J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Original research Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-­arm, phase Ib/II trial Javier Martin-­Broto ‍ ‍ ,1,2 Nadia Hindi,1,2 Giovanni Grignani ‍ ‍ ,3 Javier Martinez-­Trufero,4 Andres Redondo,5 Claudia Valverde,6 Silvia Stacchiotti,7 Antonio Lopez-­Pousa,8 Lorenzo D'Ambrosio,3 Antonio Gutierrez,9 Herminia Perez-­Vega,10 Victor Encinas-­Tobajas,10 Enrique de Alava,11,12 Paola Collini,13 Maria Peña-­Chilet,2,14,15 Joaquin Dopazo,2,14,15,16 Irene Carrasco-­Garcia,1,2 Maria Lopez-­Alvarez,2 David S Moura,2 Jose A Lopez-­Martin17,18 To cite: Martin-­Broto J, Hindi N, ABSTRACT 40 years.1–3 Immunomodulation has become a Grignani G, et al. Nivolumab Background Sarcomas exhibit low expression of factors topical area of interest in many tumors, being and sunitinib combination in related to immune response, which could explain the advanced soft tissue sarcomas: sarcoma not an exception. Nevertheless, while modest activity of PD-1 inhibitors. A potential strategy to in paradigmatic immune-­ sensitive tumors a multicenter, single-­arm, convert a cold into an inflamed microenvironment lies on such as melanoma the expression levels of phase Ib/II trial. Journal for a combination therapy. As tumor angiogenesis promotes ImmunoTherapy of Cancer tumor mutational burden (TMB), CD8+ 2020;8:e001561. doi:10.1136/ immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/ lymphocytes and Programmed death-­ligand 1 Protected by copyright. jitc-2020-001561 PD-­L1 axis (nivolumab). (PD-­L1) were in the high range, with values Methods This single-­arm, phase Ib/II trial enrolled adult of 14 mutations per DNA megabase (Mb), ►► Additional material is published online only. To view, patients with selected subtypes of sarcoma. Phase Ib 42%±23% and 35%, respectively,4 5 sarcomas please visit the journal online established two dose levels: level 0 with sunitinib 37.5 mg appear at the low range of these expression (http://​dx.​doi.​org/​10.​1136/​jitc-​ daily from day 1, plus nivolumab 3 mg/kg intravenously values. Indeed, the median TMB reported 2020-​001561). on day 15, and then every 2 weeks; and level −1 with was 2 mutations per Mb,6 the percentage of sunitinib 37.5 mg on the first 14 days (induction) and then CD8+ lymphocytes was 23%±13%7 and the Poster discussion at ASCO 25 mg per day plus nivolumab on the same schedule. The tumorous PD-­L1 expression was 6.6% in the Annual Meeting 2018, Chicago, primary endpoint was to determine the recommended Illinois, USA (doi: 10.1200/ largest series.8 dose for phase II (phase I) and the 6-­month progression-­ JCO.2018.36.15_suppl.11515, free survival rate, according to Response Evaluation Specific immune-­ checkpoint protein Journal of Clinical Oncology expression, such as PD-1/PD-­ L1 axis, has 36, no. 15_suppl (May 20, Criteria in Solid Tumors 1.1 (phase II). 2018) 11515–11515.); oral Results From May 2017 to April 2019, 68 patients not demonstrated convincing prognostic or presentation at ESMO Annual were enrolled: 16 in phase Ib and 52 in phase II. The predictive value in sarcomas.9 10 Apart from Meeting 2019, Barcelona, Spain recommended dose of sunitinib for phase II was 37.5 mg the inherent heterogeneity of STS, other (Annals of Oncology (2019) 30 as induction and then 25 mg in combination with factors that introduce bias across these studies (suppl_5): v683-­v709. 10.1093/ nivolumab. After a median follow-­up of 17 months (4–26), annonc/mdz283); and oral were different staging, diverse antibody clones presentation at CTOS Annual the 6-­month progression-­free survival rate was 48% (95% used for PD-­L1,11 12 and intrastudy variability Meeting 2019, Tokyo, Japan. CI 41% to 55%). The most common grade 3–4 adverse between tissue microarray or complete tumor events included transaminitis (17.3%) and neutropenia block section.13 A genomic approach that can Accepted 19 October 2020 (11.5%). Conclusions Sunitinib plus nivolumab is an active circumvent some constraints of PD-­L1 immu- scheme with manageable toxicity in the treatment of nohistochemistry has confirmed an indepen- selected patients with advanced soft tissue sarcoma, with dent negative prognostic value for PD-­ L1 © Author(s) (or their almost half of patients free of progression at 6 months. overexpression in a large study of patients employer(s)) 2020. Re-­use Trial registration number NCT03277924. with STS.14 The elapsed time between tumor permitted under CC BY-­NC. No commercial re-­use. See rights sampling and the time frame considered and permissions. Published by for the analysis is a common limitation of BMJ. INTRODUCTION immunostaining and genomics, which is only For numbered affiliations see Systemic treatment for advanced soft tissue eluded if biopsies are mandatory at baseline. end of article. sarcomas (STS) is an unmet need since no Using transcriptomic analysis of the micro- Correspondence to new drugs or combination schemes have environment cell population, which measures Dr Javier Martin-­Broto; offered significant overall survival (OS) the expression of eight immune and two ​jmartin@​mustbesevilla.​org benefit over doxorubicin alone in the last stromal cell populations,15 it was possible to Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 1 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access classify sarcoma into five different sarcoma immune classes 3 mg/kg intravenously on day 15 and every 2 weeks from (SIC).16 Patients grouped as SIC E were considered the then on at both dose levels. Phase I was completed when most immune-­ responsive subset, but only represented 10 dose-­limiting toxicity (DLT) evaluable patients had 17.8% of cases. Therefore, the immune cold microenvi- been treated, associated with a DLT rate of less than 0.33. ronment found in most sarcomas could explain the low There was a de-­escalation level if three or more DLTs probability of response or tumor control with anti-­PD-1 occurred at the initial dose level. compounds in monotherapy. In fact, two reported expe- Radiological assessment was performed at the local sites riences with nivolumab showed a median progression-­ as well as by a mandatory independent central review. free survival (mPFS) of 1.7 months in 43 patients with Tumor assessment was done every 8 weeks by CT scan STS17 and 1.8 months in 12 patients with STS,18 respec- or by MRI in accordance with RECIST 1.1. Other rele- tively. A pioneer study trialing pembrolizumab in the vant procedures are described in online supplemental most frequent STS and bone sarcomas reported better methods. outcomes with an mPFS of 4.2 months, 18% of responses For translational purposes, tumor biopsies were and a 6-­month progression-­free survival rate (PFSR) of required at baseline and at week 13, and blood samples 32%.19 were collected at baseline, day 1 of week 3, day 1 of week Immune barrier promoted by tumor angiogenesis 13, and after each radiological evaluation. is well established and there is an ever growing list of The HTG EdgeSeq, ran in the VERIP service lab of immune cells exhibiting the dual capacity of promoting HTG in Tucson (HTG Molecular Diagnostics, Tucson, immunosuppression and angiogenesis.20 This impelled us Arizona, USA), and ProcartaPlex immunoassay (Invit- to design a double inhibition study with antiangiogenic rogen, Carlsbad, California, USA) protocols were applied and anti-­PD-1 compounds, which could potentially syner- in the exploratory translational study, and complete gize for the treatment of some advanced soft tissue and bioinformatic analyses are described in online supple- bone sarcomas. We present herein the phase Ib, common mental methods. to both cohorts, and phase II part of the STS cohort of the IMMUNOSARC trial, which combined sunitinib and Outcomes nivolumab. The bone sarcoma cohort will be reported The main endpoint for phase Ib was to determine the Protected by copyright. separately. recommended dose for phase II. The main endpoint for phase II was 6-­month PFSR according to RECIST. The secondary endpoints were median OS (mOS), overall METHODS response rate according to RECIST 1.1 and Choi criteria, Study design and subjects toxicity profile according to Common Terminology In this phase Ib/II, single-­arm trial, STS cohort, patients Criteria for Adverse Events (CTCAE) V.4.0, and contribu- aged over 18 years with advanced STS were considered tion to translational studies. for eligibility and enrolled in eight centers in Spain and Sample size has been obtained for a one-­arm, one-­stage Italy with expertise in sarcoma care. Central pathology survival design based on Brookmeyer-­Crowley-­like test.21 review was mandatory before accrual. Patients had to The statistical test for survival probability was based on be in progression in the previous 6 months according to non-­parametric estimation of survival distribution. For Response Evaluation Criteria in Solid Tumors (RECIST) STS second-­line cohort sample size has been obtained 1.1. Eligible subtypes of sarcoma were chosen based on for the primary endpoint: 6 month PFSR. The estimated several reasons: histologies reported in transplant recip- accrual time was 24 months. In this population, a 5% ients (undifferentiated pleomorphic sarcoma (UPS), PFSR was considered not promising, whereas a 15% PFSR angiosarcoma, and synovial sarcoma), higher tumor infil- was considered promising. With a 0.05 type I error α and trating lymphocytes (UPS and epithelioid sarcoma), or a power of 0.80, 48 patients were needed in this cohort. sensitivity to antiangiogenic compounds (solitary fibrous sarcoma, extraskeletal myxoid chondrosarcoma, clear Statistical analysis cell sarcoma, alveolar soft part sarcoma (ASPS), epithe- The intention-­to-­treat population includes patients who lioid hemangioendothelioma and angiosarcoma). Other had provided written informed consent, with central relevant inclusion criteria are described in online supple- pathology confirmation, and fulfilling all the inclusion mental methods. criteria and none of the exclusion criteria. The per-­ Patients provided written informed consent before protocol population (efficacy) includes patients fulfilling participating in the study. the intention-­to-­treat population criteria, and addition- ally patients who had received sunitinib in the induction Procedures phase and at least one dose of nivolumab. The safety popu- In phase I, two dose levels were defined: the starting dose lation includes all patients of the intention-­to-­treat popu- (dose level 0) used sunitinib 37.5 mg orally on a daily lation who had received at least one dose of sunitinib. basis from day 1. The de-­escalation level (dose level −1) The radiological evaluable population includes all patients of used sunitinib 37.5 mg on the first 14 days (induction) the intention-­to-­treat population who underwent at least and from then on 25 mg per day. Nivolumab was given at one radiological assessment. 2 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access The initial dose level (sunitinib 37.5 mg/day) in phase Ib was ceased after observing three DLTs in six accrued patients: grade 3 fatigue (n=2) and grade 4 septic shock (n=1). In the subsequent de-­escalation (−1) level, only one DLT (febrile neutropenia) was reported in 10 accrued patients. Thus, the recommended dose of sunitinib for phase II was 37.5 mg/day as induction on the first 14 days, followed by sunitinib 25 mg/day plus nivolumab 3 mg/kg every 2 weeks from day 15 on. One hundred and sixty-­ eight 2-­week cycles were administered in phase Ib. Phase Ib toxicities by patients are depicted in table 2. According to RECIST there were seven partial responses among 14 evaluable patients enrolled in this part (figure 2): two patients with clear cell sarcoma, two with ASPS, and one occurring in each of the following histologies: synovial sarcoma, chondrosarcoma and angiosarcoma. In the remaining non-­responder patients, three had stable disease and four had progressive disease. The clinical cut-­off for the final data analyses for phase II was February 27, 2020. At that time, 5 (10%) of the 52 patients were still under treatment and 47 (90%) have discontinued the scheme. Of the 52 patients, 40 (77%) discontinued due to progression, 4 (7%) following patient decision and 3 (6%) due to toxicity. The latter included grade 2 cystitis (n=1), grade 4 psoriatic arthritis (n=1) and grade 3 peripheral ischemia (n=1). The median elapsed Protected by copyright. Figure 1 CONSORT diagram. CONSORT, Consolidated time between previous progression and study enrollment Standards of Reporting Trials; ECOG, Eastern Cooperative was 1.17 months (0.03–5.17). Oncology Group; RECIST, Response Evaluation Criteria in Solid Tumors. Seven hundred and sixty-­ three 2-­week cycles were administered in 49 patients of the per-­protocol popula- tion, with a median of 6 (1–23) and 12 (2–46) cycles of Time-­to-­event variables were measured from the date of sunitinib and nivolumab per patient, respectively. The enrollment and were estimated according to the Kaplan-­ median dose intensity for sunitinib and nivolumab was Meier method. Comparisons between the variables of 97% (20–142) and 100% (33–100), respectively. One interest were performed by the log-­rank test. For variables (2%) patient had dose reductions and 29 (59%) had dose not available at baseline (ie, RECIST or Choi response), interruptions of sunitinib, whereas 21 (43%) patients had a landmark analysis was performed. False discovery rate dose interruptions of nivolumab. was applied to regulate multiple comparisons. Other The most frequent treatment-­ related toxicities per statistical methods are described in online supplemental subject in phase II were fatigue in 33 of 52 patients methods. (63.5%) and increased aspartate aminotransferase (AST) in 25 out of 52 patients (48.0%). The most common reported grade 3 or 4 side effects were transaminitis in 9 out of 52 patients (17.3%) and neutropenia in 6 out of 52 RESULTS patients (11.5%) (online supplemental table 1). From May 31, 2017 to April 18, 2019, 91 patients with At a median follow-­up of 17 months (4–26), 37 of 49 advanced and progressing STS were assessed for eligibility (76%) per-­ protocol evaluable patients experienced in phase Ib and in the STS cohort of phase II. Twenty-­three progression according to central assessment and 18 of 49 patients were excluded (considering both phases) after (37%) patients died due to disease progression. screening. Sixty-­eight patients were enrolled and treated The 6-­month PFSR according to central and local assess- with the experimental compounds: 16 in phase Ib and ments was 48% (95% CI 41 to 55) and 51% (95% CI 44 52 in the STS cohort of phase II. The intention-­to-­treat to 58), respectively (figure 3). The mPFS for central and population and safety population for phase II consisted local assessments was 5.6 months (3.0–8.1) and 6.0 months of 52 eligible patients, while the per-­protocol population (3.1–9.0), respectively. Remarkably, the proportion of consisted of 49 patients, since 3 patients had not ever patients alive at 12 and 18 months was 75% (95% CI 68 received nivolumab. Radiological evaluable patients in to 81) and 67% (95% CI 59 to 74), respectively, and the phase II according to RECIST and Choi criteria were 46 mOS was 24 months (95% CI NA). Central radiological and 40, respectively (figure 1). Patients’ demographics assessment according to RECIST (figure 2) reported are depicted in table 1. 1 complete response in 46 evaluable patients (2%), 5 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 3 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Table 1 Baseline characteristics Phase Ib (n=16) Phase II (n=52) Median age (range) (months) 38 (25–78) 43 (19–77) Sex (male/female), n (%) 10 (63)/6 (37) 30 (58)/22 (42) Primary tumor localization, n (%)  Somatic 15 (94) 44 (85)  Visceral 1 (6) 8 (15) Primary tumor depth, n (%)  Deep 16 (100) 40 (77)  Superficial 0 9 (17)  UK 0 3 (6) Extension at diagnosis, n (%)  Localized 9 (56) 25 (48)  Locally advanced 2 (13) 15 (29)  Metastatic 5 (31) 12 (23) Resectable at diagnosis, n (%)  Resectable 10 (63) 38 (73)  Unresectable 6 (37) 14 (27) Median metastatic-­free interval (range) (months) 8 (0–80) 11 (0–141) Extension at baseline, n (%)  Locally advanced 0 4 (8)  Metastatic 16 (100) 48 (92) Protected by copyright. Diagnosis (central), n (%)  Synovial sarcoma 2 (13) 9 (17)  UPS 2 (13) 8 (15)  Clear cell sarcoma 4 (25) 7 (14)  Solitary fibrous tumor 0 7 (14)  Epithelioid sarcoma 0 7 (14)  Angiosarcoma 2 (13) 5 (10)  Extraskeletal myxoid chondrosarcoma 0 4 (7)  Alveolar soft part sarcoma 3 (19) 4 (7)  Epithelioid hemangioendothelioma 0 1 (2)  Osteosarcoma* 2 (13) 0  Chondrosarcoma* 1 (6) 0 ECOG PS at baseline, n (%)  0 6 (37) 25 (48)  1 10 (63) 27 (52) Median previous lines (range) 1.5 (0–5) 1 (0–4) Previous antiangiogenic lines, n (%)  0 14 (88) 41 (79)  1 2 (12) 10 (19)  2 0 1 (2) *Included in phase Ib. ECOG PS, Eastern Cooperative Oncology Group performance status; UK, unknown; UPS, undifferentiated pleomorphic sarcoma. partial responses (11%), 33 stabilizations (72%) and 7 (n=1), extraskeletal myxoid chondrosarcoma (n=1) and progressions (15%). Complete response was observed synovial sarcoma (n=1). Central assessment according in one patient with angiosarcoma and partial response to Choi criteria showed 25 patients with partial response in patients diagnosed with ASPS (n=2), angiosarcoma (63%), 10 with stable disease (25%) and 5 with progressive 4 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Table 2 Toxicity profile in phase Ib Phase Ib (n=16) Type of adverse event (n=16) Any grade, n (%) Grades 1–2, n (%) Grade 3, n (%) Grade 4, n (%) Grade 5, n (%) Hematological toxicity Leukopenia 12 (75.0) 11 (68.8) 1 (6.3) 0 0 Neutropenia 10 (62.5) 7 (43.8) 3 (18.8) 0 0 Thrombocytopenia 9 (56.3) 7 (43.8) 2 (12.5) 0 0 Anemia 8 (50.0) 6 (37.5) 2 (12.5) 0 0 Lymphopenia 2 (12.5) 2 (12.5) 0 0 0 Febrile neutropenia 1 (6.3) 0 0 1 (6.3) 0 Non-­hematological toxicity Fatigue 14 (87.5) 11 (68.8) 3 (18.8) 0 0 Hypertension 11 (68.8) 10 (62.5) 1 (6.3) 0 0 Diarrhea 8 (50.0) 8 (50.0) 0 0 0 Oral mucositis 8 (50.0) 7 (43.8) 1 (6.3) 0 0 Increased AST 7 (43.8) 6 (37.5) 1 (6.3) 0 0 Nausea 6 (37.5) 6 (37.5) 0 0 0 Increased ALT 5 (31.3) 4 (25.0) 1 (6.3) 0 0 Anorexia 4 (25.0) 4 (25.0) 0 0 0 Constipation 3 (18.8) 3 (18.8) 0 0 0 Hyponatremia 3 (18.8) 3 (18.8) 0 0 0 Protected by copyright. Hypothyroidism 3 (18.8) 2 (12.5) 1 (6.3) 0 0 Palmar-­plantar 3 (18.8) 3 (18.8) 0 0 0 erythrodysesthesia syndrome Skin/subcutaneous 3 (18.8) 3 (18.8) 0 0 0 tissue disorders Stomach pain 3 (18.8) 3 (18.8) 0 0 0 Vomiting 3 (18.8) 3 (18.8) 0 0 0 Hypokalemia 3 (18.8) 2 (12.5) 1 (6.3) 0 0 Increased ALP 2 (12.5) 2 (12.5) 0 0 0 Infection 2 (12.5) 0 1 (6.3) 1 (6.3) 0 Dysgeusia 2 (12.5) 2 (12.5) 0 0 0 Epistaxis 2 (12.5) 2 (12.5) 0 0 0 Fever 2 (12.5) 2 (12.5) 0 0 0 Hypermagnesemia 2 (12.5) 2 (12.5) 0 0 0 Periodontal disease 2 (12.5) 2 (12.5) 0 0 0 Arthralgia 1 (6.3) 1 (6.3) 0 0 0 Body pain 1 (6.3) 1 (6.3) 0 0 0 Bronchopulmonary 1 (6.3) 1 (6.3) 0 0 0 hemorrhage Renal function 1 (6.3) 1 (6.3) 0 0 0 deterioration Dry mouth 1 (6.3) 0 1 (6.3) 0 0 Flatulence 1 (6.3) 1 (6.3) 0 0 0 Headache 1 (6.3) 1 (6.3) 0 0 0 Hiccups 1 (6.3) 1 (6.3) 0 0 0 Hypercalcemia 1 (6.3) 1 (6.3) 0 0 0 Hypocalcemia 1 (6.3) 1 (6.3) Continued Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 5 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Table 2 Continued Phase Ib (n=16) Type of adverse event (n=16) Any grade, n (%) Grades 1–2, n (%) Grade 3, n (%) Grade 4, n (%) Grade 5, n (%) Hypernatremia 1 (6.3) 1 (6.3) 0 0 0 Hypomagnesemia 1 (6.3) 1 (6.3) 0 0 0 Hypophosphatemia 1 (6.3) 1 (6.3) 0 0 0 Myalgia 1 (6.3) 1 (6.3) 0 0 0 Odynophagia 1 (6.3) 1 (6.3) 0 0 0 Tumor lesions bleeding 1 (6.3) 1 (6.3) 0 0 0 Periorbital edema 1 (6.3) 1 (6.3) 0 0 0 Proteinuria 1 (6.3) 1 (6.3) 0 0 0 Thromboembolic event 1 (6.3) 0 0 1 (6.3) 0 Weight loss 1 (6.3) 1 (6.3) 0 0 0 ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase. disease (12%). Response assessment according to RECIST have potential prognostic value for PFS and OS, respec- showed significant prognostic difference for PFS and OS; tively. Hierarchical clustering, considering the 102 genes by contrast, Choi assessment only had prognostic rele- with impact on OS, distributed samples into two groups vance for PFS. Adding the 12 evaluable STS cases of phase with a distinct molecular pattern (online supplemental I to the 46 evaluable patients with STS in phase II, the figure 1). The different outcome of these two groups RECIST Overall Response Rate (ORR) was 21% (12 out was confirmed (table 3). Functional enrichment analysis Protected by copyright. of 58). The 18-­month OS proportion was 100%, 75% and showed that the genes upregulated in group 2 (molecular 44% for those with response, stable disease and progres- group with better survival) were highly associated with sive disease, according to RECIST, respectively (p=0.01) Kyoto Encyclopedia of Genes and Genomes (KEGG) path- (table 3). ways (online supplemental figure 2) cytokine-­ cytokine Ad hoc analyses showed a growth modulation index receptor interaction (hsa04060) (adjusted p=3.69×10−53) (GMI) in phase II of 0.7 (0.1–11.6), while 31% of patients or chemokine signaling pathway (hsa04062) (adjusted exhibited GMI >1.33. On the other hand, the GMI in p=2.13×10−22). On the other hand, genes upregulated phase II in subtypes with known sensitivity to antiangio- in group 1 (molecular group with worse outcome) were genic compounds was 1.01 (0.04–26.82). In the translational study, among 732 genes related to tumor immune response, 50 and 102 genes showed to Figure 3 Progression-­free survival to treatment by patient, Figure 2 Response to treatment by patient according based on RECIST central radiological assessment. Each to RECIST. All evaluable patients (N=60) from phase Ib patient in the efficacy population in phase II is represented as (n=14) and phase II (n=46) are shown. Tumor diameter was bars (n=49). The vertical dashed line represents the median measured in millimeters. The dashed lines represent 20% progression-­free survival (5.6 months). The stars represent increase in diameter and 30% decrease in diameter (RECIST patients achieving RECIST objective responses. The arrows progression and response cut-­offs, respectively). *No size represent patients non-­progressing in the last central variation. RECIST, Response Evaluation Criteria in Solid radiological assessment. RECIST, Response Evaluation Tumors. Criteria in Solid Tumors. 6 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Table 3 Univariate analysis Demographics and clinical characteristics in phase II (n=49) Median PFS PFS at 6 months, % OS at 18 months, (central) (95% CI) (95% CI) P value Median OS (95% CI) % (95% CI) P value Age 0.4 0.55  0–44 4.5 (1.8 to 7.1) 45 (36 to 55) NR 75 (65 to 84)  >44 6.5 (2.2 to 10.8) 52 (41 to 63) 24.1 (18.6 to 29.7) 61 (51 to 71) MFI (years) 0.59 0.97  0–1 4.5 (2.6 to 6.3) 43 (33 to 52) 24.1 (NA) 66 (56 to 76)  >1 6.1 (0 to 14.6) 54 (44 to 65) NR 68 (58 to 78) Baseline ECOG 0.2 0.098  0 7.3 (4.2 to 10.4) 56 (46 to 66) NR 80 (72 to 88)  1 4.1 (3 to 5.2) 40 (29 to 50) 22.5 (8.8 to 36.2) 51 (39 to 63) Baseline extension 0.9 0.22  Metastatic 6.1 (2.6 to 9.6) 50 (43 to 58) 24.1 (19.5 to 28.8) 63 (56 to 71)  Locally advanced 3.8 (1.3 to 6.2) 25 (2 to 48) NR 100 (NA) Previous lines 0.28 0.096  0–1 5.6 (0.8 to 10.3) 49 (39 to 59) NR 76 (67 to 86)  >1 4.1 (0.6 to 7.7) 47 (37 to 58) 21 (6.5 to 35.6) 55 (44 to 66) Previous antiangiogenic 0.27 0.71  No 4.4 (2.6 to 6.2) 41 (33 to 49) 24.1 (19.7 to 28.6) 65 (57 to 73)  Yes 15.5 (4.3 to 26.7) 73 (59 to 86) NR 72 (58 to 86) Protected by copyright. Central RECIST response 0.005 0.01  CR/PR 11.7 (10.9 to 12.4) 100 NR 100  SD 3.7 (1.6 to 5.9) 39 NR 75  PD 0 0 3.9 (0 to 11.6) 44 Central Choi response 0.005 0.97  PR 5.6 (0.6 to 10.6) 48 22.3 (19.3 to 25.3) 68  SD 4.4 (0 to 17.8) 50 NR 80  PD 0 0 NR 67 RNA expression genes from phase Ib and II (n=28)* PDGFD† 0.005 0.005  0–4.9 3.5 (1.7 to 5.2) 17 (6 to 27) 9.8 (7.2 to 12.5) 25 (12 to 37)  >4.9 11.5 (3.9 to 19.1) 74 (63 to 85) NR 93 (87 to 100) IL16† 0.005 0.022  0–6.1 4 (2.5 to 5.5) 24 (14 to 35) 13.9 (0.6 to 27.3) 47 (35 to 59)  >6.1 13.5 (8.2 to 18.8) 90 (80 to 99) NR 90 (80 to 99) TAL1† 0.01 0.007  0–3.5 3 (0.2 to 5.7) 12 (1 to 24) 8.4 (0 to 18.7) 25 (10 to 40)  >3.5 7.5 (3.8 to 11.1) 64 (53 to 75) NR 79 (70 to 88) IL23A† 0.27 0.018  0–4.1 5.2 (2.1 to 8.2) 38 (25 to 52) 12.7 (6.2 to 19.2) 38 (25 to 52)  >4.1 7.5 (2 to 12.9) 58 (45 to 71) NR 86 (76 to 95) TNFSF13B† 0.017 0.007  0–5.3 3 (0.1 to 5.9) 10 (0 to 19) 9.8 (0 to 21.4) 30 (15 to 44)  >5.3 7.5 (4.2 to 10.7) 71 (60 to 82) NR 82 (73 to 92) CD276† 0.005 0.005  0–8.4 9.6 (4.8 to 14.4) 67 (56 to 78) NR 83 (74 to 92)  >8.4 3 (0.5 to 5.4) 11 (1 to 22) 8.4 (0 to 17.5) 22 (8 to 36) Continued Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 7 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access Table 3 Continued Demographics and clinical characteristics in phase II (n=49) Median PFS PFS at 6 months, % OS at 18 months, (central) (95% CI) (95% CI) P value Median OS (95% CI) % (95% CI) P value PDCD1 (PD-1)† 0.007 0.17  0–4.5 4.1 (3.2 to 5) 32 (21 to 42) 21.1 (7.4 to 34.6) 53 (41 to 64)  >4.5 15.5 (12.9 to 18.1) 89 (78 to 99) NR 87 (76 to 99) CD274 (PD-­L1)† 0.19 0.009  0–4.9 4.1 (2.1 to 6.1) 33 (20 to 47) 9.9 (5.1 to 14.8) 33 (20 to 47)  >4.9 7.5 (0 to 16.3) 61 (48 to 73) NR 87 (78 to 96) Hierarchical clustering‡ 0.25 0.021  Group 1 4.1 (1.8 to 6.5) 27 12.7 (6.7 to 18.7) 27  Group 2 7.5 (6.6 to 8.3) 59 NR 59 *Samples with sufficient material for direct transcriptomics. †Genes were categorized using ROC curves for their impact on progression-­free survival and overall survival. ‡Taking into account the genes with impact on overall survival. CR, complete response; ECOG, Eastern Cooperative Oncology Group; MFI, metastasis-­free interval; NR, not-­reached; OS, overall survival; PD, progressive disease; PD-1, programmed cell death protein 1; PD-­L1, programmed death-­ligand 1; PFS, progression-­free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; ROC, receiver operating characteristic curve; SD, stable disease. greatly associated with metabolic and energetic processes histologies or those histologies more sensitive to antiangio- (online supplemental figure 3). genics as the reason for this prolonged survival, but we did Other clinical and translational results are described in not find significant differences in survival between groups. online supplemental results. The 6-­month PFSR of 48% and the mOS of 24 months Protected by copyright. showed in our trial favorably compare with the activity reported with anti-­ PD-1 or sunitinib in monotherapy in DISCUSSION previous STS trials. The SARC028 study reported 32% and In this phase Ib/II trial, we found that the 6-­month PFSR 11.4 months for 6-­month PFSR and mOS, respectively, in was 48% according to RECIST and independent central 42 patients with STS treated with pembrolizumab.19 Never- review. This outcome widely exceeds the 15% considered theless, the SARC028 study selected the four more frequent promising in the statistical assumption of this trial. This histotypes for the STS cohort, making comparison with our threshold was based on the European Organisation for study difficult since only synovial sarcoma and UPS were Research and Treatment of Cancer (EORTC) recom- common histologies in both trials. The Alliance-091401 mendation cut-­off for activity, in terms of 6-­month PFSR, trial reported 15% and 10.7 months, respectively, for the in second line drugs of advanced STS.22 This indicator same indicators in 43 patients with STS treated in the mono- was chosen considering that a valuable immunotherapy therapy arm with nivolumab.17 Another study was prema- should induce durable disease control; accordingly, turely closed, with 12 patients with uterine leiomyosarcoma 3-­month PFSR would not be useful enough in detecting treated with nivolumab, after observing an mPFS of 1.8 the potential added value of immunomodulation in sarcoma. The scheme was in general manageable even months at the interim analysis and with no patient free of when it required transient dose interruptions in up to progression at 6 months.18 Sunitinib was also trialed as mono- 59% of patients. Neutropenia, which could be related therapy in a phase II study of 50 patients with STS, reporting to FLT3 inhibition by sunitinib,23 was found at a higher a 6-­month PFSR of 22% with an mPFS of 1.8 months, while proportion than sarcoma trials with anti-­PD-1 alone19 or OS data were not provided.24 Of note, the GMI in our study sunitinib alone.24 The difference with the latter could be is comparable with those reported with active chemotherapy explained by the shorter use of sunitinib due to earlier in second line,28 and the median elapsed time of 1.17 months progression in the monotherapy trial. between previous progression and enrollment reinforces the The mOS of 24 months is worth mentioning; phase III outcome in terms of PFS. Furthermore, the GMI in the subset trials showing significant benefits of some active drugs in of subtypes with higher potential sensitivity to antiangiogenics STS second line reported mOS ranging from 12.5 to 13.5 was even better. A limitation of this study is inherent to design months.25–27 It will be important to analyze postprotocol assumption: it is not possible to distinguish separately the effi- therapies and microenvironment transformation after the cacy of antiangiogenic or anti-­PD-1. The differences detected immunomodulatory treatment since the clinical impact between immunomodulation with combination approach of the sunitinib and nivolumab scheme could also have an and monotherapy underline the feature that STS exhibits, influence on subsequent postprotocol therapies. We have in general, a cold immune microenvironment. In line with analyzed the potential bias of selecting some more indolent this, a combined immunotherapy approach tried to convert 8 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access a cold into inflamed microenvironment in sarcomas. Thus, whereas metabolic processes were linked to worse outcome. the combination arm of Alliance-091401 addressed a double The role of metabolism in tumor immune evasion has been immune-­checkpoint inhibition with nivolumab plus ipilim- previously described.32 33 Also, the significant prognostic value umab. Patients in the combination arm had a 6-­month PFSR of PDGFD or IL16 overexpression in longer survival, shown in of 28% and a mOS of 14.3 months, all the efficacy indica- online supplemental results, is a finding that deserves to be tors being superior to monotherapy arm. The lower 6-­month further explored. PFSR and the shorter OS in the combination arm in compar- Based on the findings of this study, six subtypes of sarcoma ison with our trial could be explained, at least partially, by were selected for a multicohort phase II trial, which has been the restriction in the number of ipilimumab cycles (four at recently activated, with the same regimen. In the translational maximum).17 Conceptually similar to our study, the adminis- research, only 28 samples were used for transcriptomics, tration of antiangiogenic plus anti-­PD-1 agents was explored which is a limitation of this study. However, a broad compre- in a single-­center phase II trial with axitinib plus pembroli- hensive analysis of the immune populations within the zumab . The 6-­month PFSR was 46.9% and the mOS was tumor and their association with gene signatures and clinical 18.7 months, which were both closely similar to our study. outcomes is currently ongoing and expected to be published A substantially different aspect was based on the proportion as a separate correlative study. Sunitinib inhibits several of ASPS; while in the axitinib-­pembrolizumab 36% of the tyrosine kinase receptors (TKR), including angiogenic (eg, patients had this subtype, in our trial only 7% had this diag- Vascular Endothelial Growth Factor Receptor (VEGFR) types nosis. Thus, for the non-­ASPS cases of that trial, the mPFS was 1 and 2, and PDGFR-α and PDGFR-β), pro-­oncogenic (eg, 3 months, the 6-­month PFSR was 38.1%, the mOS was 13.1 fms like tyrosine kinase 3 (FLT3), rearranged during trans- months, while no patient survived beyond 2 years. All these fection (RET), and KIT) or immune-­related pathways (eg, parameters seemed to be worse than ours, although limited Colony stimulating factor 1 receptor (CSF1R)). Although by indirect comparisons. The indolence and special sensitivity the main hypothesis of this study is to convert the sarcoma of this subtype to both antiangiogenic and immunomodula- cold microenvironment into an inflamed one, by inhibiting tion could have influenced the survival results. In our series, immunosuppression driven by angiogenesis, we cannot four of seven accrued patients with ASPS (considering both discard the potential added value of targeting other TKRs. phases) had partial response (57%), whereas in a random- In fact, it seems that CSF1 expression has been described Protected by copyright. ized phase II trial exploring cediranib versus placebo in ASPS as an adaptive mechanism of resistance to anti-­PD-1 inhi- the authors reported responses in 6 of 31 (19%) patients.29 bition in melanoma, while the combination of anti-­CSF1R In fact, excluding ASPS from the analysis of PFS due to its and anti-­PD-1 inhibitions was demonstrated to be active in inherent indolence, we were not able to find statistical differ- BRAFV600E-­ driven, transplant mouse melanomas. The effi- ences between potential antiangiogenic sensitive subtypes cacy of this combination was dependent on the elimination and others. In other words, ASPS cases could represent of tumor-­associated macrophages (TAMs).34 Likewise, it has bias for the main endpoint of 6-­month PFSR. Intriguingly, been reported that the combination of CSF1R inhibitor with ASPS does not exhibit some features of the classic immune anti-­PD-­L1/PD-1 axis blockage is also highly active in hepa- sensitive microenvironment; thus, the proportion of tumor tocellular carcinoma mouse models, increasing intratumoral infiltrating lymphocytes, or specifically CD8+ or FOXP3+ CD8+ T cells infiltrate and reducing TAMs.35 Translational subpopulations, per cubic millimeter is lower in ASPS than and preclinical studies will also address the potential role of in non-­translocation-­related sarcomas.30 Additionally, TMB is targeting these TKRs for anti-­PD-1/PD-­L1 axis inhibition effi- lower in ASPS compared with other sarcomas, such as synovial cacy in STS. sarcoma or Ewing sarcoma. The activity of anti-­PD-1 in ASPS In conclusion, our study supports the idea that the PD-1/ has been related with molecular mismatch-­repair deficiency PD-­L1 axis inhibition per se is not enough in the context of signature, even in the absence of high TMB, but a broader STS. Combination strategies promoting inflamed microenvi- number of cases to confirm this point will be required.31 ronment resulted in a higher efficacy in this setting. Targeting The proportion of responding patients, 13% in phase II or new immune-­checkpoint inhibitors and selecting histological 21% joining STS evaluable patients from phase Ib and II of subtypes could also be advantageous in future trials. Correla- our trial, is similar to the 18% reported with pembrolizumab tive studies searching predictive signatures will allow a better in the SARC028 study. This could be explained by STS hetero- selection of patients for immunotherapy. geneity, even within specific subtype; for instance, from seven evaluable patients with UPS in our phase II, only two had Author affiliations 1 Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain stabilization and five had progressive disease, with an mPFS 2 Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Sevilla, of 1.8 months. By contrast, in the SARC028 study, from nine Spain patients with UPS, four responded, three were stable and two 3 Division of Medical Oncology, Candiolo Cancer Institute, FPO - IRCCS - Str. P​ rov.​le progressed, with an mPFS of 7 months. This emphasizes the 142, km. 3,95 - Candiolo (TO) 10060, Candiolo, Italy 4 concept of the relevance of the microenvironment in the Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain 5 Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain immunomodulation results in sarcoma. A potential molec- 6 Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, ular prognostic signature with impact on survival has been Spain proposed in our exploratory translational research. Of note, 7 Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere inflammatory processes were associated with better survival, Scientifico (IRCCS) Istituto Nazionale Tumori, Via Venezian 1, Milan, Italy Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 9 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access 8 Medical Oncology Department, Sant Pau Hospital, Barcelona, Spain responsibility arising from any reliance placed on the content. Where the content 9 Medical Hematology Department, University Hospital Son Espases, Mallorca, Spain includes any translated material, BMJ does not warrant the accuracy and reliability 10 Radiology Department, University Hospital Virgen del Rocio, Sevilla, Spain of the translations (including but not limited to local regulations, clinical guidelines, 11 Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital / terminology, drug names and drug dosages), and is not responsible for any error CSIC/University of Sevilla/CIBERONC, Sevilla, Spain and/or omissions arising from translation and adaptation or otherwise. 12 Department of Normal and Pathological Cytology and Histology, School of Open access This is an open access article distributed in accordance with the Medicine, University of Seville, 41009, Sevilla, Spain Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 13 Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, permits others to distribute, remix, adapt, build upon this work non-­commercially, Diagnostic Pathology and Laboratory Medicine Department, Fondazione Istituto di and license their derivative works on different terms, provided the original work is Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, properly cited, appropriate credit is given, any changes made indicated, and the use Italy is non-­commercial. See http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 14 Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS). CDCA, Hospital Virgen del Rocio, Sevilla, Spain ORCID iDs 15 Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red Javier Martin-­Broto http://​orcid.​org/​0000-​0001-​7350-​6916 de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain Giovanni Grignani http://​orcid.​org/​0000-​0001-​5515-​569X 16 INB-­ELIXIR-­es, FPS, Hospital Virgen del Rocío, Sevilla, Spain 17 Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain 18 Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain REFERENCES 1 Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: a phase Acknowledgements The authors would like to thank Patricio Ledesma Figueroa, III, placebo-­controlled study of doxorubicin with or without Araceli Rodriguez Morales and Emanuela Marchesi for data management. Palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol 2016;34:3898–905. Contributors Conception and design of the study: JM-­B and JAL-­M. Collection 2 Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide and assembly of clinical data: JM-­B, NH, GG, JM-­T, AR, CV, SS, AL-­P, LD, IC-­G versus doxorubicin alone in locally advanced, unresectable and JAL-­M. Collection and execution of correlative studies: JM-­B and DSM. Data or metastatic soft-­tissue sarcoma (th CR-406/SARC021): an analysis and interpretation of results: JM-­B, NH, AG, HP-­V, VE-­T, EdA, PC, MP-­C, international, multicentre, open-­label, randomised phase 3 trial. JD, ML-­A, DSM and JAL-­M. Writing and revision of the manuscript: all authors. Lancet Oncol 2017;18:1089–103. Manuscript final approval: all authors. 3 Martin-­Broto J, Pousa AL, de Las Peñas R, et al. Randomized phase II study of trabectedin and doxorubicin compared with doxorubicin Funding This work was supported by GEIS and ISG. BMS and Pfizer provided drug alone as first-­line treatment in patients with advanced soft tissue supply and partial funding for shipping. Translational studies were partially funded sarcomas: a Spanish group for research on sarcoma study. J Clin by Beca Buesa from the GEIS group. Oncol 2016;34:2294–302. 4 Iglesia MD, Parker JS, Hoadley KA, et al. Genomic analysis of Protected by copyright. Competing interests JM-­B reports research grants from PharmaMar, Eisai, Immix immune cell infiltrates across 11 tumor types. J Natl Cancer Inst BioPharma and Novartis, outside the submitted work; honoraria for advisory board 2016;108:djw144. participation and expert testimony from PharmaMar, Eli Lilly and Company, Bayer 5 Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated and Eisai; and research funding for clinical studies (institutional) from PharmaMar, melanoma without BRAF mutation. N Engl J Med Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, 2015;372:320–30. 6 Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. NH reports grants, human cancer genomes reveals the landscape of tumor mutational personal fees and non-­financial support from PharmaMar, personal fees from Lilly, burden. Genome Med 2017;9:34. and grants from Eisai and Novartis, outside the submitted work, and research 7 Balch CM, Riley LB, Bae YJ, et al. Patterns of human tumor-­ funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, infiltrating lymphocytes in 120 human cancers. Arch Surg AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, 1990;125:200–5. Nektar, Forma, Amgen and Daiichi Sankyo. GG reports grants and personal fees 8 Inaguma S, Wang Z, Lasota J, et al. Comprehensive from PharmaMar, grants from Novartis, and personal fees from Lilly, Pfizer, Bayer immunohistochemical study of programmed cell death ligand 1 and Eisai, outside the submitted work. AR reports grants and personal fees from (PD-­L1): analysis in 5536 cases revealed consistent expression in trophoblastic tumors. Am J Surg Pathol 2016;40:1133–42. PharmaMar, personal fees from Lilly, Novartis, Amgen, AstraZeneca and Tesaro, 9 Pollack SM, He Q, Yearley JH, et al. T-­cell infiltration and clonality grants and personal fees from Roche, and grants from Eisai, outside the submitted correlate with programmed cell death protein 1 and programmed work. SS reports grants and personal fees from Bayer, Lilly and PharmaMar, and death-­ligand 1 expression in patients with soft tissue sarcomas. grants from GlaxoSmithKline, Novartis and Pfizer, outside the submitted work. Cancer 2017;123:3291–304. EdA reports personal fees and non-­financial support from Roche, BMS and 10 D'Angelo SP, Shoushtari AN, Agaram NP, et al. Prevalence of tumor-­ PharmaMar, and personal fees from Bayer, outside the submitted work. ML-­A infiltrating lymphocytes and PD-­L1 expression in the soft tissue declares institutional research grants from PharmaMar, Eisai, Immix BioPharma sarcoma microenvironment. Hum Pathol 2015;46:357–65. 11 Torabi A, Amaya CN, Wians FH, et al. Pd-1 and PD-­L1 expression in and Novartis, outside the submitted work. DSM reports institutional research grants bone and soft tissue sarcomas. Pathology 2017;49:506–13. from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work, 12 Oike N, Kawashima H, Ogose A, et al. Prognostic impact of the and travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer. JAL-­M reports tumor immune microenvironment in synovial sarcoma. Cancer Sci honoraria for advisory board participation and travel support from PharmaMar, Eli 2018;109:3043–54. Lilly and Company, Bayer, Eisai, Novartis, BMS, MSD, Roche, Celgene, Pierre Fabre, 13 Park HK, Kim M, Sung M, et al. Status of programmed death-­ligand Pfizer, GSK, Daiichi Sankyo, Amgen, and Chobani. All other authors declare no 1 expression in sarcomas. J Transl Med 2018;16:303. relevant relationship to disclose. 14 Bertucci F, Finetti P, Perrot D, et al. PDL1 expression is a poor-­ prognosis factor in soft-­tissue sarcomas. Oncoimmunology Patient consent for publication Not required. 2017;6:e1278100. 15 Becht E, Giraldo NA, Lacroix L, et al. Estimating the population Ethics approval Study procedures were in accordance with the guidelines abundance of tissue-­infiltrating immune and stromal cell populations established by the ethics committee of each hospital and with the Declaration of using gene expression. Genome Biol 2016;17:218. Helsinki. Approval was obtained from the ethics committees. 16 Petitprez F, de Reyniès A, Keung EZ, et al. B cells are associated Provenance and peer review Not commissioned; externally peer reviewed. with survival and immunotherapy response in sarcoma. Nature 2020;577:556–60. Data availability statement Raw data from HTG Molecular OBP panel 17 D'Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with experiments are available in the Gene Expression Omnibus (GEO) from NCBI. or without ipilimumab treatment for metastatic sarcoma (alliance A091401): two open-­label, non-­comparative, randomised, phase 2 Supplemental material This content has been supplied by the author(s). It has trials. Lancet Oncol 2018;19:416–26. not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been 18 Ben-­Ami E, Barysauskas CM, Solomon S, et al. Immunotherapy with peer-­reviewed. Any opinions or recommendations discussed are solely those single agent nivolumab for advanced leiomyosarcoma of the uterus: of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and results of a phase 2 study. Cancer 2017;123:3285–90. 10 Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 J Immunother Cancer: first published as 10.1136/jitc-2020-001561 on 17 November 2020. Downloaded from http://jitc.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Open access 19 Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced of a phase III randomized multicenter clinical trial. J Clin Oncol soft-­tissue sarcoma and bone sarcoma (SARC028): a multicentre, 2016;34:786–93. two-­cohort, single-­arm, open-­label, phase 2 trial. Lancet Oncol 28 Penel N, Demetri GD, Blay JY, et al. Growth modulation index as 2017;18:1493–501. metric of clinical benefit assessment among advanced soft tissue 20 Motz GT, Coukos G. The parallel lives of angiogenesis and sarcoma patients receiving trabectedin as a salvage therapy. Ann immunosuppression: cancer and other tales. Nat Rev Immunol Oncol 2013;24:537–42. 2011;11:702–11. 29 Judson I, Morden JP, Kilburn L, et al. Cediranib in patients with 21 Brookmeyer R, Crowley J. A confidence interval for the median alveolar soft-­part sarcoma (CASPS): a double-­blind, placebo-­ survival time. Biometrics 1982;38:29–41. controlled, randomised, phase 2 trial. Lancet Oncol 2019;20:1023–34. 22 Van Glabbeke M, Verweij J, Judson I, et al. Progression-­free rate as 30 Dancsok AR, Setsu N, Gao D, et al. Expression of lymphocyte the principal end-­point for phase II trials in soft-­tissue sarcomas. Eur immunoregulatory biomarkers in bone and soft-­tissue sarcomas. J Cancer 2002;38:543–9. Mod Pathol 2019;32:1772–85. 23 van Erp NP, Mathijssen RHJ, van der Veldt AA, et al. 31 Lewin J, Davidson S, Anderson ND, et al. Response to immune Myelosuppression by sunitinib is flt-3 genotype dependent. Br J checkpoint inhibition in two patients with alveolar soft-­part sarcoma. Cancer 2010;103:757–8. Cancer Immunol Res 2018;6:1001–7. 24 George S, Merriam P, Maki RG, et al. Multicenter phase II trial of 32 Leone RD, Zhao L, Englert JM, et al. Glutamine blockade induces sunitinib in the treatment of nongastrointestinal stromal tumor divergent metabolic programs to overcome tumor immune evasion. sarcomas. J Clin Oncol 2009;27:3154–60. Science 2019;366:1013–21. 25 van der Graaf WTA, Blay J-­Y, Chawla SP, et al. Pazopanib for 33 DeBerardinis RJ. Tumor microenvironment, metabolism, and metastatic soft-­tissue sarcoma (PALETTE): a randomised, double-­ immunotherapy. N Engl J Med 2020;382:869–71. blind, placebo-­controlled phase 3 trial. Lancet 34 Neubert NJ, Schmittnaegel M, Bordry N, et al. T cell-­induced CSF1 2012;379:1879–86. promotes melanoma resistance to PD1 blockade. Sci Transl Med 26 Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine 2018;10:eaan3311. in previously treated patients with advanced liposarcoma or 35 Zhu Y, Yang J, Xu D, et al. Disruption of tumour-­associated leiomyosarcoma: a randomised, open-­label, multicentre, phase 3 macrophage trafficking by the osteopontin-­induced colony-­ trial. Lancet 2016;387:1629–37. stimulating factor-1 signalling sensitises hepatocellular carcinoma to 27 Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety anti-­PD-­L1 blockade. Gut 2019;68:1653–66. of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results Protected by copyright. Martin-­Broto J, et al. J Immunother Cancer 2020;8:e001561. doi:10.1136/jitc-2020-001561 11