In the past few years, immune checkpoint inhibitors have transformed the treatment landscape in oncology.6 However, although immune checkpoint inhibitors achieve durable responses in subsets of patients, only a fraction of patients respond to treatment, and among those who respond, resistance develops frequently. Therefore, strategies to further augment the benefits of cancer immunotherapy are highly desired. Recent research revealed immunosuppressive, angiogenesis-independent roles of VEGF signaling in the tumor microenvironment, affecting several aspects of cancer immunity.7,8 Specifically, VEGF-induced immunosuppression occurs through impairment of functional maturation of dendritic cells, inhibition of trafficking of primed and activated T cells to the tumor site, promotion of apoptosis in activated T cells and expansion of immunosuppressive cell types such as myeloid-derived suppressor cells and immunosuppressive regulatory T cells. This intimate relationship between VEGF and immunosuppression provides a strong scientific rationale for the combination of immune checkpoint inhibitors and VEGF-targeting angiogenesis inhibitors, with the possibility for synergistic benefits. Indeed, several Phase III clinical studies investigating combinations of such angiogenesis inhibitors and immune checkpoint inhibitors such as bevacizumab and atezolizumab in a range of solid cancer indications have already delivered on this promise.
In non-small-cell lung cancer (NSCLC), IMpower150 demonstrated significant clinical benefits for addition of atezolizumab to bevacizumab and chemotherapy in progression-free survival (PFS) (8.3 vs 6.8 months; hazard ratio [HR]: 0.52, 95% confidence interval [CI] 0.52-0.74; p<0.001) and overall survival (OS) (19.2 vs 14.7 months; HR: 0.78, 95% CI 0.64-0.96; p=0.02) compared to bevacizumab and chemotherapy alone. Adverse events were consistent with the known safety profiles of the individual treatments.9 These effects were observed regardless of PD-L1 status, and PFS benefits were further enhanced in patients with a high effector T cell gene signature (11.3 vs 6.8 months; HR: 0.51, 95% CI 0.38-0.68; p<0.001), indicative of active adaptive immune responses. Based on these results, the combination of bevacizumab with atezolizumab and chemotherapy obtained US FDA approval in 2018 for first-line treatment of patients with NSCLC.10
In hepatocellular carcinoma (HCC), IMbrave150 demonstrated significant clinical benefits for the combination of bevacizumab with atezolizumab for the co-primary endpoints OS (HR: 0.58, 95% CI 0.42-0.79; p<0.001) and median PFS (6.8 months vs 4.3 months, HR: 0.59, 95% CI 0.47-0.76; p<0.001) compared to sorafenib; adverse events were consistent with the known safety profiles of the individual treatments.11 Based on these results, this combination recently obtained FDA approval for treatment of patients with unresectable or metastatic HCC, a very challenging to treat condition.12
In mRCC, IMmotion151 demonstrated significant clinical benefits for the combination of bevacizumab with atezolizumab for the co-primary endpoint PFS in the PD-L1 positive population (11.2 vs 7.7 months; HR: 0·74, 95% CI 0·57–0·96; p=0·0217) compared to sunitinib, with a favorable safety profile.13 In the overall study population, overall survival (co-primary endpoint) was not different between groups as per an interim analysis.
Furthermore, the combination of bevacizumab and atezolizumab is investigated in ongoing Phase III clinical trials in a range of other advanced cancer indications, including in first-line treatment of deficient DNA mismatch repair-deficient metastatic colorectal cancer (COMMIT), ovarian cancer in the front-line setting (IMagyn050) and in the recurrent platinum-sensitive (ATALANTE) or platinum-resistant (AGO OVAR.2.29, NRG-GY009) settings, and in front-line cervical cancer (BEATcc).8
Overall, results from clinical studies investigating treatment combinations of immune checkpoint inhibitors with bevacizumab or other angiogenesis inhibitors suggest that this combined treatment approach may further enhance immune checkpoint inhibitors in RCC and other advanced cancers.
Written by: Josep Garcia, Global Development Team Leader, Roche, Basel, Switzerland, and Diego Rebella, MD, Global Medical Director & Scientific Communications Director, Roche, Basel, Switzerland
- Garcia, Josep, Herbert I. Hurwitz, Alan B. Sandler, David Miles, Robert L. Coleman, Regula Deurloo, and Olivier L. Chinot. "Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook." Cancer Treatment Reviews (2020): 102017.
- EEscudier, Bernard, Joaquim Bellmunt, Sylvie Négrier, Emilio Bajetta, Bohuslav Melichar, Sergio Bracarda, Alain Ravaud, Sophie Golding, Sangeeta Jethwa, and Vesna Sneller. "Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival." J Clin Oncol 28, no. 13 (2010): 2144-2150.
- Escudier, Bernard, Anna Pluzanska, Piotr Koralewski, Alain Ravaud, Sergio Bracarda, Cezary Szczylik, Christine Chevreau et al. "Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial." The Lancet 370, no. 9605 (2007): 2103-2111.
- Rini, Brian I., Susan Halabi, Jonathan E. Rosenberg, Walter M. Stadler, Daniel A. Vaena, Laura Archer, James N. Atkins et al. "Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206." Journal of clinical oncology 28, no. 13 (2010): 2137.
- Rini, Brian I., Susan Halabi, Jonathan E. Rosenberg, Walter M. Stadler, Daniel A. Vaena, San-San Ou, Laura Archer et al. "Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206." Journal of Clinical Oncology 26, no. 33 (2008): 5422.
- Ribas, Antoni, and Jedd D. Wolchok. "Cancer immunotherapy using checkpoint blockade." Science 359, no. 6382 (2018): 1350-1355.
- Hegde, Priti S., Jeffrey J. Wallin, and Christoph Mancao. "Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics." In Seminars in cancer biology, vol. 52, pp. 117-124. Academic Press, 2018.
- Rahma, Osama E., and F. Stephen Hodi. "The intersection between tumor angiogenesis and immune suppression." Clinical Cancer Research 25, no. 18 (2019): 5449-5457.
- Socinski, Mark A., Robert M. Jotte, Federico Cappuzzo, Francisco Orlandi, Daniil Stroyakovskiy, Naoyuki Nogami, Delvys Rodríguez-Abreu et al. "Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC." New England Journal of Medicine 378, no. 24 (2018): 2288-2301.
- FDA. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. 2018 [cited. Available from: https://www.fda.gov/drugs/fda-approves-atezolizumab-chemotherapy-and-bevacizumab-first-line-treatment-metastatic-non-squamous.
- Finn, Richard S., Shukui Qin, Masafumi Ikeda, Peter R. Galle, Michel Ducreux, Tae-You Kim, Masatoshi Kudo et al. "Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma." New England Journal of Medicine 382, no. 20 (2020): 1894-1905.
- FDA. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. 2020 [cited. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma.
- Rini, Brian I., Thomas Powles, Michael B. Atkins, Bernard Escudier, David F. McDermott, Cristina Suarez, Sergio Bracarda et al. "Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial." The Lancet 393, no. 10189 (2019): 2404-2415.