From November 30, 2021, to December 1, 2023, 93 patients were screened for eligibility and 80 patients were enrolled from 11 centers (10 in phase Ib and 70 in phase II), including 30 patients with NPC, 13 with small cell lung cancer (SCLC), 12 with lung adenocarcinoma (adNSCLC), 9 with squamous non-small cell lung cancer (sqNSCLC), 8 with esophageal squamous cell carcinoma (ESCC), 5 with head and neck squamous cell carcinoma (HNSCC), and 3 with cervical cancer (CCA). All patients had progressed after standard therapies, and 35 patients (43.8%) had received two or more prior lines of treatment. Additionally, 47 patients (58.8%) had previously received anti-PD-(L)1 immunotherapy. The baseline characteristics of the enrolled patients are summarized in Table 1.

At the data cutoff on July 26, 2024, the median follow-up was 26.0 (range, 0.6–29.4) months. The median duration of therapy was 5.0 months (range, 0.3–24.7). All 80 patients discontinued the study treatment for the following reasons: 59 due to disease progression, seven due to withdrawal of consent, five after completing 2 years of treatment, seven due to AEs and two due to death. Among the five patients who completed 2 years of treatment, two IO-naïve and one IO-treated NPC patient achieved PRs, while one IO-naïve and one IO-treated NPC patient achieved SDs.

Five patients discontinued treatment without any post-baseline imaging evaluations. Thus, antitumor activity was assessed in the remaining 75 patients (93.8%). Ten patients (13.3% [95% CI, 6.6–23.2%]) achieved a confirmed objective response. No CRs were reported, while PRs were observed in patients with NPC (n = 6), sqNSCLC (n = 2), HNSCC (n = 1) and ESCC (n = 1). The DCR was 54.7% (95% CI, 42.7–66.2%). Efficacy results are summarized in Table 2; Figs. 1 and 2 and Supplement Figure S2.

Tumor response assessment and Kaplan-Meier survival plots. Efficacy of LBL-007/toripalimab combination in patients with advanced solid tumors. Five patients who had nonvaluable response and were not included. (A) Waterfall plot showing the maximum changes in tumor size. (B) Kaplan-Meier plot of progression-free survival in NPC patients stratified by prior immunotherapy. (C) Kaplan-Meier plot of progression-free survival in patients stratified by NPC and other tumors. Abbreviations: adNSCLC: lung adenocarcinoma; CCA: cervical cancer; ESCC: esophageal squamous cell carcinoma; HNSCC: head and neck squamous cell carcinoma; IO: immunotherapy; NPC: nasopharyngeal carcinoma; PD: progressive disease; PR: partial response; SCLC: small cell lung cancer; SD: stable disease; sqNSCLC: squamous non-small cell lung cancer

Swimmer plot showing tumors responses and duration of treatment in patients. Five patients who had nonvaluable response and were not included. Abbreviations: adNSCLC: lung adenocarcinoma; CCA: cervical cancer; ESCC: esophageal squamous cell carcinoma; HNSCC: head and neck squamous cell carcinoma; NPC: nasopharyngeal carcinoma; PD: progressive disease; PR: partial response; SCLC: small cell lung cancer; SD: stable disease; sqNSCLC: squamous non-small cell lung cancer

Among the 12 IO-naive NPC patients, the ORR was 33.3% (95% CI, 9.9–65.1%), the DCR was 75.0% (95% CI, 42.8–94.5%), the median PFS was 10.8 months (95% CI, 1.3 to NE), and the median DOR was 15.0 months (95% CI, 5.5 to NE). Among the 17 IO-treated NPC patients, the ORR was 11.8% (95% CI, 1.5–36.4%), the DCR was 64.7% (95% CI, 38.3–85.8%), the median PFS was 2.7 months (95% CI, 1.4 to 4.9), and the median DOR was 13.5 months (95% CI, 12.5 to NE). Notably, among the six NPC responders, 83.3% maintained partial responses for more than 12 months. The one-year PFS rate was 40% for IO-naive NPC patients and 21.2% for IO-treated NPC patients.

Among patients with other tumors, the ORR was 8.7% (95% CI, 2.4–20.8%), and the DCR was 45.7% (95% CI, 30.9–61.0%). Among the eight patients with sqNSCLC, one out of six IO-naive patients achieved a PR, and one out of two IO-treated patients achieved a PR. Among the eight patients with ESCC, the only IO-naive patient achieved a PR, while no PRs were observed in the seven IO-treated patients. Among the four IO-naive HNSCC, one patient achieved a PR. No objective responses were observed in three patients with CCA and 13 patients with SCLC.

In phase Ib, LBL-007 was administered intravenously at doses of 200 mg in four patients and 400 mg in six patients once every 3 weeks. No dose-limiting toxicities were observed. Therefore, the 400 mg dose of LBL-007 was selected as the RP2D and administered to 70 patients in phase II. All 80 patients received toripalimab at a fixed dose of 240 mg once every 3 weeks and were included in the safety population.

Any-grade TRAEs were reported in 61 patients (76.3%) (Table 3). Grade 3 or 4 TRAEs occurred in 9 patients (11.3%). The most common grade 3 or 4 TRAEs included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Serious TRAEs were reported in 10.0% of patients, and 8.8% of patients experienced TRAEs leading to treatment discontinuation, including one patient with grade 4 neutropenia and grade 4 leukopenia, one patient with grade 3 anemia, one patient with grade 4 paralysis of the lower limbs, one patient with grade 4 constrictive pericarditis, one patient with grade 2 myocarditis, one patient with grade 2 elevated myocardial enzymes and one patient with grade 3 hyponatremia. No treatment-related deaths occurred. The most common immune-related adverse events were hypothyroidism (10.0%), increased aspartate aminotransferase (5.0%), increased alanine aminotransferase (3.8%), fatigue (3.8%) and increased gamma-glutamyl transferase (2.5%). Grade 3 or 4 irAEs occurred in 3.8% of patients. All irAEs were well manageable with corticosteroids.

Exploratory analysis based on LAG-3 and PD-L1 expression was performed in 38 patients with available efficacy data. High LAG-3 expression (≥ 2+) was observed in 25 patients (65.9%), and 12 patients (31.6%) showed positive PD-L1 expression (TC ≥ 1%).

Among the 38 patients, those with LAG-3 expression ≥ 2 + had an ORR of 28.0% versus 7.7% in those with LAG-3 expression < 2+ (Table 4). Among the 15 NPC patients, those with LAG-3 expression ≥ 2 + had an ORR of 40% versus 20% in those with LAG-3 expression < 2+. To note, of the eight patients achieving a confirmed objective response in the biomarker-evaluable population, seven (87.5%) had LAG-3 expression ≥ 2+. However, the association between efficacy and PD-L1 expression was elusive, as similar ORR was observed in PD-L1 positive and negative populations (25.0% versus 19.2%).