Solange Peters, MD, PhD
Therapies that inhibit angiogenesis are attracting fresh interest in combination regimens with immune checkpoint immunotherapy in tumor types such as hepatocellular carcinoma (HCC), urothelial carcinoma, and endothelial cancer.
The rationale for pursing this approach is grounded in tumor biology. Tumor masses contain regulatory lymphocytes, dendritic cells, alternatively activated macrophages, and myeloid-derived suppressor cells, as well as dysregulated and functionally impaired immune cells, Solange Peters, MD, PhD, said at the European Society for Medical Oncology (ESMO) 2018 Molecular Analysis for Personalised Therapy Congress. She said the hy pothesi s behind combining angiogenesis inhibitors and immunotherapy is that ablation or “reprogramming” the microenvironment might boost the efficacy of anticancer therapy.
“All these mechanisms might contribute. Angiogenic response and immune response are very importantly correlated,” said Peters, ESMO president-elect and head of the Medical Oncology Service and chair of thoracic oncology in the Oncology Department at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. “Angiogenic factors impair lymphocyte trafficking across endothelia. VEGF has profound effects on cancer immunity.”
VEGF promotes the formation of blood vessels and tumor vasculature (FIGURE). Additionally, VEGF induces proliferation of regulatory T cells, favors accumulation of myeloid-derived suppressor cells, and inhibits dendritic cell maturation, antigen presentation, and T-cell responses such as upregulation of PD-L1. Results from studies have shown that VEGF blockade induces antitumor immune response while also increasing T-cell homing and improving vaccine therapy.
As a result, investigators have explored the combination of antiangiogenic agents, such as lenvatinib (Lenvima), ramucirumab (Cyramza), and bevacizumab (Avastin), with immunotherapy agents, including pembrolizumab (Keytruda) and atezolizumab (Tecentriq), for years, hoping to improve outcomes.
Peters reviewed data from 3 studies presented first at the 2018 American Society of Clinical Oncology Annual Meeting showing the progress investigators have made with these agents.
Figure. Process of Angiogenesis and Inhibition in Cancer
Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma
PD-1/PD-L1 checkpoint inhibitors have been associated with promising activity as monotherapy in patients with HCC, and VEGF inhibition with bevacizumab has shown “modest activity” in this population. Based on positive results from phase III trials analyzing this combination in the first line for patients with renal cell carcinoma and non–small cell lung cancer, investigators hypothesized that bevacizumab might boost the efficacy of atezolizumab by “reversing VEGF-mediated immunosuppression and promoting T-cell infiltration into the tumor.”1
In a phase Ib clinical trial cohort (NCT02715531), treatment-naïve patients with advanced, unresectable, or metastatic HCC were assigned to 1200 mg of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks until progression, unacceptable toxicity, or loss of clinical benefit. Patients who received any amount of the study combination (n = 43) were included in the safety evaluation, and those followed for a minimum of 16 weeks (n = 23) were included in the efficacy assessment.
At a median follow-up of 10.3 months (range, 3.5-17.3), the objective response rate (ORR) was 61% according to investigator assessment and 65% by independent review facility. Both assessments determined that 14 patients had partial responses. The independent review also determined that 1 patient (4%) had a complete response.
As assessed by investigators, the median duration of treatment has not yet been reached (range, 1.7+ to 14.0+ months). Similarly, median progression-free survival (PFS) and overall survival (OS) have not been reached. The 6-month PFS rate was 65%, and the 6-month OS rate was 86%, according to both investigator and independent assessments. As of January 2018, 10 of 14 responses were ongoing for ≥6 months. Three responses were ongoing for ≥1 year, according to investigator assessment.
There were 15 (35%) grade 3/4 adverse events (AEs) recorded, 12 (28%) of which were treatment related. The most common (≥5%) grade 3/4 treatment-related AE was hypertension (16%). There were 11 (26%) serious AEs, 3 (7%) of which were treatment related.
Two patients died in the study. Neither death was related to the study treatment. Results from this small study led to an FDA breakthrough designation for the combination of atezolizumab and bevacizumab for use as a frontline regimen for patients with advanced or metastatic HCC in July 2018.