{
  "abstract": "Background Despite the transformative impact of PD-1/PD-L1 inhibitors across solid tumors, their fixed dosing lacks pharmacodynamic rationale. Current regimens often reflect legacy or convenience standards, ignoring early evidence showing receptor saturation at serum levels well below typical doses. 1–3 Immune-related adverse events (irAEs) remain prevalent, and dose de-escalation may reduce both toxicity and cost.4–6 Quantifying the exposure-toxicity relationship is thus a critical unmet need.Methods We conducted a registry-level, arm-based meta-analysis using structured adverse event data from ClinicalTrials.gov (2014–2025). Seventy-seven monotherapy arms (n=8,684 patients) with anti-PD-1/PD-L1 agents (nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab) for adult solid tumors were analyzed. Dose density (mg·kg – 1·wk– 1) was normalized by weight and schedule. Outcomes included incidence of any-grade and grade ≥3 irAEs. Dose-toxicity relationships were assessed via random-effects meta-regression with restricted cubic splines, adjusting for tumor site heterogeneity.7 8 Results Median dose density across included arms was 0.95 mg·kg – 1·wk– 1 (IQR: 0.64–1.20). The dose-toxicity relationship, modeled via restricted cubic spline meta-regression, showed no significant increase in irAE risk across clinically relevant dose ranges. Predicted any-grade irAE incidence was 94.0% at 0.25 mg·kg– 1·wk– 1 compared to 93.2% at 2.0 mg·kg– 1·wk– 1 (Δ = 0.8 percentage points; p=0.059). Grade ≥3 events exhibited similar stability, with rates of 44.3% at low doses and 43.0% at upper-quartile doses (p=0.28). These findings indicate a plateau effect, where increasing dose density does not correspond to increasing toxicity. Tumor site explained 38% of between-arm heterogeneity, while dose density had no statistically significant interaction effect with toxicity outcomes. Visual inspection of the spline curve and individual data points (figure 1) confirmed the flat association. Stratified subgroup analyses across tumor types, agents, and dosing schedules showed consistent patterns. Robustness checks, including leave-one-out diagnostics, sensitivity to linear assumptions, and alternate modeling strategies, supported the null slope and validated the overall stability of the findings (table 1).Conclusions In this large meta-analysis of 8,684 patients, PD-1/PD-L1 dose density did not influence irAE risk. Higher doses conferred no additional toxicity, suggesting that safe dose de-escalation is feasible and clinically justifiable. These findings support Level II-2 evidence for testing lower fixed-dose regimens, e.g., pembrolizumab 100 mg Q6W, in trials or maintenance settings. 9 Tumor immune contexture, not systemic exposure, may better explain toxicity variation.4 10 This analysis challenges legacy dosing assumptions3 and encourages a personalized, cost-conscious immunotherapy paradigm.5 6 Future prospective studies should validate these findings and extend this framework to novel checkpoint inhibitors, with potential impact on regulatory guidelines.11 References Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690Brahmer JR, et al. Nivolumab versus docetaxel in advanced squamous-cell NSCLC. N Engl J Med. 2015;373(2):123–135. https://doi.org/10.1056/NEJMoa1504627Zhao X, et al. Optimization of dosing regimens for PD-1 blockade. Clin Cancer Res. 2017;23(20):6001–6009. https://doi.org/10.1158/1078-0432.CCR-17-1342Wang DY, et al. Toxicities of immune checkpoint inhibitors. JAMA Oncol. 2018;4(1):76–82. https://doi.org/10.1001/jamaoncol.2017.3626Mailankody S, Prasad V. Five years of cancer drug approvals. JAMA Oncol. 2015;1(4):539–540. https://doi.org/10.1001/jamaoncol.2015.0373Carlson RW, et al. Immunotherapy budget impact. JNCCN. 2022;20(4):408–415. https://doi.org/10.6004/jnccn.2022.0001Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3). https://doi.org/10.18637/jss.v036.i03Haslam A, Prasad V. Estimating US cancer patients benefiting from immunotherapy. JAMA Netw Open. 2019;2(5):e192535. https://doi.org/10.1001/jamanetworkopen.2019.2535ClinicalTrials.gov Final Rule (2017). U.S. FDA Results Posting Mandate. https://clinicaltrials.gov/ct2/manage-recs/fdaaaFeng Y, et al. Systemic exposure and safety of PD-1/PD-L1 inhibitors. Clin Pharmacokinet. 2020;59(6):701–718. https://doi.org/10.1007/s40262-019-00846-4De Velasco G, et al. Comprehensive meta-analysis of PD-1/PD-L1 inhibitors. Cancer Treat Rev. 2017;57:20–28. https://doi.org/10.1016/j.ctrv.2017.04.007Abstract 1055 Figure 1Restricted cubic spline meta-regression shows a flat association between PD-1/PD-L1 dose density and any-grade immune-related adverse events. Points represent trial arms by tumor type; shaded area indicates 95% CIAbstract 1055 Table 1Predicted incidence of immune-related adverse events by PD-1/PD-L1 dose densityEstimated rates of any-grade and grade ≥3 immune-related adverse events (irAEs) at representative dose densities from the spline meta-regression model. Minimal variation in irAE risk is observed across the clinically relevant dosing range.",
  "authors": [
    {
      "affiliations": [
        "Pakistan Institute of Medical Sciences, Islamabad, Pakistan"
      ],
      "name": "Manzer Ali"
    },
    {
      "affiliations": [
        "Internal Medicine Residency Program, Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Saad Rashid"
    },
    {
      "affiliations": [
        "Mercy Catholic Medical Center, Darby, PA, USA"
      ],
      "name": "Aftab Ahmed"
    },
    {
      "affiliations": [
        "Oncology Program, Moffitt Cancer Center, Tampa, FL, USA"
      ],
      "name": "Mohammed Al-Jumayli"
    },
    {
      "affiliations": [
        "Rutgers-Trinitas Regional Medical Center, Elizabeth, NJ, USA"
      ],
      "name": "Hanzala Jahangir"
    },
    {
      "affiliations": [
        "Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Abhinav Kakuturu"
    },
    {
      "affiliations": [
        "Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Elizabeth Kaji"
    },
    {
      "affiliations": [
        "Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Manuji Bandara"
    },
    {
      "affiliations": [
        "Aziz Bhatti Shaheed Hospital, Gujrat, Pakistan"
      ],
      "name": "Abdullah Akram"
    },
    {
      "affiliations": [
        "Cleveland Clinic Akron General, Akron, OH, USA"
      ],
      "name": "Kirti Arora"
    },
    {
      "affiliations": [
        "The New York Medical College Graduate Medical Education Program at St. Mary’s General Hospital and Saint Clare’s Health, Denville, NJ, USA"
      ],
      "name": "Bolivia Fernandes"
    }
  ],
  "title": "1055 Flat toxicity curve across PD-1/PD-L1 inhibitor dose densities: meta-analysis supports dose de-escalation without increased immune-related adverse event risk",
  "uid": "768a6690-b5dd-5c1c-a272-48c661ed364a"
}