Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial

Wu, Siyu; Xu, Ying; Chen, Li; Fan, Lei; Ma, Xiao-Yan; Song, Xiao-Qing; Hu, Xin; Yang, Wentao; Chai, Wen-Jun; Guo, Xiaomao; Chen, Xi-Zi; Xu, Yanhui; Zhu, Xiaoyu; Zou, Jianjun; Wang, Zhonghua; Jiang, Yi‐Zhou; Shao, Zhi-Ming

doi:10.1186/s12943-022-01536-6

Cited by 56 publications

(40 citation statements)

References 44 publications

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“…Antiangiogenic therapy and immunotherapy both act on the tumor microenvironment, and previous preclinical studies have shown that immunotherapy combined with anti-angiogenic drugs synergistically inhibit tumor growth and metastasis ( 33 ). Some clinical trials also confirmed the value of antiangiogenic therapy in combination with immunotherapy ( 34 , 35 ). However, the application of anlotinib combined with ICIs in breast cancer has not yet been reported, our present study shows that anlotinib combined with immunotherapy has also achieved good clinical efficacy in metastatic breast cancer.…”

Section: Discussionmentioning

confidence: 84%

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer

Shao

Luo²,

Yu³

et al. 2022

Front. Oncol.

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BackgroundAntiangiogenic agents provides an optional treatment strategy for patients with metastatic breast cancer. The present study was conducted to evaluate the efficacy and safety of anlotinib as third-line or above therapy for patients with HER-2 negative metastatic breast cancer.MethodsPatients with HER-2 negative metastatic breast cancer who have failed from prior therapy and treated with anlotinib monotherapy or combined with chemotherapy or immunotherapy from June 2018 to December 2020 were retrospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety.Results47 patients with HER-2 negative metastatic breast cancer received anlotinib monotherapy or combination therapy as third-line or above therapy. In the general population, 10 patients achieved PR, 25 patients had SD and 12 patients had PD. The overall ORR and DCR were 21.3% and 74.5%, respectively. Subgroup analysis suggested that there were no statistically significant differences in ORR and DCR with respect to HR status (positive vs. negative), treatment programs (monotherapy vs. combination) and treatment type in combination group (chemotherapy vs. immunotherapy). The patients who did not received previously anti-angiogenesis therapy had superior DCR (84.8% vs. 50.0%, P=0.012). Median PFS and OS were 5.0 months (95% CI=4.3-5.7) and 21.0 (95% CI=14.9-27.1) months, respectively. The PFS (6.5m vs. 3.5m, P=0.042)and OS (28.2m vs. 12.6m, P=0.040) were better in HR positive patients than HR negative patients. And simultaneously, patients who received anlotinib combination therapy obtained better PFS (5.5m vs. 3.0m, P=0.045). The incidence of Grade 3-4 adverse events(AEs) was 31.9%.ConclusionsAnlotinib monotherapy or combination therapy provide a viable third-line or above therapeutic strategy in patients with HER-2 negative metastatic breast cancer, a median PFS of 5.0 months was obtained with well tolerated toxicity.

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Section: Discussionmentioning

confidence: 84%

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer

Shao

Luo²,

Yu³

et al. 2022

Front. Oncol.

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“…The presence of tumor-infiltrating lymphocytes (TILs) is predictive of a better response to immunotherapy and a favorable prognosis in BC (37)(38)(39)(40). CD8+ T-cell infiltration in BC is independently associated with a reduced relative risk of cancer-related death (41), while TNBCs with CD8 positivity have greater possibilities to benefit from immunotherapy (42). These findings correspond to our results of more CD8+ T cells in the TME of pyroptosis subtype A and low-risk group that had higher expression of PD-1 and PD-L1 and better OS.…”

Section: Discussionmentioning

confidence: 99%

Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer

Luo

Wang

et al. 2022

Front. Immunol.

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The survival outcome of triple-negative breast cancer (TNBC) remains poor, with difficulties still existing in prognosis assessment and patient stratification. Pyroptosis, a newly discovered form of programmed cell death, is involved in cancer pathogenesis and progression. The role of pyroptosis in the tumor microenvironment (TME) of TNBC has not been fully elucidated. In this study, we disclosed global alterations in 58 pyroptosis-related genes at somatic mutation and transcriptional levels in TNBC samples collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Based on the expression patterns of genes related to pyroptosis, we identified two molecular subtypes that harbored different TME characteristics and survival outcomes. Then, based on differentially expressed genes between two subtypes, we established a 12-gene score with robust efficacy in predicting short- and long-term overall survival of TNBC. Patients at low risk exhibited a significantly better prognosis, more antitumor immune cell infiltration, and higher expression of immune checkpoints including PD-1, PD-L1, CTLA-4, and LAG3. The comprehensive analysis of the immune landscape in TNBC indicated that alterations in pyroptosis-related genes were closely related to the formation of the immune microenvironment and the intensity of the anticancer response. The 12-gene score provided new information on the risk stratification and immunotherapy strategy for highly heterogeneous patients with TNBC.

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“…Identification of biomarkers is important for treatment strategy development. A recently published biomarker analysis study showed that famitinib (an angiogenesis inhibitor) plus camrelizumab and chemotherapy had an impressive clinical benefit in patients with CD8-positive advanced TNBC, with an ORR of 81.3% and a median PFS of 13.6 months, and those with CD8-and PD-L1-positive tumors benefit more from this regimen [30]. However, combining anti-PD-1/PD-L1 antibody with anti-angiogenesis agent showed clinical benefit irrespective of PD-L1 expression in several other tumor types [31][32][33].…”

Section: Discussionmentioning

confidence: 99%

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer

Zhang

Shao

Tong

et al. 2022

BMC Med

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Background Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC. Methods This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT). Results A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9–22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3–79.3). The median progression-free survival was 5.2 months (95% CI, 3.6–7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0–88.8). Conclusions Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC. Trial registration ClinicalTrials.gov NCT03945604 (May 10, 2019).

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Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial

Cited by 56 publications

References 44 publications

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer

Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer

A phase Ib study of camrelizumab in combination with apatinib and fuzuloparib in patients with recurrent or metastatic triple-negative breast cancer

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