Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC).

Abstract

673 Background: Blockade of the PD-L1/PD-1 axis is a proven immunologic approach for treatment of many cancers; however, not all pts respond to monotherapy. Bev, an anti–VEGF-A antibody, has demonstrated clinical efficacy in mCRC and enhanced T-cell infiltration in tumors in preclinical studies. Thus, we postulated that combining atezo (anti-PD-L1) with bev would augment anti-tumor immune responses, resulting in improved and more durable clinical benefit. We report results from the first study of an anti-PD-L1 agent + VEGF-A blockade in MSI-high mCRC. Methods: A Ph Ib study (NCT01633970) investigated atezo + various chemotherapeutic/biologic regimens (eg, bev) in pts with advanced solid tumors, including mCRC. Pts received atezo 1200 mg q3w plus bev 15 mg/kg q3w (data cutoff, May 20, 2016). The primary objective was to evaluate the safety of atezo + bev. Secondary objectives included anti-tumor activity per RECIST v1.1. MSI status was tested locally. Results: Ten MSI-high mCRC pts were enrolled. Three pts had received 1 prior chemotherapy and 7 pts had received ≥ 2. Median age was 52.5 y. The minimum (range) of safety follow-up was 2.6 (2.6-20.3) mo. Median (range) treatment duration with atezo + bev was 10.1 (2-20) and 9.0 (2-19) mo, respectively. Efficacy results are shown below; the confirmed ORR per RECIST v1.1 was 30% (95% CI, 6.7%-65.3%). Median OS had not been reached with a median follow-up of 11.1 mo. Treatment-related all-grade AEs occurred in 80% of pts; 40% of pts had a related G3/4 AE. The most common related AE was proteinuria (40%; n = 3 G2 and n = 1 G3). No G5 events occurred. One AE led to discontinuation of atezo and 3 AEs led to discontinuation of bev. Biomarker data will be presented. Conclusions: Initial clinical activity was observed in heavily pretreated pts with MSI-high mCRC receiving atezo + bev; the disease control rate was 90%. This combination was well tolerated without unexpected toxicities. Further follow-up is ongoing. Clinical trial information: NCT01633970. [Table: see text]

Some aspects of immunotherapy in colon cancer

“…Воздействие на ангиогенез, в частности моноклональными антителами к фактору роста эндотелия сосудов (vascular endothelial growth factor, VEGF), может проявлять синергизм с анти-PD-1-ингибиторами в отношении противоопухолевого эффекта [44], это было показано и на мышиных моделях РТК с высоким уровнем VEGF-A, но такая комбинация приводила к уменьшению в опухоли доли CD8 + -Т-лимфоцитов, экспрессирующих иммунные чекпоинты [49]. Однако значимого усиления эффективности анти-PD-L1-антител в клиническом исследовании получено не было: комбинация атезолизумаба с бевацизумабом у 10 больных MSI-положительным РТК привела к подтвержденному объективному эффекту у 30 % пациентов, к стабилизации -у 60 % [50].…”

Product review on the Anti-PD-L1 antibody atezolizumab

“…A combination of atezolizumab with bevacizumab was explored in a separate cohort of the above study and preliminary outcomes were reported for a subset of patients with metastatic colorectal cancer with microsatellite instability (MSI-high). 40 Patients received atezolizumab 1200 mg with bevacizumab 15 mg/kg every 3 weeks. In this subset, the RR was 30% and 40% of patients experienced a treatment related AE though only one led to discontinuation of atezolizumab.…”

Anti-Angiogenics: Their Value in Colorectal Cancer Therapy

“…In a murine CRC model, a synergistic antitumor effect was observed with simultaneous VEGFR-2 and programmed cell death 1-ligand 1 (PD-L1) blockade, with increased CD8-positive and CD4-positive T cell infiltration into tumor tissue [41]. In the clinical setting, phase I/II trials are ongoing, assessing combinational therapies with anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and anti-PD-(L)1 antibodies and bevacizumab in MSI-CRC and in unselected mCRC [42,43]. First results were promising, and the initiation of larger phase III studies is ongoing.…”