PD-1, PD-L1-Targeting Agent Shows Promise in Treatment of Patients with Non–Small Cell Lung Cancer

Non–small cell lung cancer (NSCLC) accounts for 87% of all lung cancer cases, but only 25% to 30% of patients will respond to treatment, highlighting the significant need for advanced therapies. Immune checkpoint inhibitors, such as monoclonal antibodies (mAbs) and bispecific antibodies (bsAbs), have greatly improved outcome for patients, offering them more targeted treatments with better safety profiles. Compared with mAbs, bsAbs have been shown to enhance antitumor activity while maintaining favorable safety.^1,2

Interaction between PD-1 and PD-L1 blocked by antibodies | Image Credit: ©Juan Gärtner - stock.adobe.com

In lung cancer, the discovery of actionable biomarkers, such as EGFR mutations, ALK rearrangements, and PD-L1 expression, transformed the therapeutic landscape, providing patients with more effective and tailored treatment options. The significance of PD-1 and PD-L1 in lung cancer lies in their role in immune evasion. PD-1, a checkpoint receptor expressed on T cells, interacts with its ligands, PD-L1 and PD-L2, to suppress the immune response, allowing cancerous cells to evade detection by the immune system.³

Some studies explored the development of bsAbs targeting these key biomarkers, such as IBI318 (Innovent Biologics Inc and Eli Lilly and Company). IBI318 is a novel, fully human recombinant IgG1 bsAb targeting both PD-1 and PD-L1 in small tumors, demonstrating safety and preliminary efficacy in patients with treatment-naïve NSCLC and immunotherapy-naïve nasopharyngeal carcinoma (NPC) patients. These clinical benefits were observed in an open-label, multicenter phase 1a/1b study (NCT03936959).^4,5

To enhance treatment response rates and safety of anti-PD-1/PD-L1-based immunotherapy, the researchers evaluated the use of IBI318 in 103 patients with NSCLC or NPC. The trial involved 2 phases. Phase 1a (n=55) focused on dose escalation and safety dose expansion, and phase 1b (n=48) evaluated preliminary safety and efficacy. During phase 1a, patients received BI318 at doses ranging from 0.3 to 1200 mg every 2 weeks (Q2W), which was used to determine the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D established in the first phase. The primary end point was safety with secondary end points including efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics.⁴

At a median follow-up of 10.1 months, the researchers determined that the RP2D for IBI318 was 300 mg Q2W. Across all trial participants in each cohort, there was an objective response rate (ORR) of 15.5% and a disease control rate of 49.5%. In phase 1b, the ORRs were 45.5% and 30% in patients with NSCLC and NPC, respectively.⁴

Treatment-related adverse events (TRAEs) occurred in 85.4% of patients, of which the most common included increased aspartate aminotransferase (15.5%), rash (13.6%), and proteinuria (12.6%). The most frequent grade ≥ 3 TRAEs reported by the researchers were immune-mediated hepatitis (3.9%) and infusion related reactions (2.9%).⁴

The findings show promise for the development and continued study of in dual targeting PD-1 and PD-L1 therapies. Some limitations of the study included the design, namely the absence of randomization and a control group. Due to lack of interest, the study was terminated as of January 2025, and therefore, did not reach its primary objective.^4,5

Emerging interest in dual targeting both PD-1 and PD-L1 continues and has led to the identification and development of other therapies. For example, another agent, JMB2005, demonstrated great potential in preclinical mouse models. As lung cancer cases rise, there is a significant need for a multitude of therapeutic options to meet the challenges and needs of individual patients. Development of PD-1 and PD-L1 agents may present patients with additional therapeutic opportunities that are safe and efficacious.⁶

REFERENCES

1. Key statistics for lung cancer. American Cancer Society. January 16, 2025. Accessed January 28, 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html

2. Gerlach A. Novel deep-learning model may predict immune checkpoint inhibitor responses in patients with non−small cell lung cancer. Pharmacy Times. January 2, 2025. Accessed January 28, 2025. https://www.pharmacytimes.com/view/novel-deep-learning-model-may-predict-immune-checkpoint-inhibitor-responses-in-patients-with-non-small-cell-lung-cancer

3. Parvez A, Choudhary F, Mudgal P, et al. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Frontiers. November 30, 2023. doi:10.3389/fimmu.2023.1296341

4. Ruan D, Wei X, Liu F, et al. The first-in-class bispecific antibody IBI318 (LY3434172) targeting PD-1 and PD-L1 in patients with advanced tumors: a phase Ia/Ib study. J Hematol Oncol. November 29, 2024. doi:10.1186/s13045-024-01644-4

5. A study of LY3434172, a PD-1 and PD-L1 bispecific antibody, in advanced cancer. Updated January 15, 2025. Accessed January 28, 2025. https://clinicaltrials.gov/study/NCT03936959

6. Liu P, Gu C, Cao X, et al. Discovery of a common light chain bispecific antibody targeting PD-1 and PD-L1 by Hybridoma-to-Phage-to-Yeast (H2PtY) platform. Antibody Therapeutics. October 10, 2024. doi:10.1093/abt/tbae027