Jing Xu

Purpose:Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B- and T-lymphocyte attenuator. Co-blockade of B- and T-lymphocyte attenuator and programmed death-1 pathways improved outcomes in nonclinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer.Patients and Methods:Eligible patients with pathologically confirmed advanced non–small cell lung cancer (NSCLC) without sensitive EGFR variation and anaplastic lymphoma kinase fusion who failed standard treatment including one PD-1/PD-L1 inhibitor or those with refractory extensive-stage small cell lung cancer (SCLC) received tifcemalimab (200 mg) and toripalimab (240 mg) every 3 weeks intravenously until disease progression or intolerable toxicity. The Simon two-stage optimal design was used in the expansion part. The primary endpoints included safety and objective response rate (ORR) per RECIST version 1.1.Results:Twenty-four patients with NSCLC and 43 with SCLC were enrolled (median age of all patients, 60.0 years). All patients with NSCLC and 14 (32.6%) with SCLC had received previous immunotherapy. Fifty-five (82.1%) patients experienced treatment-related adverse events, and five (7.5%) patients reported grade ≥3 immune-related adverse events. For NSCLC, the ORR was 4.3%, and disease control rate was 47.8%. The median progression-free survival and overall survival were 1.5 and 18.9 months, respectively. For SCLC, the ORR and disease control rate were 35.0% and 55.0%, respectively. The median duration of response, progression-free survival, and overall survival were 5.7, 2.8, and 12.3 months, respectively.Conclusions:Tifcemalimab plus toripalimab showed promising antitumor activities with acceptable safety, especially in advanced refractory SCLC.

Supplementary Table 2. Representativeness of study participants.

Supplementary Figure 5. The exploratory analysis of PFS according to HVEM and PD-L1 expression.

Supplementary Figure 1. Kaplan-Meier estimation of progression-free survival in (A) squamous non-small cell lung cancer (NSCLC), (B) adenocarcinoma NSCLC, overall survival in (C) squamous NSCLC and (D) adenocarcinoma NSCLC.

Supplementary Figure 2. Kaplan-Meier estimation of DOR.

Supplementary Figure 3. Kaplan-Meier estimation of PFS and OS in SCLC with immunotherapy or not.

Supplementary Table 3. Treatment-related treatment-emergent adverse events occurring in ≥5% of all patients.

Supplementary Table 4. Immune-related treatment-emergent adverse events of any grade and grade 3 or higher.

Supplementary Table 1. Subsequent systemic antitumor therapy.

Supplementary Figure 4. Representative immunohistochemistry staining.