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A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030)
  1. Juan Francisco Grau,
  2. Lorena Farinas-Madrid and
  3. Ana Oaknin
  1. Vall d’Hebron University Hospital Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
  1. Correspondence to Professor Ana Oaknin, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain; aoaknin{at}vhio.net

Abstract

Background Patients with metastatic, recurrent, or persistent cervical cancer not amenable to local control and/or distant metastases have a very poor prognosis, only being candidates for palliative-systemic therapy. First line standard treatment in this scenario is based on cisplatin/paclitaxel plus bevacizumab (GOG 240 regimen) with a short median overall survival (16.8 months) and progression-free survival (8.2 months).

Primary objective To determine whether the addition of atezolizumab to cisplatin-paclitaxel and bevacizumab improves overall survival, compared with cisplatin-paclitaxel plus bevacizumab in patients with metastatic, recurrent, or persistent cervical cancer.

Study hypothesis The primary hypothesis is whether the addition of atezolizumab to cisplatin-paclitaxel and bevacizumab improves overall survival in metastatic, recurrent, or persistent cervical cancer.

Trial design The BEATcc study is a phase III, randomized, open-label, multi-center clinical trial. The study will be performed on an intent-to-treat population. The control arm is the administration of chemotherapy (platinum plus paclitaxel) and bevacizumab, while the experimental arm is the administration of atezolizumab in combination with the same chemotherapy regimen (1:1 randomization). The trial will be run under the ENGOT umbrella alongside JGOG and GOG-F. GEICO is the lead group on behalf of ENGOT.

Major Inclusion/Exclusion criteria Women over 18 years old with histologically or cytologically confirmed diagnosis of squamous cell carcinoma, adenocarcinoma, or adenosquamous metastatic, recurrent, or persistent cervical cancer, not amenable for curative treatment with surgery and/or radiation therapy, will be included. Women are not eligible if they have received prior systemic anti-cancer therapy for metastatic or persistent/recurrent disease or they have disease involving the bladder or rectum at the screening/baseline pelvic magnetic resonance imaging.

Primary endpoint Overall survival, defined as the observed length of life from entry into the study (day of randomization) to death from any cause or the date of last contact.

Sample size A total of 404 patients are expected to be recruited into the study, assuming a total 10% drop-out rate. In order to test whether the experimental arm improves overall survival, the study will have 80% power using one-sided α of 0.025. There will be one interim analysis to close the study in case of early efficacy results in the experimental arm.

Estimated dates for completing accrual and presenting results The trial was launched in Q3 2018 and the trial is estimated to close in Q3 2022. We expect to be able to report mature data from the BEATcc trial by 2023.

Trial registration ClinicalTrials.gov (NCT03556839)

  • cervical cancer

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Introduction

Cervical cancer is the second most common malignancy in women worldwide.1 Although most patients diagnosed at early stages will be cured, 15–20% will recur. In addition, up 70% of locally advanced cancer will relapse following concurrent chemo-radiation treatment. Unfortunately, patients with recurrent or metastatic disease have a very poor prognosis with less than 20% 5 year overall survival. For the last 25 years, the standard of care for metastatic, recurrent, or persistent cervical cancer treatment consisted of cisplatin-doublet chemotherapy.

Evidence that angiogenesis plays an important role in cervical cancer, induced, in part, by vascular endothelial growth factor (VEGF), has led to the development of anti-angiogenic therapies in metastatic, recurrent, or persistent cervical cancer in the last years.2 As a result, bevacizumab, a recombinant humanized monoclonal antibody directed against VEGF-A, has been approved in this setting by both the US Food and Drug Administration (FDA) in 2014 and the European Medicines Agency in 2015, following the results of the Gynecologic Oncology Group (GOG) 240.3 This study demonstrated that the addition of bevacizumab to combination chemotherapy was associated with a significant improvement in overall survival (16.8 vs 13.3 months, respectively) and progression-free survival (8.2 vs 6.0 months, respectively).4

Regarding immunotherapy strategies, cervical cancer may represent a unique setting where these therapies may be further developed, due to the well-recognized causative role of human papillomavirus (HPV) infection. The immune checkpoint inhibition has emerged in an effort to reverse the immune-privileged state often encountered in the malignant microenvironment. Cancer cells take advantage of the programmed death-1 (PD-1) inhibitory pathway to silence the anti-tumor immune system response.5 Recent data show that programmed death ligand 1 (PD-L1) may be a biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies, suggesting that anti-PD-L1 therapy may have a role in the treatment of cervical cancer.6

Currently, we have evidence of the clinical activity of PD-1 inhibition in the setting of metastatic, recurrent or persistent cervical cancer. Pembrolizumab (anti-PD-1) has received regulatory approval by the FDA for use in advanced cervical cancer expressing PD-L1 with progressive disease either during or after platinum based chemotherapy, on the basis of the phase 2 KEYNOTE-158 trial’s results showing an overall response rate of 12% and 14.6% in all population and PD-L1 positive tumor (combined positive score ≥1), respectively.7 The activity of nivolumab was studied in 19 patients in the phase I/II study CheckMate358. The overall response rate was 26.3% with a disease control rate of 68.4% regardless of PD-L1 status. Remarkably, in chemo-naïve patients the overall response rate and disease control rate were higher, 28.6% (95% CI 3.7% to 71.0%) and 71.4%, respectively.8

Given that both 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, recurrent, or persistent cervical cancer.9 There are emerging data supporting the proposal 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.

The BEATcc trial will integrate the efficacy of combining the anti-PD-L1 agent atezolizumab with the current standard of care in metastatic, recurrent, or persistent cervical cancer patients, namely cisplatin-paclitaxel plus bevacizumab. We will explore the combination of bevacizumab plus atezolizumab, with no patient selection based on PD-L1 expression, allowing an all-comer assessment of atezolizumab activity.

Methods

Trial design

BEATcc is a phase III, randomized, open-label, multi-center study to assess the efficacy of atezolizumab administered concurrent to the combination of cisplatin-paclitaxel plus bevacizumab in previously untreated patients with metastatic, recurrent, or persistent cervical cancer. A total of 404 patients will be randomized in a 1:1 ratio to the treatments as specified below (Figure 1):

Figure 1

Study design. ADK, adenocarcinoma; ECOG, Eastern Cooperative Oncology Group; GOG, Gynecologic Oncology Group; HRQoL, health-related quality of life; ORR, overall response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PRO, patient reported outcome; RT, radiotherapy; SSC, squamous cell carcinoma;

  • Control arm: cisplatin 50 mg/m2+paclitaxel 175 mg/m2+bevacizumab 15 mg/kg intravenously (IV) day 1 every 3 weeks.

  • Experimental arm: cisplatin 50 mg/m2+paclitaxel 175 mg/m2+bevacizumab 15 mg/kg+atezolizumab 1200 mg IV day 1 every 3 weeks

In both arms, treatment cycles are repeated every 21 days until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination by the sponsor, whichever occurs first.

Patients who achieve a complete response after ≥6 cycles may be allowed to continue only on biologics therapy, namely bevacizumab and/or atezolizumab, after discussion with the principal investigator. The main reason to drop the chemotherapy will be that to continue on chemotherapy plus biologic therapy will not increase the benefit already obtained from the chemotherapy-based regimen, while it may increase the risk of developing prohibitive toxicity, at the treating physician’s discretion. If chemotherapy needs to be interrupted due to toxicity, patients can continue only on biologics treatment. In patients who develop unacceptable toxicity to bevacizumab and/or atezolizumab, these can be discontinued and the rest of the treatment agents will continue to be administered as planned. Crossover after treatment discontinuation from the control arm to the experimental arm is not allowed.

Randomization will be stratified by three factors:

  • Prior concomitant chemo-radiation.

  • Histology (squamous cell carcinoma vs adenocarcinoma and adenosquamous carcinoma).

  • Chemotherapy backbone (cisplatin vs carboplatin). The use of carboplatin may be allowed once the results from the CECILIA trial (NCT02467907) become available and on sponsor agreement.

Independent Data Monitoring Committee

In order to preserve the safety of the study population an Independent Data Monitoring Committee (IDMC) will be set up. The IDMC will be in charge of monitoring the safety of the enrolled patients at regular intervals and more frequently if appropriate to provide recommendations on study continuation to the sponsor.

Participants

Key inclusion criteria are as follows:

  • Women over 18 years old with a histologically or cytologically confirmed diagnosis of metastatic, recurrent, or persistent cervical cancer (histologies other than squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma will be excluded) not amenable for curative treatment with surgery and/or radiation therapy.

  • No prior systemic anti-cancer therapy for metastatic or recurrent disease is permitted. In the case of prior concurrent chemo-radiotherapy as a primary or adjuvant treatment, this must have been completed ≥3 months (90 days) before enrollment.

Key exclusion criteria are as follows:

  • Disease suitable for local therapy with curative intent.

  • Patients with stage IVA not amendable to concurrent chemo-radiation as primary treatment.

  • Ongoing disease involving the bladder or rectum at the screening/baseline pelvic magnetic resonance imaging.

  • Exclusion criteria for bevacizumab, namely clinically significant cardiovascular or cerebrovascular disease, history of abdominal fistula or gastrointestinal perforation, as well as acute intestinal obstruction or sub-occlusion, and active bleeding.

Additionally, patients with a history of autoimmune disease, especially when uncontrolled and/or requiring active treatment, or those having recently received therapeutic antibiotics, systemic immunostimulatory agents, or systemic immunosuppressive medications, will not be eligible either.

Study objectives

The primary objective of the study is to determine whether the addition of atezolizumab to cisplatin-paclitaxel plus bevacizumab improves overall survival compared with cisplatin-paclitaxel plus bevacizumab, in patients with metastatic, recurrent, or persistent cervical cancer.

The secondary objectives are:

  • To determine the progression-free survival of combining atezolizumab with cisplatin-paclitaxel plus bevacizumab compared with cisplatin-paclitaxel and bevacizumab. Progression-free survival is based on investigator assessment using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)

  • To determine overall response rate using RECIST v1.1

  • To evaluate the safety and tolerability of combining atezolizumab to chemotherapy plus bevacizumab compared with cisplatin-paclitaxel plus bevacizumab

  • To evaluate duration of response

  • To determine time from randomization to first subsequent therapy or death

  • To determine time from randomization to second progression

  • To evaluate patient-reported outcomes of function and health related quality of life (HRQoL) associated with atezolizumab+cisplatin-paclitaxel+bevacizumab compared with bevacizumab+cisplatin-paclitaxel alone, as measured by the functional and Global Health Status/HRQoL scales of EORTC QLQ-C30

  • To characterize the pharmacokinetics of atezolizumab and determine the incidence of anti-therapeutic antibodies

  • As key exploratory endpoints, we will assess changes from baseline score in disease/treatment-related symptoms between treatment arms, the relationship between tumor immune-related, disease type-related (mutational burden, PD-L1, HPV infection, tumor-infiltrating lymphocytes, and CD8) and plasma biomarkers (circulating cell-free DNA, proteins, and cytokines) and clinical outcomes.

Sample size

A total of 404 patients are expected to be recruited into the study. To assess the hypothesis testing in the primary endpoint a one-sided stratified log-rank test will be conducted at an overall 2.5% level of significance with 80% power.

Sample size is calculated according the Lachin and Foulkes method followed by group sequential design. The spending function provided by Lan and DeMets has been used to control alpha spending in the interim analysis.

Randomization and blinding

Once the eligibility of a patient has been confirmed, the investigator should contact the Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) Centralized Randomization Center for allocation of randomized study treatment. The actual treatment given to individual patients will be determined by a randomization scheme that has been loaded into the IVRS/IWRS database. The randomization scheme will be produced by a computer software program that incorporates a standard procedure for generating random numbers. A blocked randomization will be generated and all centers will use the same list in order to minimize any imbalance in the number of patients assigned to each treatment group.

With regard to blinding, 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, persistent, or recurrent cervical cancer because of its impact on overall survival.

  • The primary endpoint of the study is overall survival which is unlikely to be directly impacted by the investigator assessment.

  • The treatment schedule is the same in the control and experimental arms, so equivalent patient assessment and monitoring between arms is ensured.

  • Patient-reported outcomes assessment will consist of an exploratory and descriptive analysis.

Statistical methods

Time-to-event variables (progression-free survival, progression-free survival, time to first subsequent therapy or death, and time from randomization to second progression) will be analyzed according to the Kaplan-Meier method. The stratified log-rank test on the intent to treat analysis population will be primarily used to compare the time-to-event variables, and Cox regression models will be used to calculate the risk reduction. HR with 95% CIs will be reported to evaluate the impact of treatment, stratification variables, and other potential prognostic factors on the time-to-event efficacy endpoints.

The primary endpoint (overall survival) will be evaluated in the interim analysis. If early efficacy results in the experimental arm are not found, a final analysis will be performed with 80% power.

Discussion

Nowadays, there is still room to improve outcomes of patients with metastatic, recurrent, or persistent cervical cancer, since the median overall survival, even with the addition of bevacizumab, is limited to 17 months. In this adverse scenario arises the BEATcc trial (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030), a phase III, randomized, open-label, multi-center study to assess the efficacy of atezolizumab administered concurrent to the combination of cisplatin-paclitaxel plus bevacizumab in untreated patients with metastatic, recurrent, or persistent cervical cancer. The study aims to demonstrate that the combination with cisplatin-paclitaxel plus bevacizumab and atezolizumab is more effective in terms of overall survival than the standard treatment, with a target reduction of the hazard of death by 30%, and an acceptable safety profile.

There is growing clinical evidence of the use of immunotherapy in cervical cancer, as demonstrated by the results of immune checkpoint inhibitors. Looking into its biological rationale, it is well known that an appropriate immune response will prevent most of the women infected by HPV from the development of an invasive cervical cancer. However, a process known as immune-editing allows HPV-infected cells to overcome immune surveillance in some women, permitting selection of cancer clones with increased resistance to immune detection and elimination, resulting in tumor growth. In cervical cancer, immunotherapy could restore that initial immune response against cancer cells. The activation of the PD-1/PD-L1 pathway is involved in cervical cancer and other HPV-related squamous cell cancers. Many authors have demonstrated expression of PD-1/PD-L1 in about 54–67% of squamous cervical cancer which is correlated with progression of pre-cancerous lesions to invasive cancer, tumor grade, and prognosis.10 11

Additionally, the VEGF plays a role in cancer immune evasion through several different mechanisms. VEGF may reduce lymphocyte adhesion to vessel walls, thus contributing to decreased immune cell recruitment to the tumor site. 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. Some experiments have shown that tumor hypoxia promotes the recruitment of T reg cells, which promotes tumor tolerance and angiogenesis. In turn, the anti-tumor effect of angiogenesis blockade requires CD8+ T cells, supporting the notion that VEGF-A does not simply promote tumor growth through angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs seem closely connected and cooperate to sustain tumor growth.

The synergy between immunotherapy and anti-VEGF therapies may result in improved and more durable clinical benefit. Recently, the clinical advantage of this dual inhibition has been demonstrated in a metastatic renal cancer population. Patients with untreated metastatic renal cancer were enrolled in the phase II IMmotion150 study and randomized to three arms: atezolizumab 1200 mg IV every 3 weeks+bevacizumab 15 mg/kg IV every 3 weeks, atezolizumab alone or sunitinib 50 mg orally every day 4 weeks on and 2 weeks off. PD-L1 status was scored on tumor-infiltrating immune cells (IC, SP142 immunohistochemical (IHC) assay). The primary analysis was IRF (independent review facility)-assessed progression-free survival (RECIST v1.1) in intent to treat population and patients with PD-L1 expression on ≥1% of IC (PD-L1+). In PD-L1+ patients (54% of the population) first line treatment resulted in a median progression-free survival of 14.7 months vs 7.8 months for atezolizumab+bevacizumab and for sunitinib, respectively (HR 0.64, 95% CI 0.38 to 1.08; p=0.095). Remarkably, safety was comparable to the known individual profiles of atezolizumab and bevacizumab.12 In this hypothesis generating trial, the dual inhibition based on anti-VEGF plus anti-PD-L1 agents has been superior to the sole angiogenesis inhibition, therefore warranting further investigation of the combination in other tumor types, and it seems that cervical cancer may be the perfect scenario.

Our objective is that the therapeutic strategy employed in the BEATcc trial—exploring the synergistic combination of chemotherapy, bevacizumab and atezolizumab—will lead to improvements in the current survival outcomes of patients with metastatic, recurrent, or persistent cervical cancer, resulting in a new standard of treatment.

References

Footnotes

  • Contributors AO has contributed to the development of the study and the design of the trial. She has also contributed to the writing of the manuscript. FG and LF-M have contributed to the the writing of the manuscript.

  • Funding This study was supported by F. Hoffmann-La Roche.

  • Competing interests AO has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, PharmaMar, Roche, and Tesaro and received support for travel or accommodation from AstraZeneca, PharmaMar, Roche, and Tesaro.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.