Overcoming Resistance to Immunotherapy Combining Gemcitabine With Ivonescimab in Advanced NSCLC

Lung cancer is the most frequently diagnosed cancer worldwide, with approximately 2.5 million new cases and 1.8 million deaths annually. Most cases are diagnosed at an advanced stage, necessitating systemic therapy. Although chemoimmunotherapy (CIT) has improved outcomes, disease progression remains inevitable, and second-line treatments offer limited efficacy. Gemcitabine, a cytidine analogue, interferes with DNA synthesis and exhibits immunomodulatory effects, including increased effector T-cell infiltration and reduced regulatory T-cell activity. Preclinical studies have shown that gemcitabine enhances antitumor immune responses when combined with immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies. Ivonescimab (AK112/SMT112) is a bispecific antibody targeting PD-1 and VEGF, designed to simultaneously modulate immune and angiogenic pathways. It binds to PD-1 on activated T cells and VEGF involved in tumor angiogenesis. The combination of gemcitabine and ivonescimab is hypothesized to synergistically improve antitumor activity in patients with advanced NSCLC who have progressed after CIT. Preclinical evidence from mouse models of mesothelioma demonstrated that combining gemcitabine with immunotherapy significantly increased survival and lymphocyte infiltration at the tumor site. This effect was negated by dexamethasone, highlighting the importance of immune modulation. Clinical observations in mesothelioma patients further support the potential of this combination. Gemcitabine is a standard of care (SoC) for several solid tumors, including NSCLC. Its immunostimulatory properties make it a suitable candidate for combination with ICIs. Ivonescimab has shown superior efficacy compared to pembrolizumab in PD-L1+ NSCLC patients in first-line settings. Despite ongoing trials exploring similar combinations, none have investigated gemcitabine with ivonescimab. This Phase II trial aims to assess the antitumor activity of gemcitabine combined with ivonescimab in patients with advanced NSCLC who have limited therapeutic options. Gemcitabine will be administered according to standard treatment recommendations, while ivonescimab will be given at 20 mg/kg every three weeks (q3w), consistent with previous trials. The primary objective is to evaluate the objective response rate (ORR) based on RECIST v1.1 criteria, with independent response review. The study is inclusive across sex, gender, and ethnicity, and all materials will use gender-inclusive language. A positive outcome may support the adoption of this combination as a new standard treatment for relapsed NSCLC.