Table 1.
Published results of immunotherapy in sarcoma. AEs: adverse effects; irAEs: immune-related adverse effects; ORR: objective response rate (RECIST criteria); mPFS: median progression-free survival; mOS: median overall survival; m: months; w: weeks; PR: partial response; SD: stable disease; DCR: disease control rate (PR+SD); mDR: median duration of response; NA: not available; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BS: bone sarcoma; STS: soft-tissue sarcoma; OST: osteosarcoma; ES: Ewing sarcoma; CS: chondrosarcoma; LMS: leiomyosarcoma; LPS: liposarcoma; SS: synovial sarcoma; UPS: undifferentiated pleomorphic sarcoma; KS: Kaposi sarcoma; ALP: alkaline phosphatase; CK: creatine kinase; mCP: metronomic cyclophosphamide; AS: angiosarcoma; ASPS: alveolar soft-part sarcoma; DDLPS: dedifferentiated liposarcoma; PPS: palmar-plantar syndrome; LDH: lactate dehydrogenase; MDSCs: myeloid-derived suppressor cells; MRCL: myxoid/round cell liposarcoma; NY-ESO1: New York esophageal squamous cell carcinoma 1; MAGE-A4: melanoma-associated antigen A4; DC: dendritic cells; MLS: myxoid liposarcoma; CRS: cytokine release syndrome; RMS: rhabdomyosarcoma; adj: adjuvant; maint: maintenance; mono: monotherapy.
| Clinical Trial | Agent | Tumor | N | Age Range | Outcomes | Reported G3/G4 AEs |
|---|---|---|---|---|---|---|
| Immune checkpoint inhibitors (ICI) | ||||||
| Maki et al. (phase I/II) [85] |
Ipilimumab | Synovial sarcoma | 6 | 23–57 | ORR 0% mPFS 1.5 m mOS 8.8 m |
Nausea (50%), diarrhea (33.3%), lymphopenia (33.3%), hyperbilirubinemia (16.7%), thrombopenia (16.7%) |
| Merchant et al. (phase I) [86] | Ipilimumab | Pediatric sarcoma | 17 | 2–17 | ORR 0%; DCR 17.6% (3 SD) mPFS/mOS: NA |
Diarrhea (9%), AST/ALT increase (6%), endocrinopathies (3%), other irAEs (9%) |
| Ben-Ami et al. (phase II) [87] | Nivolumab | Uterine leiomyo-sarcoma | 12 | 29–73 | ORR 0% mPFS 1.8 m; mOS NA |
Lipase/amylase increase (8.3%), fatigue (8.3%), abdominal pain (8.3%) |
| Tawbi et al. (phase II) (SARC028) [54] | Pembrolizumab | BS cohort (22 OST, 13 ES, 5 CS) |
40 | 16–70 | mPFS 8 w; mOS 52 w OST: ORR 5%; DCR 32% (1 PR, 6 SD) ES: ORR 0%; DCR 15% (2 SD) CS: ORR 20%; DCR 40% (1 PR, 1 SD) |
Interstitial nephritis (2%), infectious pneumonia (2%), bone pain (2%), pleural effusion (2%), hypoxia (2%) |
| STS cohort (10 LMS, 10 LPS, 10 SS, 10 UPS) | 40 | 18–81 | mPFS 18 w; mOS 49 w LMS: ORR 0%; DCR 60% (6 SD) / LPS: ORR 20%; DCR 60% (2 PR, 4 SD)/SS: ORR 10%; DCR 30% (1 PR, 2 SD)/UPS: ORR 40%; DCR 70% (1 CR, 3 PR, 3 SD) |
Pulmonary embolism (2%), adrenal insufficiency (2%), pneumonitis (2%) |
||
| Blay et al. (phase II) (AcSé) [88] | Pembro-lizumab | Advanced rare sarcoma | 98 | >18 (NA) | ORR 15.3%; DCR 49% (1 CR, 14 PR, 33 SD); mDR 8.2 m; mPFS 2.8 m; mOS 19.7 m | NA |
| Delyon et al. (phase II) [89] | Pembrolizumab | Classic/ endemic KS |
17 | NA | ORR 70.1%; DCR 88% (1 CR, 10 PR, 4 SD) |
Reversible acute cardiac decompensation (6%) |
| D’Angelo et al. (phase II) (Alliance A091401) [90] |
Nivo/ipi vs. ipi | Advanced sarcoma (BS and STS) | 85 | 21–81 | ORR 16% vs. 5%; mDR 6.2 mmPFS 4.1 m vs. 1.7 m mOS 14.3 m vs. 10.7 m |
Pain (7% vs. 5%), thrombopenia (0% vs. 2%), pulmonary edema (2% vs. 0%), respiratory failure (5% vs. 5%), skin infection (2% vs. 0%), intestinal obstruction (2% vs. 2%), spinal fracture (0% vs. 2%), thrombo-embolic event (2% vs. 2%), urinary tract infection (7% vs. 2%), urinary obstruction (0% vs. 5%), fistula (2% vs. 0%), vomiting (0% vs. 2%) |
| Somaiah et al. (phase II) [91] | Durva-lumab + tremeli-mumab | Advanced sarcoma (BS and STS) | 57 | 35–59 | mPFS 2.8 m; mOS: 21.6 m; PFS at 12 m (all): 28%; PFS at 12 m (ASPS): 80% ORR (irRECIST) (all): 12%; ORR (irRECIST) (ASPS): 40% |
Lipase increase (7%), pneumonitis (6%), colitis (6%), myocarditis (4%), autoimmune disorders (4%), endocrine disorders (2%), diarrhea (2%), gastrointestinal disorders (2%), lung infection (2%), ALP increase (2%), amylase increase (2%), myositis (2%) |
| Immune checkpoint inhibitors (ICI) + conventional CT | ||||||
| Livingston et al. (phase II) [92] | Pembro + doxorubicin | Anthracy-cline naïve STS |
30 | NA | ORR 36.7%; DCR 80% (1 CR, 10 PR, 13 SD) mPFS 5.7 m; mOS 17 m PFS at 6 m: 44% PFS at 12 m: 62% |
Neutropenia (36.7%), anemia (26.7%), febrile neutropenia (16.7%), arthralgia (13.3%), lymphopenia (13.3%), nausea (13.3%), fatigue (10.0%), hyponatremia (10.0%), vomiting (10.0%), lung infection (10.0%), muscle weakness (10.0%) |
| Pollack et al. (phase I/II) [93] |
Pembro + doxorubicin | Anthracy-cline naïve STS |
37 | 25–80 | ORR 19%; DCR 78% (7 PR, 22 SD); mPFS 8.1 m; mOS 27.6 m PFS at 12 m: 27% |
Neutropenia (27.0%), oral mucositis (8.1%), anemia (5.4%), febrile neutropenia (5.4%), lymphopenia (5.4%), ejection fraction decrease (5.4%), anorexia (5.4%), diarrhea (2.7%), hypothyroidism (2.7%), nausea (2.7%), weight loss (2.7%) |
| Toulmonde et al. (phase II) [79] | Pembro + mCP | Advanced STS | 50 | 18–84 | ORR 2%; DCR 34% (1 PR, 16 SD); PFS at 6 m: 0% (LMS, UPS), 11.1% (GIST), 14.3% (others) | Anemia (7.0%), fatigue (3.5%), lymphopenia (3.5%), oral mucositis (3.5%) |
| Gordon et al. (phase I/II) (SAINT) [94] | Ipi/nivo + trabectedin (trab) | Advanced STS | 79 | NA | ORR 25.3%; DCR 87.3% (6 CR *, 14 PR, 49 SD) mPFS 6.7 m; mOS 24.6 m * One surgical CR |
ALT increase (25%), fatigue (8.7%), AST increase (8.7%), decreased neutrophil count (5.4%), anemia (4.6%) |
| Pink et al. (phase II) (NITRA-SARC) [95] | Nivo + trab | Advanced STS | 25 | NA | ORR 8%; DCR 48% (2 PR, 10 SD); mPFS 4 m | Leukopenia (47.2%), neutropenia (41.7%), thrombopenia (33.3%), increased ALT (30.6%), anemia (27.8%) |
| Smrke et al. (phase I) [96] | Pembro + gemcitabine | LMS, UPS | 13 | 40–67 | LMS (11): DCR 73% (8 SD) UPS (2): DCR 100% (2 PR) | NA |
| Nathenson et al. (phase II) [97] | Pembro + eribulin | LMS cohort | 19 | 48–80 | ORR 5.3%; DCR 26.3% (1 PR, 5 SD); mPFS 11 w | Most commonly, neutropenia, anemia, weight loss, diarrhea, lipase/ALP increase |
| Wagner et al. (phase I/II) [98] | Avelumab + trab | LMS, LPS | 23 | NA | ORR 13%; DCR 56% (3 PR, 10 SD); mPFS 8.3 m | NA |
| Toulmonde et al. (phase Ib) [99] | Durva + trab | Advanced STS cohort | 16 | NA | ORR 7%; PFS at 6 m: 28.6% | NA |
| Immune checkpoint inhibitors (ICI) + tyrosine–kinase inhibitors/antiangiogenic drugs | ||||||
| Martin-Broto et al. (phase I/II) (IMMU-NOSARC) | Nivo + suni-tinib | BS cohort (17 OST, 14 CS, 8 ES, 1 UPS) [100] | 40 | 21–74 | ORR 5%; DCR 60% (1 CR, 1 PR, 22 SD) mPFS 3.7 m; mOS 14.2 m |
Neutropenia (10%), anemia (10%), AST/ALT increase (7.5%), fatigue (5%), oral mucositis (5%), hemorrhage (2.5%), dysphagia (2.5%), thrombopenia (2.5%), malaise (2.5%), thromboembolism (2.5%), pneumonitis (2.5%) |
| STS cohort [101] | 43 | 19–77 | ORR 9.3%; DCR 69.3% (1 CR, 3 PR, 26 SD); mPFS 5.9 m; mOS not reached (follow up 6.1 m) |
AST increase (11.8%), ALT increase (9.8%), neutropenia (9.8%), fatigue (5.9%), thrombopenia (3.9%), diarrhea (3.9%), renal failure (3.9%) | ||
| Wilky et al. (phase II) [102] | Pembro + axitinib | 12 ASPS, 6 LMS, 5 UPS, 2 DDLPS, 8 others (2 BS) | 33 | 27–62 | ORR 25%; DCR 53.1% (8 PR, 9 SD); mPFS (all): 4.7 m; mOS (all): 18.7 m; mPFS (ASPS): 12.4 m; mPFS (others): 3.0 m. | Hypertension (15%), autoimmune toxic effects (15%), nausea (6%), ALT/AST increase (3%), oral mucositis (3%), diarrhea (3%), abdominal pain (3%), hemoptysis (3%), hyperlipidemia (3%) |
| Xie et al. (phase II) [103] | Camre-lizumab + apatinib | CT-refractory OST | 43 | 11–43 | ORR 20.1% (9 PR) mDR 6.2 m mPFS 6.2 m; mOS 11.3 m |
Wound dehiscence (14%), ALP increase (9.3%), AST/ALT increase (9.3%), blood bilirubin increase (9.3%), hypertriglyceridemia (7.0%), anorexia (7.0%), weight loss (7.0%), pneumothorax (7.0%), platelet count decrease (4.7%), diarrhea (4.7%), PPS (4.7%), limb pain (4.7%), leukopenia (4.7%), rash (4.7%), oral mucositis (4.7%), hypertension (4.7%), toothache (4.7%), nausea (4.7%), non-cardiac chest pain (4.7%), hypothyroidism (2.3%), LDH increase (2.3%), proteinuria (2.3%), cough (2.3%), hemorrhage (2.3%), fatigue (2.3%), peripheral neuroinflammation (2.3%) |
| Kim et al. (phase II) [104] | Durva + pazopanib | Advanced STS | 47 | NA | ORR 28.3% (1 CR, 12 PR) mPFS 8.6 m |
NA |
| Cousin et al. (phase II) [105] | Avelumab + regorafenib | Advanced STS | 43 | NA | ORR 9.3%; DCR 48.8% (4 PR, 17 SD); mDR 7.8 m; mPFS 1.8 m; mOS 15.1 m | PPS (12.2%), fatigue (10.2%), diarrhea (10.2%) |
| Kelly et al. (phase II) [106] | Pembro + epacadostat | Advanced STS | 29 | 24–78 | ORR 3%; DCR 48% (1 PR, 13 SD); mPFS 8 w; PFS at 24 w 27.9%; mOS NA | AST increase (10%), ALT increase (3%), anemia (3%), hypophosphatemia (3%), lipase increase (3%) |
| Schöffski et al. (phase Ib) [107] | Pembro + olaratumab | Advanced STS | 28 | NA | ORR 21.4%; DCR 53.5%; mDR 16.2 m; mPFS 2.7 m; mOS 14.8 m | NA |
| Immune checkpoint inhibitors (ICI) + other agents | ||||||
| Kelly et al. (phase II) [108] | Pembro + T-VEC | Advanced STS | 20 | 24–90 | ORR 35%; DCR 70% (7 PR, 7 SD); mPFS 17.1 w | Pneumonitis (5%), fever (5%), anemia (5%) |
| Chawla et al. (phase II) [109] | Trabectedin + nivo + T-VEC | Advanced sarcoma | 36 | NA | ORR 8.3%; DCR 86.1% (3 PR, 27 SD); mPFS 5.5 m; mOS 9.0 m; OS at 6 m 73% | Anemia (33.3%), ALT increase (22.2%), fatigue (11.1%), thrombopenia (11.1%), neutropenia (11.1%) |
| D’Angelo et al. (phase I) [110] | Nivo + bempegal-desleukin | Advanced STS | 84 | 13–80 | ORR 10.4% (PR: 3/8 in AS, 1/4 in ASPS, 2/10 in UPS, 1/10 in LMS, 1/10 in CS); mDR 9.3 m | Anemia (10%), lipase increase (10%), amylase increase (7%), hypertension (7%), pain (8%), thromboembolic events (5%) |
| Somaiah et al. (phase I) [111] | LV305 | STS (13 SS, 6 MRCL) | 24 | 25–72 | ORR 4.2%; DCR 62.5% (1 PR, 14 SD); mPFS 4.6 m; mOS 33 m |
No G3/G4 adverse events |
| Rosenbaum et al. (phase I) [112] | Avelumab + DCC-3014 | Advanced STS (7 LMS) | 13 | 32–71 | DCR 23% (3 SD); decreased circulating MDSCs in 5/7 patients (median 26.9%) | ALT/AST increase (31%), CK increase (23%), amylase/lipase increase (16%), anemia (8%), hypertension (8%) |
| Chawla et al. (phase I) [113] | Avelumab + SNK01 | Advanced sarcoma | 15 | 20–75 | ORR 13.3%; DCR 33.3% (2 PR, 3 SD); mPFS 11.1 w | No G3/G3 adverse events related to SNK01 |
| Therapeutic vaccines | ||||||
| Kawaguchi et al. (phase I) [114] | SYT-SSX vaccine | SS | 21 | 21–69 | DCR 50% (6 SD out of 12 assessable patients) | NA |
| Takahashi et al. (phase II) [115] | Peptide vaccine | Advanced sarcoma | 20 | 23–75 | DCR 30% (6 SD); mOS 9.6 m | NA |
| Pipia et al. (phase I/II) [116] | DC vaccine | Advanced STS | 74 | NA | Cohort 1 (adj/maint): mOS 24.4 m; cohort 2 (mono): mOS 14.2 m | NA |
| Chawla et al. (phase II) [117] | Atezo +/− CMB305 | SS, MLS | 89 | NA | mPFS 2.6 m vs. 1.6 m mOS 18 m in both groups |
4 G3/G4 events in each group (not specified) |
| Adoptive cell therapy | ||||||
| Robbins et al. (phase II) [118] | NY-ESO1 TCR | SS | 18 | 19–65 | ORR 61% (1 CR, 10 PR); PFS 3–47 m; estimated 3-y OS: 38% | No toxicities attributed to the transferred cells * |
| D’Angelo et al. (phase II) [119] | NY-ESO1 TCR | SS | 45 | NA | ORR 33% (1 CR, 14 PR); mPFS 8.6–22.4 w | No toxicities attributed to the transferred cells * |
| Van Tine et al. (phase I) [120] | MAGE-A4 TCR | SS | 8 | NA | ORR 50%; DCR 87.5% (4 PR, 3 SD) |
No toxicities attributed to the transferred cells * |
| D’Angelo et al. (phase II) [121] | MAGE-A4 TCR | STS (23 SS,2 MLS) | 25 | 24–73 | ORR 40%; DCR 84% (2 CR, 8 PR, 11 SD) |
CRS (5%) * |
| Ahmed et al. (phase I/II) [122] | Her2-CAR T cells | Advanced sarcoma (16 OST, 3 others) | 19 | 7–29 | DCR 23.5% (4 SD); mOS 10.3 m | Anemia (5.3%), muscle weakness (5.3%), back pain (5.3%) |
| Navai et al. (phase I) [123] | Her2-CAR T cells | Advanced sarcoma (5 OST, 5 others) | 10 | 4–54 | ORR 20%; DCR 50% (2 CR, 3 SD) (CR in 1 OST and 1 RMS) | No toxicities attributed to the transferred cells * |
* All patients experienced transient neutropenia and thrombopenia induced by the lymphodepleting CT with fludarabine plus cyclophosphamide and the transient toxicities associated with IL-2 infusion.