374 A phase IB trial of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors
Bibliographic record
Abstract
Background Angiogenic factors play a role in regulating immune suppression in the tumor microenvironment and driving resistance to immune checkpoint inhibitor therapy.1 Ziv-aflibercept is a soluble decoy receptor that ”traps” endogenous vascular endothelial growth factor (VEGF) with 100-fold increased binding affinity compared to Bevacizumab.2 The combination of ziv-aflibercept with either cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) blockade has shown promising antitumor efficacy in mouse models.3 4 We hypothesized that a novel combination of ziv-aflibercept and anti-PD-1 would be tolerable and lead to clinical benefits in tumors that traditionally do not respond to checkpoint blockade. Methods This is a multicenter phase 1B dose escalation study (NCT02298959) of the combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg) administered intravenously every 2 weeks with expansion cohorts in PD-1/PD-L1 naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (MSS CRC), and ovarian cancer (figure 1). The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose of the combination. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Exploratory objectives included correlation of clinical efficacy and immune population densities in the tissue and periphery. Results Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities (DLTs) were reported in the initial dose level. Ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg every 2 weeks was established as the MTD. Grade ≥3 treatment-related adverse events occurred in 19/33 patients (58%), the most common being hypertension (36%) and proteinuria (18%). ORR in the dose expansion cohort was 16.7% (5/30; 95% CI, 7–32%). Complete responses occurred in melanoma (n=2), partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Efficacy outcomes by tumor type are shown in table 1 and figure 2. Median OS was as follows: melanoma, not reached; RCC, 15.7 months (90% CI, 2.5–15.7); CRC, 3.3 months (90% CI, 0.6–3.4), ovarian, 12.5 months (90% CI, 3.8–13.6), other solid tumors, not reached (figure 3). Activated tumor infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression (figure 4), and increased memory CD8 T cells in the periphery (figure 5) correlated with clinical response to the combination therapy. Conclusions The combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors. The combination is currently being studied in sarcoma and anti-PD-1 resistant melanoma. Acknowledgements This trial was supported by the National Cancer Institute (NCI) and by Merck, Sharpe, and Dohme and Sanofi via Cooperative Research and Development Agreements with the NCI. PLB was supported by NCI UM1 Grant CA186644. Trial Registration NCT02298959 References Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res September 15 2019;25(18):5449–5457. doi:10.1158/1078-0432.CCR-18-1543 Holash J, Davis S, Papadopoulos N, et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proceedings of the National Academy of Sciences 2002;99(17):11393–11398. doi:10.1073/pnas.172398299 Burova E, Ioffe E, Taduriyasas C, et al. Abstract 5035: blockade of VEGF with ziv-aflibercept (VEGF Trap) enhances anti-tumor efficacy of CTLA-4 blocking antibody in an Fc dependent manner. Cancer Research 2014;74(19 Supplement):5035–5035. doi:10.1158/1538-7445.am2014-5035 Di Tacchio M, Macas J, Weissenberger J, et al. Tumor vessel normalization, immunostimulatory reprogramming, and improved survival in glioblastoma with combined inhibition of PD-1, angiopoietin-2, and VEGF. Cancer Immunology Research 2019;7(12):1910–1927. doi:10.1158/2326-6066.cir-18-0865 Ethics Approval This trial (NCT02298959) was approved by all participating IRBs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".