Foundation L1 expression (Spearman coefficient, 0.24; 95% CI, 20.1 Journal of Clinical Oncology 2623 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Capdevila et al A 9 1 33 19 24 17 5 39 20 Mutant 35 36 Mutant 18 23 21 Mutant 7 38 Mutant 32 Mutant 6 3 Overall response Patient 29 Mutant 25 Mutant CR 22 PR 15 14 SD 11 4 PD 34 Mutant 30 UNK 37 40 Baseline PD-L1 42 Mutant 41 < 1% 27 16 1%-49% 13 Mutant 12 50% 8 2 Missing 28 Mutant Ongoing 26 Mutant 10 31 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Median exposure Duration of Exposure (months) B 100 RECIST v1.1 irRC PD ORR, % (95% CI) 19.0 (8.6 to 34.1) 23.8 (12.1 to 39.5) 75 PD PD PD PD DCR, % (95% CI) 31.0 (17.6 to 47.1) 35.7 (21.6 to 52.0) Best Percentage Change From Baseline 50 PD PD PD PD PD PD PD PD PD 25 PD SD PD PD PD PD UNK UNK UNK UNK UNK UNK UNK UNK SD 0 SD –25 SD –30 PD Baseline PD-L1 SD PD –50 < 1% 1%-49% –75 50% PR PR PR PR Missing PR BRAF mutation status –100 V600E by PCR CR CR CR K601E by NGS 8 10 11 26 27 28 30 34 40 41 42 15 32 6 22 2 14 12 3 31 25 13 23 37 16 36 4 29 19 17 7 35 20 38 18 9 24 33 21 1 5 39 Patient FIG 1. Duration of exposure to spartalizumab and percentage change from baseline in sum of diameters of target lesions, by programmed death-ligand 1 (PD- L1) expression at baseline. (A) Duration of exposure to spartalizumab. Mutant denotes BRAF mutation. (B) Best percentage change from baseline in sum of diameters of target lesions. Thirty-one patients were evaluable for best percentage change; 11 patients were not evaluable because of discontinuation or death before first postbaseline assessment (n 5 8) or missing postbaseline assessment (n 5 3). Best overall response by RECIST v1.1 is indicated. Where available, BRAF mutation status is indicated. Patient number refers to number in Data Supplement. CR, complete response; DCR, disease control rate [CR 1 PR 1 SD]; irRC, immune-related response criteria; NGS, next-generation sequencing; ORR, overall response rate [CR 1 PR]; PCR, polymerase chain reaction; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. 2624 © 2020 by American Society of Clinical Oncology Volume 38, Issue 23 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. PD-1 Blockade in Anaplastic Thyroid Carcinoma 100 Categorized baseline PD-L1 Events/Total Median (95% CI) < 1% 10/12 1.6 (1.0 to 19.6) 90 1%-49% 5/11 NE (3.4 to NE) ≥ 50% 8/17 NE (4.3 to NE) 80 + Censor 70 Overall Survival (%) 60 50 40 FIG 2. Overall survival by PD-L1 expression at base- 30 line. NE, not estimable; PD-L1, programmed death- 20 ligand 1. 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) No. at risk: (No. cumulative events) < 1% 12 (0) 5 (7) 3 (8) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9) 1 (9) 1 (9) 0 (10) 1%-49% 11 (0) 9 (1) 7 (3) 6 (4) 5 (5) 5 (5) 4 (5) 2 (5) 1 (5) 1 (5) 1 (5) 1 (5) 1 (5) 0 (5) ≥ 50% 17 (0) 14 (3) 13 (4) 11 (6) 9 (8) 7 (8) 6 (8) 5 (8) 3 (8) 1 (8) 1 (8) 1 (8) 1 (8) 0 (8) to 0.7). The ORR was numerically higher in patients with detectable BRAF mutation. Of eight patients (19%) with tumors containing CD8 $ 1% compared with patients a response according to RECIST criteria, six were ongoing with CD8 expression , 1% (25% [95% CI, 7.3% to at the time of data cutoff, lasting more than a year after 52.4%] v 14% [95% CI, 3.0% to 36.3%]; Fisher’s exact starting therapy. Additional responses to treatment were two-sided test, P 5 .437; Data Supplement). There were observed by irRC, with an ORR of 24%. ATC diagnosis was 14 patients with tumors positive for both PD-L1 and CD8; the ORR in this subgroup was 29% (95% CI, 8.4% to CR Best Percentage Change per RECIST v1.1 58.1%). PR SD Tumor samples were analyzed for BRAF mutation status, PD 50 available for 38 patients; of these, a third had BRAF mu- tation (n 5 12/38; 32%). The ORR was lower in patients with BRAF mutation than in those without (8% [95% CI, 0.2% to 38.5%] v 23% [95% CI, 9.0% to 43.6%]; Fisher’s 0 exact two-sided test, P 5 .395; Data Supplement). Nine of 12 patients with a BRAF mutation by polymerase chain reaction had a PD-L1 of $ 1%. Baseline tumor samples were also evaluated for gene ex- −50 pression by RNAseq. In data available from 18 patients, a correlation was observed between the best percentage change from baseline in sum of diameters of target lesions −100 and IFNg signature (Fig 3; Spearman coefficient, 20.67; 95% CI, 20.9 to 20.3). 0 2 4 6 8 DISCUSSION IFNγ Signature Spartalizumab was well tolerated in this patient population, FIG 3. Interferon g (IFNg) signature, by best percentage change from and toxicities were consistent with those seen with other baseline in sum of diameters of target lesions. Best overall response PD-1–targeting monoclonal antibodies.19,20 Treatment with by RECIST v1.1 is indicated. Data were available for 18 patients. spartalizumab achieved durable responses in a subset of Spearman coefficient, 20.67; 95% CI, 20.9 to 20.3. CR, complete patients, with three complete and five partial responses to response; PD, progressive disease; PD-L1, programmed death-ligand treatment, including seven responses in patients without 1; PR, partial response; SD, stable disease. Journal of Clinical Oncology 2625 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Capdevila et al confirmed by central pathology review in 95% of 40 Overall, TMB was low across the analyzed patients, with evaluable patients; all responding patients had ATC. This only one patient with TMB . 10 mutations/Mb; these evidence of clinical benefit in ATC, a disease with an es- findings are consistent with published reports.5,6 Patient pecially grave prognosis, is striking. responses despite a low or intermediate TMB have been Response to treatment with spartalizumab was particularly observed in other cancers, including renal cell carcinoma, notable in patients with evidence of an inflamed tumor where a high prevalence of insertions and deletions has microenvironment at baseline, as suggested by higher PD- been postulated as a mechanism for neoantigen forma- L1 expression, presence of CD81 lymphocytes, and ex- tion,22 and Merkel cell polyomavirus–positive tumors, pression of genes involved in IFNg signaling. An association where the presence of viral antigens may explain check- was also seen between PD-L1 expression at baseline and point activity.23,24 Additional investigation will be necessary survival, with median OS not yet reached in the subset of to characterize the mechanism for the efficacy observed patients with PD-L1 $ 1% expression at baseline. These with checkpoint inhibition in ATC. The rapid disease pro- findings are consistent with the mechanism of action of gression and very short OS in spartalizumab nonresponders spartalizumab and with data reported for inhibitors of PD-1 highlight an important unmet need to build on PD-1–based in other indications.11 immunotherapy to further improve treatment of patients with ATC. The mechanism underlying the immune activation seen in ATC is unclear. Response to PD-1 blockade is asso- In summary, spartalizumab demonstrated promising ciated with higher levels of novel antigens created by clinical activity and a good safety profile in a patient chronic exposure to mutagens, such as tobacco smoke or population with aggressive incurable disease and short UV light, or by defects in DNA repair, such as is found in life expectancy. Targeting PD-1/PD-L1 may provide microsatellite-unstable colorectal cancer.21 A subset of a much-needed treatment option for patients with PD- these neoantigens are immunogenic and provide targets L1–positive advanced ATC, including the BRAF wild-type for recognition by the immune system and disease control. population. AFFILIATIONS EQUAL CONTRIBUTION 1 Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, J.C. and L.J.W. are joint lead authors. A.V. and M.T. are joint senior Universitat Autònoma de Barcelona, Barcelona, Spain authors. 2 Massachusetts General Hospital and Harvard Medical School, Boston, MA 3 PRIOR PRESENTATION Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Presented in part at the American Society of Clinical Oncology Annual Universitätsklinikum Jena, Jena, Germany 4 Meeting, Chicago, IL, June 1-5, 2018. University Hospital 12 de Octubre, Madrid, Spain 5 National Taiwan University Hospital, Taipei, Taiwan 6 Poznań University of Medical Sciences, Poznań, Poland SUPPORT 7 Princess Margaret Cancer Centre, University Health Network, Toronto, Supported by Novartis Pharmaceuticals. Ontario, Canada 8 IUCT Oncopole, Toulouse, France 9 CLINICAL TRIAL INFORMATION Leiden University Medical Center, Leiden, the Netherlands 10 NCT02404441 Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy 11 San Raffaele Hospital, Milan, Italy 12 University Hospital Essen, Essen, Germany AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF 13 University Hospital Ulm, Ulm, Germany INTEREST AND DATA AVAILABILITY STATEMENT 14 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Disclosures provided by the authors and data availability statement (if University School of Medicine, Baltimore, MD applicable) are available with this article at DOI https://doi.org/10.1200/ 15 Uniwersyteckie Centrum Kliniczne, Gdansk, Poland JCO.19.02727. 16 IRCCS Humanitas Clinical and Research Center–Humanitas University, Rozzano, Italy 17 Novartis Institutes for BioMedical Research, Cambridge, MA 18 AUTHOR CONTRIBUTIONS Novartis Pharmaceuticals, East Hanover, NJ 19 Conception and design: Jaume Capdevila, Lori J. Wirth, Angelica Fasolo, Novartis Institutes for BioMedical Research, Basel, Switzerland 20 Geraldine Bostel, Scott Cameron Gustave Roussy Cancer Campus, Paris, France 21 Financial support: Scott Cameron Oregon Health & Science University, Portland, OR Administrative support: Scott Cameron Provision of study material or patients: Jaume Capdevila, Lori J. Wirth, CORRESPONDING AUTHOR Chia-Chi Lin, Rodryg Ramlau, Marcus O. Butler, Jean-Pierre Delord, Jaume Capdevila, Medical Oncology Department, Gastrointestinal and Hans Gelderblom, Angelica Fasolo, Dagmar Führer, Marie Luise Hütter- Endocrine Tumor Unit, Vall d’Hebron University Hospital, Vall d’Hebron Krönke, Anna Wrona, Scott Cameron Institute of Oncology (VHIO), Pg Vall d’Hebron, 119-129, 08035 Collection and assembly of data: Jaume Capdevila, Lori J. Wirth, Thomas Barcelona, Spain; Twitter: @Ja_Capdevila; E-mail: jacapdevila@ Ernst, Chia-Chi Lin, Rodryg Ramlau, Marcus O. Butler, Jean-Pierre vhebron.net. Delord, Hans Gelderblom, Angelica Fasolo, Dagmar Führer, Marie Luise 2626 © 2020 by American Society of Clinical Oncology Volume 38, Issue 23 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. PD-1 Blockade in Anaplastic Thyroid Carcinoma Hütter-Krönke, Patrick M. Forde, Anna Wrona, Peter M. Sadow, Manuscript writing: All authors Sebastian Szpakowski, Geraldine Bostel, Jason Faris, Scott Cameron, Final approval of manuscript: All authors Matthew Taylor Accountable for all aspects of the work: All authors Data analysis and interpretation: Jaume Capdevila, Lori J. Wirth, Santiago Ponce Aix, Chia-Chi Lin, Rodryg Ramlau, Marcus O. Butler, Hans ACKNOWLEDGMENT Gelderblom, Paolo A. Ascierto, Angelica Fasolo, Dagmar Führer, Patrick We thank the patients who participated in the trial and their families and M. Forde, Armando Santoro, Peter M. Sadow, Sebastian Szpakowski, thank the physicians, nurses, research coordinators, and other staff at Hongqian Wu, Jason Faris, Scott Cameron, Andreea Varga, Matthew each site who assisted with the study. We also thank Jennifer Mataraza, Taylor Victor Antona, Antonio Silva, and Emilie Bossuge for their contributions to this study. Editorial assistance was provided by Laura Hilditch, PhD, and was funded by Novartis Pharmaceuticals. REFERENCES 1. Haddad RI, Nasr C, Bischoff L, et al: NCCN guidelines insights: Thyroid carcinoma, version 2.2018. J Natl Compr Canc Netw 16:1429-1440, 2018 2. Smallridge RC, Ain KB, Asa SL, et al: American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22: 1104-1139, 2012 3. Smallridge RC, Copland JA: Anaplastic thyroid carcinoma: Pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol) 22:486-497, 2010 4. Tiedje V, Stuschke M, Weber F, et al: Anaplastic thyroid carcinoma: Review of treatment protocols. 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Turajlic S, Litchfield K, Xu H, et al: Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: A pan-cancer analysis. Lancet Oncol 18:1009-1021, 2017 23. Maleki Vareki S: High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer 6:157, 2018 24. Kaufman HL, Russell JS, Hamid O, et al: Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after $1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 6:7, 2018 n n n Journal of Clinical Oncology 2627 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Capdevila et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST PD-1 Blockade in Anaplastic Thyroid Carcinoma The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Jaume Capdevila Patrick M. Forde Consulting or Advisory Role: Bayer, Eisai, Sanofi, Exelixis, Novartis, Ipsen, Consulting or Advisory Role: AstraZeneca/MedImmune, Bristol-Myers Squibb, Pfizer, Merck Serono, Advanced Accelerator Applications Janssen, AbbVie Speakers’ Bureau: Bayer, Eisai, Sanofi, Novartis, Ipsen, Pfizer, Merck Serono Research Funding: Bristol-Myers Squibb (Inst), AstraZeneca/MedImmune Research Funding: Eisai (Inst), AstraZeneca (Inst), Advanced Accelerator (Inst), Kyowa Hakko Kirin (Inst), Novartis (Inst), Corvus Pharmaceuticals Applications (Inst), Novartis (Inst), Ipsen (Inst), Bayer (Inst), Pfizer (Inst) Anna Wrona Travel, Accommodations, Expenses: Pfizer, Ipsen, Eisai Speakers’ Bureau: BMS, Roche, Pfizer Lori J. Wirth Travel, Accommodations, Expenses: BMS, Roche, Pfizer Consulting or Advisory Role: Merck, Loxo, Blueprint Medicines, Eisai, Ayala Armando Santoro Pharmaceuticals, CUE Biopharma, Genentech, Rakuten Medical, Lilly, Bayer, Consulting or Advisory Role: Bristol-Myers Squibb, SERVIER, Gilead Sciences, Exelexis Pfizer, Eisai, Bayer, MSD, Sanofi, ARQULE Thomas Ernst Speakers’ Bureau: Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, Consulting or Advisory Role: Novartis, Bristol-Myers Squibb, Pfizer, Incyte ArQule, Eli Lilly, Sandoz, Novartis, BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD Santiago Ponce Aix Consulting or Advisory Role: Roche, Bristol-Myers Squibb, Merck Peter M. Sadow Speakers’ Bureau: Bristol-Myers Squibb, Merck, Roche Consulting or Advisory Role: Novartis, Interpace Diagnostics, Veracyte Travel, Accommodations, Expenses: AstraZeneca, Roche, Merck Sebastian Szpakowski Chia-Chi Lin Employment: Novartis, Compass Therapeutics (I) Honoraria: Novartis, Roche, Daiichi Sankyo Stock and Other Ownership Interests: Novartis, Compass Therapeutics (I), Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Blueprint Sarepta Therapeutics (I), Alexion Pharmaceuticals (I) Medicines Travel, Accommodations, Expenses: Novartis, Compass Therapeutics (I) Travel, Accommodations, Expenses: Lilly, Daiichi Sankyo, BeiGene, Novartis, Hongqian Wu Daiichi Sankyo Employment: Novartis Pharmaceuticals Rodryg Ramlau Stock and Other Ownership Interests: Biohaven Pharmaceuticals (I), Nektar, Consulting or Advisory Role: BMS, Boehringer Ingelheim, MSD Oncology, One Medical (I), Amarin Merck, Roche, Novartis, Takeda, AstraZeneca, Pfizer Travel, Accommodations, Expenses: Novartis Pharmaceuticals Travel, Accommodations, Expenses: BMS, Boehringer Ingelheim, Roche, Geraldine Bostel AstraZeneca Employment: Novartis Pharmaceuticals, Novartis Pharmaceuticals (I) Marcus O. Butler Stock and Other Ownership Interests: Novartis Pharmaceuticals, Novartis Honoraria: Roche, Merck, Bristol-Myers Squibb, Novartis Pharmaceuticals (I) Consulting or Advisory Role: Merck, Bristol-Myers Squibb, Novartis, Jason Faris Immunovaccine, Immunocore, Adaptimmune, EMD Serono, GlaxoSmithKline, Employment: Novartis Genzyme, Sanofi Canada, LaRoche Possey Stock and Other Ownership Interests: Novartis Research Funding: Merck, Takara Bio Expert Testimony: Merck Scott Cameron Employment: Novartis Jean-Pierre Delord Leadership: Novartis Consulting or Advisory Role: Novartis, Roche/Genentech, Bristol-Myers Squibb, Stock and Other Ownership Interests: Novartis MSD Oncology Patents, Royalties, Other Intellectual Property: Patents related to drugs being Research Funding: Genentech (Inst), Bristol-Myers Squibb (Inst), MSD developed by Novartis Oncology (Inst) Travel, Accommodations, Expenses: Novartis Hans Gelderblom Andreea Varga Patents, Royalties, Other Intellectual Property: Amgen, Boehringer-Ingelheim, Research Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Roche Pfizer, Novartis, Pharmamar, Daiichi, Five Prime (Inst) (Inst), Sanofi (Inst), Bristol-Myers Squibb (Inst), Boehringer Ingelheim (Inst), Paolo A. Ascierto Merck (Inst), Janssen-Cilag (Inst) Stock and Other Ownership Interests: PrimeVax Travel, Accommodations, Expenses: AstraZeneca, Roche, Boehringer Consulting or Advisory Role: Bristol-Myers Squibb, Roche/Genentech, Merck Ingelheim Sharp & Dohme, Novartis, Amgen, Array BioPharma, Merck Serono, Pierre Matthew Taylor Fabre, Newlink Genetics, Genmab, Incyte, MedImmune, AstraZeneca, Syndax, Consulting or Advisory Role: Bristol-Myers Squibb, Eisai, Array BioPharma, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, Sanofi/Genzyme Italfarmaco Speakers’ Bureau: Bristol-Myers Squibb, Eisai, Merck Research Funding: Bristol-Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst) No other potential conflicts of interest were reported. Travel, Accommodations, Expenses: Merck Sharp & Dohme © 2020 by American Society of Clinical Oncology Volume 38, Issue 23 Downloaded from ascopubs.org by 90.162.46.151 on February 21, 2022 from 090.162.046.151 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.