Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors

Our plain-English summary of Phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors, by O.E. Rahma, K. Tyan, A. Giobbie-Hurder, et al (Journal for Immunotherapy of Cancer, 2022).

The study

• Authors: O.E. Rahma, K. Tyan, A. Giobbie-Hurder, A.S. Brohl, P.L. Bedard, D.J. Renouf, E. Sharon, H. Streicher, E. Hathaway, R. Cunningham, M. Manos, M. Severgnini, S. Rodig, F. Stephen Hodi
• Journal: Journal for Immunotherapy of Cancer
• Published: 2022;10(3)
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The combination of antiangiogenic agents with immune checkpoint inhibitors could potentially overcome immune suppression driven by tumor angiogenesis. We report results from a phase IB study of ziv-aflibercept plus pembrolizumab in patients with advanced solid tumors.

Methods: This is a multicenter phase IB dose-escalation study 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 programmed cell death protein 1 (PD-1)/programmed death-ligand 1(PD-L1)-naïve melanoma, renal cell carcinoma (RCC), microsatellite stable colorectal cancer (CRC), and ovarian cancer. The primary objective was to determine 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 with tumor and peripheral immune population densities.

Results: Overall, 33 patients were enrolled during dose escalation (n=3) and dose expansion (n=30). No dose-limiting toxicities 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 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, 90% CI 7% to 32%). Complete responses occurred in melanoma (n=2); partial responses occurred in RCC (n=1), mesothelioma (n=1), and melanoma (n=1). Median OS was as follows: melanoma, not reached (NR); RCC, 15.7 months (90% CI 2.5 to 15.7); CRC, 3.3 months (90% CI 0.6 to 3.4); ovarian, 12.5 months (90% CI 3.8 to 13.6); other solid tumors, NR. Activated tumor-infiltrating CD8 T cells at baseline (CD8+PD1+), high CD40L expression, and increased peripheral memory CD8 T cells correlated with clinical response.

Conclusion: 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.

Trial Registration Number: NCT02298959.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This was an early-stage (phase IB) drug trial at four cancer centers in the USA and Canada. It tested two drugs given together by vein every 2 weeks: ziv-aflibercept, which blocks a blood-vessel growth signal called VEGF, and pembrolizumab, an immunotherapy drug. Between April 2015 and March 2017, 33 patients with advanced solid tumors were enrolled. Most had melanoma, kidney, colorectal or ovarian cancer, and three had mesothelioma. The article does not discuss asbestos. No dose-limiting side effects were reported, and ziv-aflibercept 4 mg/kg plus pembrolizumab 2 mg/kg became the recommended dose. Severe (grade 3 or higher) treatment-related side effects occurred in 19 of 33 patients (58%), most often high blood pressure and protein in the urine. One death, from cardiac arrest, was judged treatment-related. Of 30 patients at the higher dose, 5 (16.7%, 90% confidence interval 7% to 32%) responded, one of them a patient with mesothelioma who had a partial response. The authors concluded the combination had an acceptable safety profile with antitumor activity. They noted the small size and lack of a comparison group as limits.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase IB, multicenter, open-label dose-escalation (3+3 design) and dose-expansion clinical trial, with no control arm
• Who was studied: 33 patients with advanced solid tumors enrolled at four centers in the USA and Canada between April 2015 and March 2017: 6 melanoma, 8 ovarian, 7 renal cell carcinoma, 6 colorectal, and 6 other solid tumors. The other solid tumors were clear cell sarcoma, triple-negative breast cancer and mesothelioma in cohort 1, and epithelioid mesothelioma (2) and triple-negative breast cancer (1) in cohort 2.
• Exposure: Treatment, not asbestos: pembrolizumab 2 mg/kg plus ziv-aflibercept 2 mg/kg (dose level 1, 3 patients) or 4 mg/kg (dose level 2, 30 patients), given intravenously every 2 weeks. Dose level 2 was established as the maximum tolerated and recommended dose.
• Main results:
  • Grade 3 or higher treatment-related adverse events occurred in 19 of 33 patients (58%). The most common were hypertension (12/33, 36%) and proteinuria (6/33, 18%).
  • One of three deaths in the study was deemed treatment-related, due to cardiac arrest in a patient with colorectal cancer on dose level 2.
  • Response rate among the 30 patients treated at dose level 2 was 16.7% (5/30, 90% CI 7% to 32%): complete responses in 2 melanoma patients, and partial responses in 1 melanoma, 1 renal cell carcinoma and 1 mesothelioma patient.
  • Partial responses included one patient with mesothelioma.
  • Disease-control rate (complete response, partial response or stable disease) at dose level 2 was 40% (12/30, 90% CI 25% to 57%).
  • Response rate in the 'other solid tumors' group (which included the mesothelioma patients) was 17% (1/6, 90% CI 1% to 48%). In this group, median progression-free survival was 15.1 months (90% CI 1.0 to 27.5) and median overall survival was not reached.
  • Responders had statistically significantly higher pretreatment levels of CD8+/PD1+ cells in the tumor than non-responders (mean 83.5 vs 21.2 cells/mm2, p=0.02).
  • Treatment-related hypertension had non-significantly increased odds of response (OR 4.2, 90% CI 0.7 to 25.9, p=0.19).
• The authors' conclusion: The authors concluded that the combination of ziv-aflibercept and pembrolizumab demonstrated an acceptable safety profile with antitumor activity in solid tumors, and that the study established the recommended dose for future larger studies.
• Limitations the authors state:
  • Small sample size, no control arm receiving a single-agent PD-1 inhibitor, and limited availability of paired biopsies.
  • The small sample size precluded meaningful conclusions in tumors such as MSS colorectal and ovarian cancer.

Topics

Medical terms in this study, explained in our Lexicon: Pembrolizumab (Keytruda), checkpoint inhibitors, Angiogenesis, PD-L1, Carcinoma, Colorectal Cancer, Ovarian Cancer, Overall Survival.

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