Last updated on December 2019

Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab in Metastatic Carcinoma of the Cervix

Brief description of study

The study will integrate the efficacy of combining the anti programmed death-ligand 1 (anti-PD-L1) agent atezolizumab with the current standard of care in Stage IVB , persistent or recurrent carcinoma of the cervix, namely cisplatin/paclitaxel/bevacizumab. It will be explored the combination of bevacizumab plus atezolizumab, with no patient selection based on PD-L1 expression, allowing an all-comer assessment of atezolizumab activity.

The study is a randomized open label phase III trial to investigate the impact of atezolizumab in combination with bevacizumab and cisplatin/paclitaxel chemotherapy on overall survival and will employ the intent to treat principle, and random assignment to one of the 2 arms will be balanced according to disease histology (squamous versus adenocarcinoma), prior platinum therapy as a radiation sensitizer (no prior cis-Radiotherapy (RT) versus prior cis-RT) and chemotherapy backbone (cisplatin versus carboplatin).

This trial will be run in an open label design due to the following considerations: the control arm is the standard of care for women diagnosed with metastatic, persistant or recurrent cervical cancer because of its impact on overall survival and the primary endpoint of the study is overall survival (OS), so blinding is not needed to ensure a robust assessment.

Detailed Study Description

Given that both Vascular Endothelial Growth Factor (VEGF) and PD-L1 appear important in cervical cancer pathogenesis, this study is designed to test the hypothesis that breaking of immune tolerance by PD-1/PD-L1 blockade will enhance the efficacy of anti-VEGF therapy in the treatment of patients with metastatic , persistent or recurrent cervical cancer. There are several data suggesting that atezolizumab and bevacizumab may be synergistic. Enhanced tumor angiogenesis is commonly associated with absence of tumor-infiltrating T cells in patients. There is evidence in ovarian cancer that tumor expression of VEGF is negatively correlated to the density of CD8+ TILs and this phenotype is associated with early recurrence, consistent with prior studies showing a correlation of VEGF to early recurrence and short survival. Furthermore, in ascites, high levels of VEGF correlate to low numbers of NK T-like CD3+CD56+ cells.

In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF plays a role in cancer immune evasion through several different mechanisms. Indeed, emerging evidence suggests that the endothelium acts as a selective barrier, allowing certain T cell subsets, notably T regulatory (Treg) cells, to traffic more effectively into the tumor contributing to tumor immune tolerance. In addition, some experiments have shown that tumour hypoxia promotes the recruitment of regulatory T (T reg) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis.

Some immunosuppressive activities of VEGF, however, can be reversed by inhibition of VEGF signaling. Mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell function, which could be restored by blockade of VEGFR2.

In turn, the anti-tumor effect of angiogenesis blockade requires CD8+ T cells supporting the notion that VEGF-A do not simply promote tumor growth through angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs seem closely connected and cooperating to sustain tumour growth.

In addition, there is evidence that anti-VEGF therapy and immunotherapy act synergistically. Motz et al have suggested that the combination of anti-VEGF-A antibody and immunotherapy with adoptive T cell transfer led to a superior infiltration of tumor-reactive T cells than any single approach. Indeed, in a murine melanoma model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by improved anti-tumor activity, prolonged survival, and increased trafficking of T cells into tumors. These data are reminiscent of the additive benefit observed in patients by combining recombinant interferon-alpha therapy and bevacizumab, a recombinant, humanized therapeutic antibody directed against VEGF, for the treatment of metastatic renal cell carcinoma.

More evidence has come from a clinical study of subjects with melanoma combining the checkpoint inhibitor (anti-CTLA-4) ipilimumab and bevacizumab. In 46 patients, the combined therapy yielded a 19.6% objective response rate, stable disease in 13%. All responses were durable >6 months and median survival was 25.1 months, much prolonged compared to ipilimumab's expectation in metastatic melanoma. Activated vessel endothelium with extensive CD8+ T cell and macrophage cell infiltration was observed in post-treatment biopsies, as well as marked increases in CD4/CCR7/CD45ROm central memory cells in peripheral blood in the majority of patients.

Thus, an emerging paradigm supported by the data above is that angiogenesis and immune suppression are two facets of a linked biological program. Tumors seem to co-opt these existing mechanisms that are normally required to limit excessive inflammation and promote tissue recovery during infection or wound healing. The execution of this program sustains tumor growth and promotes immunologic tolerance. Because of the intimate relationship between angiogenesis and immunosuppression, it is thus expected that inhibiting both pathways will result in improved and more durable clinical benefit.

Clinical Study Identifier: NCT03556839

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