Table 1.
LAG-3 immunotherapy clinical trial (https://www.ClinicalTrials.gov).
| Drugs | Drug form | Target | Trial identifier | Cohort | Patient group | Status | Phase | Results | Reference |
|---|---|---|---|---|---|---|---|---|---|
| Relatlimab- Nivolumab | IgG4 McAb | LAG-3; PD-1 | NCT01968109 | Relatlimab- Nivolumab (n=68) | Melanoma | Active, not recruiting | I/II | In 61 efficacy-evaluable patients, ORR was 11.5% (1 CR, 6 PR); DCR was 49%. Median DOR was not reached. | (55) |
| Relatlimab- Nivolumab | IgG4 McAb | LAG-3; PD-1 | NCT04080804 | Relatlimab- Nivolumab (n=13) v. s. Nivolumab- Ipilimumab (n=10) v.s. Nivolumab (n=10) | HNSCC | Recruiting | II | 41 patients have been enrolled, with 33 evaluable for this analysis. In the relatlimab- nivolumab (n=13)/nivolumab- Ipilimumab (n=10)/nivolumab (n=10) groups, 1/0/0 patients achieved PR, 10/5/8 patients remained SD, 2/5/2 patients developed PD (RECIST). 7/3/4 patients had a minor partial pathological response (10- 49%), 2/2/0 patients had a partial pathological response (50- 90%), 1/1/0 patients had a major pathological response (> 90%), and 1/0/0 patients had complete pathological. | (56) |
| Relatlimab- Nivolumab | IgG4 McAb | LAG-3; PD-1 | NCT03470922 | Relatlimab- Nivolumab (n=355) v. s. Nivolumab (n=359) | Melanoma | Active, not recruiting | II/III | Median PFS (relatlimab-nivolumab v. s. nivolumab): 10.1 months v.s. 4.6 months; PFS at 12 months (relatlimab–nivolumab v.s. nivolumab): 47.7% v.s. 36.0%; The ratio of grade 3 or 4 TRAEs (relatlimab-nivolumab v. s. nivolumab): 18.9% v.s. 9.7%. | (10) |
| Sym022 | IgG4 McAb | LAG-3 | NCT03489369; NCT03311412; NCT03489343 | Sym021- Sym022 (n=20) v.s. Sym021 (n=17) v.s. Sym022 (n=15) | Metastatic cancer; Solid Tumor; Lymphoma | Completed | I | In the Sym021- Sym022/Sym021/Sym022 arms, 0/1/0 achieved CR and 1/1/1 achieved PR. | (57) |
| Ieramilimab(LAG525)- Spartalizumab (PDR001) | IgG4 McAb | LAG-3; PD-1 | NCT03365791 | LAG525- PDR001 (n=72) | Ovarian adenocarcinoma; GC; DLBCL; SCLC; NET; Prostate; Sarcoma | Completed | II | NET, SCLC, and DLBCL cohorts all met the expansion criteria with the posterior probability that clinical benefit exceeds historical control of 0.971, 0.975, and 0.804 respectively. Clinical benefit rate at 24 weeks were as follows; NET: 0.86 (6/7), SCLC: 0.27 (4/15), DLBCL: 0.43 (3/7). | (58) |
| Ieramilimab (LAG525) | IgG4 McAb | LAG-3 | NCT02460224 | LAG525- PDR001 (n=99) v.s. LAG525 (n=115) | Advanced solid tumors | Active, not recruiting | I/II | LAG525- spartalizumab led to durable RECIST responses (11 PR, 1 CR) in a variety of solid tumors, including mesothelioma (2/8 patients) and triple-negative breast cancer (2/5 patients). | (59) |
| Ieramilimab(LAG525) | IgG4 McAb | LAG-3 | NCT03499899 | LAG525- PDR001 (n=20) v.s. LAG525- PDR001- carbo (n=34) v.s. LAG525- carbo (n=34) | TNBC | Active, not recruiting | II | ORR (LAG525- PDR001 v.s. LAG525- PDR001- Carboplatin v.s. LAG525- Carboplatin):7.1% v.s. 32.5% v.s. 18.4%; DOR (LAG525- PDR001 v.s. LAG525- PDR001- Carboplatin v.s. LAG525- Carboplatin):4.9 months v.s. 13.6 months v.s. 12.6 months. | (60) |
| INCAGN02385 | IgG1-Fc | LAG-3 | NCT03538028 | INCAGN02385 (n=22) | GC; ovarian cancer; HCC; NSCLC; melanoma; Urothelial carcinoma | Completed | I | The doses of INCAGN02385 ≥250 mg led to trough LAG-3 receptor occupancy of ≥90% in peripheral blood and increased markers for CD4+ T-cell proliferation. DCR was 27%. | (61) |
| LBL-007 and Toripalimab | IgG4 McAb | LAG-3; PD-1 | NCT04640545 | Part A: LBL-007- Toripalimab (n=68); Part B: LBL-007- Toripalimab- Axitinib (n=11) | Melanoma | Recruiting | I | Part A: ORR was 45.4% (including 4 mucosal and 1 acral), DCR was 72.7%, and median PFS was 5.5 months. Part B: ORR was 45.4%, DCR was 72.7%, and mPFS was 5.5 months | (62) |
| Fianlimab (REGN3767)-Cemiplimab | IgG4 McAb | LAG-3 | NCT03005782 | REGN3767- Cemiplimab (n=42) v.s. REGN3767 (n=27) | Malignancies | Active, not recruiting | I | The best response was stable disease in 11 patients (RECIST 1.1) in the REGN3767 monotherapy group (n=27); 2 (both small cell lung cancer) combination group patients and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional patients who crossed over from monotherapy group to combination group had partial responses; pharmacokinetics: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combination. | (63) |
| Fianlimab (REGN3767)-Cemiplimab | IgG4 McAb | LAG-3 | NCT03005782 | REGN3767-Cemiplimab: anti–PD-(L)1 naive group (n=33) v.s. anti–PD-(L)1 experienced group (n=15) | Advanced melanoma | Active, not recruiting | I | By investigator assessment, ORR was 63.6% (3 CRs and 18 PRs) for patients who had no prior anti–PD-(L)1 treatment and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced patients; mPFS and mDOR for the patients who had no prior anti–PD-(L)1 treatment cohort have not been reached. | (64) |
| Miptenalimab (BI 754111)- ezabenlimab (BI 754091) | IgG4 McAb | LAG-3; PD-1 | NCT03433898 | Cohort A: patients with gastric/gastroesophageal junction cancer (n=36) v.s. Cohort B: esophageal cancer (n=37) | Neoplasms | Completed | I | Confirmed PR was observed in 4/7 patients in cohorts A/B; ORR was 11% and 19%. SD was observed in 10/8 (28/22%) patients in cohorts A/B and DCR was 39/41%. | (65) |
| Tebotelimab (MGD013) | BsAb | LAG-3; PD-1 | NCT03219268 | MGD013: 50 patients were treated in dose-escalation, and 157 patients in dose-expansion. | metastatic neoplasms | Completed | I | Among 41 response-evaluable dose-escalation patients, 3 patients were observed confirmed PR (triple negative breast cancer, mesothelioma, GC; RECIST 1.1), while 21 patients had SD. Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2/15) and TNBC (n=2). SD has been observed in epithelial ovarian cancer (n=7/15) and TNBC (n=5/14). | (66) |
| Tebotelimab (MGD013)-Niraparib | BsAb | LAG-3; PD-1 | NCT04178460 | MGD013- Niraparib (n=27) | GC | Terminated | I | In patients with target lesions on the recommended phase II dose (tebotelimab 600 mg / 2 weeks plus niraparib / individualized starting doses once daily; n=19), one confirmed PR (RECIST v1.1) was observed and 9 patients had SD, with a 5.3% ORR and a 52.6% dcr. Inpatients on recommended phase II dose (n=21), median PFS and median OS were 2.7 and 6.5 months, respectively, after a median follow-up of 7.7 months. | (67) |
| RO7247669 | BsAb | LAG-3; PD-1 | NCT04140500 | RO7247669 (n=35) | NSCLC; metastatic melanoma | Recruiting | I/II | ORR was 17.1 %, and DCR was 51.4 %. Responses have been observed in checkpoint inhibitors naive patients (4/23) as well as in checkpoint inhibitors experienced patients (2/12). | (68) |
| Eftilagimod alpha (IMP321)- Avelumab | Soluble protein | LAG-3; PD-L1 | NCT03252938 | Cohort 1: Avelumab-IMP321 6mg (n=6) v.s. Cohort 2: Avelumab+IMP321 30mg (n=6) | Solid Tumors; Peritoneal carcinomatosis | Recruiting | I | As of September 2020, 12 patients with advanced solid tumors were treated with IMP321 and avelumab, 4 patients have achieved PR and 3 patients have progressed. 2 patients progressed clinically and 3 patients did not undergo tumor evaluation. | (69) |
| Eftilagimod alpha (IMP321)- Paclitaxel | Soluble protein | LAG-3 | NCT02614833 | Cohort 1: Paclitaxel-IMP321 6mg (n=6) v.s. Cohort 2: Paclitaxel- IMP321 30mg (n=9) | Adenocarcinoma breast (Stage IV) | Completed | II | An increased number of circulating monocytes, dendritic cells, and increased activation were observed with the treatment of IMP321. Seven patients (47 %) had a PR according to RECIST 1.1 (mean duration of 9 months). The DCR was 87 %. | (70) |
| Eftilagimod alpha (IMP321) Pembrolizumab | Soluble protein | LAG-3; PD-1 | NCT02676869 | IMP321-Pembrolizumab (n=18) | Melanoma (Stage III-IV) | Completed | I | 16 patients were eligible for response evaluation. In 8 (50 %) patients, a tumor reduction was observed. This includes one patient with a confirmed CR after initial progression on pembrolizumab monotherapy. | (71) |
| Eftilagimod alpha (IMP321)- Pembrolizumab | Soluble protein | LAG-3; PD-1 | NCT03625323 | IMP321+Pembrolizumab (n=38) | HNSCC | Active, not recruiting | II | 35 patients were evaluated for response (cut-off Jan 2021) with 4 (11 %) patients showing CR, 7 (20 %) patients PR, 3 (9 %) patients SD, 16 (46 %) patients PD with 5 (14 %) patients being not evaluable (iRECIST). ORR was 31.4 % and DCR was 40 %. Median PFS was 2.1 months and 35 % were progression-free at 6 months. The median OS was 12.6 months. | (72) |
| Eftilagimod alpha (IMP321)- Pembrolizumab | Soluble protein | LAG-3; PD-1 | – | IMP321+Pembrolizumab (n=24): IMP321 at doses 1 mg, 6 mg, or 30 mg/injection for up to 6 months (part A) and 30 mg/injection for up to 12 months (part B) | Melanoma | – | – | Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-γ, a Th1 signature cytokine. An ORR of 33% was observed in patients partly with pembrolizumab-refractory of part A and an ORR of 50% was observed in patients with PD-1 naïve of part B. | (73) |
| FS-118 | BsAb | LAG-3; PD-L1 | NCT03440437 | FS-118 (n=43) | Advanced Cancer; Metastatic Cancer; HNSCC | Active, not recruiting | I/II | The DCR was 46.5%; Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. | (74) |
BsAb, bispecific antibody; McAb, monoclonal antibody; HNSCC, head and neck squamous cell carcinoma; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; HCC, hepatocellular carcinoma; GC, gastric cancer; TNBC, triple-negative breast cancer; NET, neuroendocrine tumor; DLBCL, diffuse large B-cell lymphoma; PR, partial response; CR, complete response; SD, stable disease; PD, progressive disease; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; DOR, duration of overall response.