Immune checkpoint inhibitors (ICIs) Combined with Anti-Angiogenic Therapy in Advanced Sarcoma

Immune checkpoint inhibitors (ICIs; anti-PD-1/PD-L1 and anti-CTLA4 antibodies) are a compelling new option for the treatment of various advanced cancers, including sarcomas. Previous studies have shown that the expression of PD-1/PD-L1 in sarcoma patients has a strong positive correlation with T cell infiltration and B cell activation (Kim, Kim et al. 2021) (Petitprez, de Reyniès et al. 2020). In the SARC028 and Alliance A0914401 clinical trials, anti-PD-1 agents (pembrolizumab and nivolumab) or those combined with an anti-CTLA agent (ipilimumab) have shown clinical benefits in advanced/metastatic sarcoma, but the overall response rate (ORR) in all cohorts was only 18 and 16%, respectively (Tawbi, Burgess et al. 2017, D'Angelo, Mahoney et al. 2018). Most non-responders have a significant correlation with restricted infiltration of immune cells, such as T cells and macrophages, and PD-L1 expression levels. The immunosuppressive tumor microenvironment (TME) generated by the dysfunctional tumor immune system leads to resistance to immunotherapy (Rabinovich, Gabrilovich et al. 2007). It has been proved that angiogenesis contributed to the maintenance of immunosuppressive TME in renal cell carcinoma and melanoma and was associated with antitumor activity (Yang, Yan et al. 2018, You, Guo et al. 2021)

Vascular endothelial growth factor (VEGF) is considered to be the main driver gene of angiogenesis, leading to tumor growth and metastasis, and it also contributes to suppression of the immunotherapy response (Fukumura, Kloepper et al. 2018). Therefore, the anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) display anti-cancer activity against STS, including anlotinib, pazopanib, and regorafenib (Berry, Basson et al. 2017, Chi, Fang et al. 2018, Weiss, Chen et al. 2020). Notably, on the basis of the role of VEGF in the suppressive TME, immune checkpoint inhibitor–based therapies combined with TKIs have exhibited favorable outcomes in various types of cancers (Fukumura, Kloepper et al. 2018).

A phase II single-arm study by Wilky et al. combined axitinib, an oral TKI, with pembrolizumab in 33 patients with advanced sarcoma(Wilky, Trucco et al. 2019). ORR was 25% with clinical benefit rate of 53.1%. In the intention to treat analysis, median PFS was 4.7 months and median OS was 18.7 months. In this study, 11 patients had alveolar soft part sarcoma (ASPS), the ORR in the ASPS cohort was 54.5%. The response rate in the ASPS was greater than that would be expected with either axitinib or pembrolizumab alone.

A recent phase Ib/II trial evaluated the combination of nivolumab with sunitinib in 68 patients with advanced soft tissue sarcoma (Martin-Broto, Hindi et al. 2020). The 6-month PFS was 48% with a median PFS of 5.6 months. The median overall survival was 24 months with an 18-month survival of 67%. The ORR was 21%, with 100% of responding patients alive at 18 months. These response rates, PFS and OS are favorable compared with activity in anti-PD-1 or sunitinib monotherapy in previous trials (George, Merriam et al. 2009, Tawbi, Burgess et al. 2017, Eulo and Van Tine 2022)

In a retrospective study, You, Guo et al. collected data from 61 STS patients treated with ICIs or ICIs combined with TKIs, including leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months) compared to ICI treatment alone (6.81 months. The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% to 42.90%. In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. (You, Guo et al. 2021).

In an immunomodulatory activity study, the role of TKIs and PD-1 based therapy was examined in in vitro cocultures of sarcoma. The data indicate that the treatment of sarcoma cells with TKI sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas. (Ocadlikova, Lecciso et al. 2021).

CD137 (TNFRSF9, 4-1BB) is suggested to provide co-stimulatory signals and activates cytotoxic effects of CD8(+) T cells and helps to form memory T cells. In addition, CD137 signaling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples(Hashimoto 2021). CD137 targeting molecules in combination with TKIs have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in STS.

Definitions of Oncology Drug Endpoints*

PFS

The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the PFS is one way to see how well a new treatment works. Also called progression-free survival.

OS

The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the OS is one way to see how well a new treatment works. Also called overall survival.

DFS

In cancer, the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer. In a clinical trial, measuring the DFS is one way to see how well a new treatment works. Also called disease-free survival, relapse-free survival, and RFS.

TTP

The length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. In a clinical trial, measuring the TTP is one way to see how well a new treatment works. Also called time to progression.

ORR

The percentage of people in a study or treatment group who have a partial or complete response to the treatment within a certain period of time. A partial response (PR) is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response (CR) is the disappearance of all signs of cancer in the body. In a clinical trial, measuring the ORR is one way to see how well a new treatment works. Also called overall response rate.

DCR or CBR

Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease (SD) to a therapeutic intervention in clinical trials of anticancer agents.

*Source: National Cancer Institute at the National Institutes of Health (www.cancer.org)

Comparison of WHO, RECIST v1.0 and RECIST v1.1 response criteria used as the standard method for tumor evaluation (Aykan and Özatlı 2020) ¹.

¹Modified from Choi et al (Choi, Ahn et al. 2005) , and extended with adding Response Evaluation Criteria in Solid Tumors version 1.1 (Borcoman, Nandikolla et al. 2018);

²Minimum interval between baseline assessment and first response evaluation;

On detection of new lesions, fluorodeoxyglucose-positron emission tomography scan is included. CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; WHO: World Health Organization; RECIST: Response Evaluation Criteria in Solid Tumors.³

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Reference

Aykan, N. F. and T. Özatlı (2020). "Objective response rate assessment in oncology: Current situation and future expectations." World J Clin Oncol 11(2): 53-73.

Berry, V., L. Basson, E. Bogart, O. Mir, J. Y. Blay, A. Italiano, F. Bertucci, C. Chevreau, S. Clisant-Delaine, B. Liegl-Antzager, E. Tresch-Bruneel, J. Wallet, S. Taieb, E. Decoupigny, A. Le Cesne, T. Brodowicz and N. Penel (2017). "REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis." Cancer 123(12): 2294-2302.

Borcoman, E., A. Nandikolla, G. Long, S. Goel and C. Le Tourneau (2018). "Patterns of Response and Progression to Immunotherapy." Am Soc Clin Oncol Educ Book 38: 169-178.

Chi, Y., Z. Fang, X. Hong, Y. Yao, P. Sun, G. Wang, F. Du, Y. Sun, Q. Wu, G. Qu, S. Wang, J. Song, J. Yu, Y. Lu, X. Zhu, X. Niu, Z. He, J. Wang, H. Yu and J. Cai (2018). "Safety and Efficacy of Anlotinib, a Multikinase Angiogenesis Inhibitor, in Patients with Refractory Metastatic Soft-Tissue Sarcoma." Clin Cancer Res 24(21): 5233-5238.

Choi, J. H., M. J. Ahn, H. C. Rhim, J. W. Kim, G. H. Lee, Y. Y. Lee and I. S. Kim (2005). "Comparison of WHO and RECIST criteria for response in metastatic colorectal carcinoma." Cancer Res Treat 37(5): 290-293.

D'Angelo, S. P., M. R. Mahoney, B. A. Van Tine, J. Atkins, M. M. Milhem, B. N. Jahagirdar, C. R. Antonescu, E. Horvath, W. D. Tap, G. K. Schwartz and H. Streicher (2018). "Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials." Lancet Oncol 19(3): 416-426.

Eulo, V. and B. A. Van Tine (2022). "Immune checkpoint inhibitor resistance in soft tissue sarcoma." Cancer Drug Resist 5(2): 328-338.

Fukumura, D., J. Kloepper, Z. Amoozgar, D. G. Duda and R. K. Jain (2018). "Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges." Nat Rev Clin Oncol 15(5): 325-340.

George, S., P. Merriam, R. G. Maki, A. D. Van den Abbeele, J. T. Yap, T. Akhurst, D. C. Harmon, G. Bhuchar, M. M. O'Mara, D. R. D'Adamo, J. Morgan, G. K. Schwartz, A. J. Wagner, J. E. Butrynski, G. D. Demetri and M. L. Keohan (2009). "Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas." J Clin Oncol 27(19): 3154-3160.

Hashimoto, K. (2021). "CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development." Cancers (Basel) 13(10).

Kim, S. K., J. H. Kim, S. H. Kim, Y. H. Lee, J. W. Han, W. Baek, H. Y. Woo, M. K. Jeon and H. S. Kim (2021). "PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma." BMC Cancer 21(1): 336.

Martin-Broto, J., N. Hindi, G. Grignani, J. Martinez-Trufero, A. Redondo, C. Valverde, S. Stacchiotti, A. Lopez-Pousa, L. D'Ambrosio, A. Gutierrez, H. Perez-Vega, V. Encinas-Tobajas, E. de Alava, P. Collini, M. Peña-Chilet, J. Dopazo, I. Carrasco-Garcia, M. Lopez-Alvarez, D. S. Moura and J. A. Lopez-Martin (2020). "Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial." J Immunother Cancer 8(2).

Ocadlikova, D., M. Lecciso, J. M. Broto, K. Scotlandi, M. Cavo, A. Curti and E. Palmerini (2021). "Sunitinib Exerts In Vitro Immunomodulatory Activity on Sarcomas via Dendritic Cells and Synergizes With PD-1 Blockade." Front Immunol 12: 577766.

Petitprez, F., A. de Reyniès, E. Z. Keung, T. W. Chen, C. M. Sun, J. Calderaro, Y. M. Jeng, L. P. Hsiao, L. Lacroix, A. Bougoüin, M. Moreira, G. Lacroix, I. Natario, J. Adam, C. Lucchesi, Y. H. Laizet, M. Toulmonde, M. A. Burgess, V. Bolejack, D. Reinke, K. M. Wani, W. L. Wang, A. J. Lazar, C. L. Roland, J. A. Wargo, A. Italiano, C. Sautès-Fridman, H. A. Tawbi and W. H. Fridman (2020). "B cells are associated with survival and immunotherapy response in sarcoma." Nature 577(7791): 556-560.

Rabinovich, G. A., D. Gabrilovich and E. M. Sotomayor (2007). "Immunosuppressive strategies that are mediated by tumor cells." Annu Rev Immunol 25: 267-296.

Tawbi, H. A., M. Burgess, V. Bolejack, B. A. Van Tine, S. M. Schuetze, J. Hu, S. D'Angelo, S. Attia, R. F. Riedel, D. A. Priebat, S. Movva, L. E. Davis, S. H. Okuno, D. R. Reed, J. Crowley, L. H. Butterfield, R. Salazar, J. Rodriguez-Canales, A. J. Lazar, Wistuba, II, L. H. Baker, R. G. Maki, D. Reinke and S. Patel (2017). "Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial." Lancet Oncol 18(11): 1493-1501.

Weiss, A. R., Y. L. Chen, T. J. Scharschmidt, Y. Y. Chi, J. Tian, J. O. Black, J. L. Davis, J. C. Fanburg-Smith, E. Zambrano, J. Anderson, R. Arens, O. Binitie, E. Choy, J. W. Davis, A. Hayes-Jordan, S. C. Kao, M. L. Kayton, S. Kessel, R. Lim, W. H. Meyer, L. Million, S. H. Okuno, A. Ostrenga, M. T. Parisi, D. A. Pryma, R. L. Randall, M. A. Rosen, M. Schlapkohl, B. L. Shulkin, E. A. Smith, J. I. Sorger, S. Terezakis, D. S. Hawkins, S. L. Spunt and D. Wang (2020). "Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial." Lancet Oncol 21(8): 1110-1122.

Wilky, B. A., M. M. Trucco, T. K. Subhawong, V. Florou, W. Park, D. Kwon, E. D. Wieder, D. Kolonias, A. E. Rosenberg, D. A. Kerr, E. Sfakianaki, M. Foley, J. R. Merchan, K. V. Komanduri and J. C. Trent (2019). "Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial." Lancet Oncol 20(6): 837-848.

Yang, J., J. Yan and B. Liu (2018). "Targeting VEGF/VEGFR to Modulate Antitumor Immunity." Front Immunol 9: 978.

You, Y., X. Guo, R. Zhuang, C. Zhang, Z. Wang, F. Shen, Y. Wang, W. Liu, Y. Zhang, W. Lu, Y. Hou, J. Wang, X. Zhang, M. Lu and Y. Zhou (2021). "Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis." Frontiers in Molecular Biosciences 8.