Unfortunately, in the search for targeted therapies, mesothelioma has largely evaded our efforts. Angiogenesis is a hallmark of cancer and has been targeted in mesothelioma, with mixed results. Two randomized clinical trials have demonstrated survival benefits by targeting VEGF or its receptor in first or later lines of therapy, with different chemotherapy backbones. These trials have strengthened the support for incorporating anti-angiogenesis therapy into the treatment of pleural mesothelioma.
Whereas targeted therapies are typically selected based on the detection of a predictive biomarker, robust, validated biomarkers for anti-angiogenesis therapy have not been identified. VEGF-A has been the primary target of anti-angiogenesis therapies, but other proteins such as basic fibroblast growth factor and platelet-derived growth factor are also critical regulators. Regardless, VEGF is overexpressed in malignant mesothelioma cell lines compared to normal mesothelial cells. Pleural effusions from patients with mesothelioma have also contained higher levels of VEGF than effusions from patients with non-malignant pleural disease, with a significant inverse correlation between serum VEGF levels and patient survival.1
With this growing evidence that VEGF may affect patient survival by promoting tumor angiogenesis and stimulating tumor growth, inhibitors of VEGF increasingly are being investigated as potential treatment of malignant mesothelioma. There is also evidence that targeting VEGF may modulate tumor-induced immunosuppression.
Multikinase inhibitors target multiple aspects of angiogenesis. Cediranib (a TKI targeting VEGFR 1-3, c-Kit, and PDGFR-β) and nintedanib (a TKI targeting VEGFR 1-3, FGFR 1-3, and PDGFR α/β and Src-family members) appeared to be effective when combined with chemotherapy in malignant pleural mesothelioma (MPM), but ultimately were limited by significant toxicity and lack of reproducibility in larger studies, respectively.2-6
More promising results were seen in the MAPS study, which demonstrated that bevacizumab, a humanized anti-VEGF-A monoclonal antibody, improved survival when combined with chemotherapy compared to chemotherapy alone (median overall survival, or OS: 18.8 months vs. 16.1 months) in MPM in the frontline setting.7 This finding was somewhat surprising as a prior randomized phase 2 clinical trial failed to demonstrate a survival benefit when adding bevacizumab to a chemotherapy backbone of cisplatin and gemcitabine compared to placebo with cisplatin and gemcitabine.8 Regardless, the results of the MAPS trial led to bevacizumab’s inclusion into the U.S. National Comprehensive Cancer Network (NCCN) guidelines as potential first-line treatment for unresectable MPM. However, bevacizumab does not have U.S. Food and Drug Administration (FDA) approval for the indication of mesothelioma. It should also be noted that the survival advantage came with an increase in grade 3-4 adverse events, including hypertension and thrombotic events.
The RAMES study also yielded a survival advantage. This trial showed that ramucirumab, a humanized anti-VEGFR2 monoclonal antibody, improved survival when combined with gemcitabine, as compared to chemotherapy alone (median OS: 13.8 months vs. 7.5 months), in patients with previously treated MPM (patients who had experienced disease progression during or after first-line pemetrexed/platinum-based chemotherapy).9 Similar to the MAPS trial, treatment-related adverse effects were more common in the combination therapy group, with thromboembolism the most common serious adverse event. As of February 2022, ramucirumab in combination with gemcitabine is not approved by the FDA and is not included in NCCN guidelines for mesothelioma.
Whereas MAPS and RAMES showed benefit of anti-angiogenesis therapy in combination with chemotherapy, the BEAT-meso study is investigating whether the addition of immunotherapy to chemotherapy and bevacizumab improves outcomes compared to chemotherapy with bevacizumab alone in the frontline setting. This multicenter phase 3 study is estimated to reach completion in 2024.10
Combination VEGF inhibition and immunotherapy has also been explored in peritoneal mesothelioma. A recent study of patients with peritoneal mesothelioma with unresectable disease and progression or intolerance to first-line platinum-based therapy showed that treatment with atezolizumab and bevacizumab resulted in a response rate of 40% by RECIST and a median response duration of 12.8 months, regardless of PD-L1 expression by tumor cells.11 Although these results are from a relatively small, single-arm trial, there are almost no other prospective trial data with systemic therapy for peritoneal mesothelioma. The sustained responses suggest a possible second-line therapy option for advanced peritoneal mesothelioma. These data also suggest that targeting both VEGF and PD-L1 may provide synergistic activity against mesothelioma.
With the rise of immunotherapy, agents such as nivolumab plus ipilimumab (PD-1 plus CTLA-4 inhibitor) are now FDA-approved for various solid cancers, including pleural mesothelioma. Specifically, the CheckMate 743 (CM743) study showed an OS benefit for nivolumab plus ipilimumab versus chemotherapy in patients with untreated, unresectable MPM (18.1 months vs. 14.1 months).12 The survival benefit was more pronounced in patients with non-epithelioid variants of mesothelioma. CM743 did not include a VEGF inhibitor in the control arm given the timing of the initiation of that trial and the lack of regulatory approval of bevacizumab.
As it stands, there is strong evidence that including bevacizumab with a platinum doublet—and reasonable evidence that including ramucirumab with gemcitabine—improve survival outcomes. As these trials were conducted before the use of frontline immunotherapy, there are uncertainties as to how different sequences may impact survival outcomes, but in our opinion these uncertainties should not preclude the incorporation of anti-angiogenesis therapy into the therapeutic arsenal against mesothelioma.
In summary, we have seen both bevacizumab and ramucirumab improve survival outcomes in combination with chemotherapy in the frontline or second-line treatment of pleural mesothelioma, respectively. It is uncertain why multikinase inhibitors which also target angiogenesis have not been effective in this setting. In parallel, immunotherapy has rapidly been adopted for the treatment of pleural mesothelioma, and there is evidence of efficacy for the combination of immunotherapy with bevacizumab in peritoneal mesothelioma. With ongoing clinical trials for pleural mesothelioma, the preferred therapy for first and later lines of therapy may continue to change. However, the survival data from the MAPS and RAMES studies strongly support the inclusion of angiogenesis inhibitors in clinical trials and as considerations for clinical management, as allowed by local regulatory frameworks and supported by guidelines.
- 1. Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001;193(4):468-475.
- 2. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65(10):4389-4400. doi:10.1158/0008-5472.CAN-04-4409
- 3. Garland LL, Chansky K, Wozniak AJ, et al. Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol. 2011;6(11):1938-1945. doi:10.1097/JTO.0b013e318229586e
- 4. Tsao AS, Miao J, Wistuba II, et al. Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905). J Clin Oncol. 2019;37(28):2537-2547. doi:10.1200/JCO.19.00269
- 5. Grosso F, Steele N, Novello S, et al. Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial. J Clin Oncol. 2017;35(31):3591-3600. doi:10.1200/JCO.2017.72.9012
- 6. Scagliotti GV, Gaafar R, Nowak AK, et al. LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma. Clin Lung Cancer. 2017;18(5):589-593. doi:10.1016/j.cllc.2017.03.010
- 7. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomized, controlled, open-label, phase 3 trial. Lancet. 2016;387(10026):1405-1414. Published correction appears in Lancet. 2016;387(10026):e24.
- 8. Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol. 2012;30(20):2509-2515. doi:10.1200/JCO.2011.41.5869
- 9. Pinto C, Zucali PA, Pagano M, et al. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2021;22(10):1438-1447. doi:10.1016/S1470-2045(21)00404-6
- 10. European Thoracic Oncology Platform. A Multicentre Randomized Phase III Trial Comparing Atezolizumab Plus Bevacizumab and Standard Chemotherapy Versus Bevacizumab and Standard Chemotherapy as First-Line Treatment for Advanced Malignant Pleural Mesothelioma. Clinicaltrials.gov identifier: NCT03762018 Accessed November 22, 2021. https://clinicaltrials.gov/ct2/show/NCT03762018.
- 11. Raghav K, Liu S, Overman MJ, et al. Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma. Cancer Discov. 2021;11(11):2738-2747. doi:10.1158/2159-8290.CD-21-0331
- 12. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomized, open-label, phase 3 trial. Lancet. 2021;397(10272):375-386. Published correction appears in Lancet. 2021;20;397(10275):670.