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Abstract
Background Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment.
Primary objective To test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab.
Study hypothesis The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months.
Trial design Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status.
Major inclusion/exclusion criteria Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria.
Primary endpoint Overall survival and progression-free survival are co-primary endpoints.
Sample size It is planned to randomize 664 patients.
Trial registration NCT03353831.
- ovarian cancer
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Introduction
Despite optimal primary surgery and carboplatin/paclitaxel-based chemotherapy, the majority of patients with newly diagnosed advanced ovarian cancer will relapse. Treatment options for recurrent disease depend on treatment-free interval, prior therapy, BRCA-status, symptoms, and patient’s preference. Further treatment depends on eligibility for further platinum-based treatment. In patients who are not eligible for another platinum-based treatment, a non-platinum-based drug such as pegylated liposomal doxorubicin (PLD), gemcitabine, paclitaxel, or topotecan is the cytotoxic treatment of choice. The AURELIA trial showed a significant progression-free survival benefit of adding bevacizumab to single-agent chemotherapy in this patient cohort (HR 0.48; 95% CI 0.38 to 0.60; P<0.001).1 Therefore, bevacizumab-based treatment is a standard option in patients with platinum-resistant ovarian cancer.
A spontaneous antitumor immune response has been demonstrated in approximately 55% of the patients with ovarian cancer in the form of tumor-infiltrating lymphocytes2 which has been repeatedly associated with a prolonged survival among ovarian cancer patients.3 Pembrolizumab, an anti-PD1 humanized antibody achieved three confirmed responses (11.5% [(95% Cl, 2.4–30.2]) in 26 patients treated in a phase IB study and three additional patients had a tumor reduction of at least 30%.4 In a small study including 12 patients who received ≥2 previous therapy lines in advanced ovarian cancer, at increasing doses of 0.3–15 mg/kg, safety, clinical activity, and biomarkers of atezolizumab have been studied. Treatment-related adverse events were mainly grade I/II fatigue and pain. Two out of nine evaluable patients at the 10 or 15 mg/kg dose levels showed a long-lasting response.5
There is increasing evidence that vascular endothelial growth factor plays a role in cancer immune evasion through several different mechanisms.6 A randomized phase III trial with 915 patients in metastatic renal cell carcinoma has shown the superiority of bevacizumab in combination with atezolizumab vs sunitinib. Safety was comparable to the known individual profiles of atezolizumab and bevacizumab.7 Further supporting evidence for the combination of atezolizumab and bevacizumab has been shown in IMpower 150 in non-small-cell lung cancer.8
Because of the intimate relationship between angiogenesis and immunosuppression, it is expected that inhibiting both pathways will result in improved and more durable clinical benefit.
Therefore, we aim to test the efficacy of atezolizumab in combination with non-platinum-based chemotherapy and bevacizumab vs the combination of a non-platinum-based chemotherapy and bevacizumab alone.
After initiation of study recruitment in Germany, data from a phase III trial in platinum-resistant ovarian cancer, JAVELIN 200,9 with avelumab, a monoclonal anti-PD-L1 antibody was reported and suggested that PD-L1 positive patients derived a greater benefit than PD-L1 negative patients. To date there is no accepted gold standard for immuno-histochemistry for ovarian cancer-based PD-L1 testing and diagnostic assays, scoring methods as well as cut-offs vary between different tumor types and therapeutic antibodies. However, overall there are consistent reports from several tumor entities, that PD-L1 status is a predictive factor for benefit from immune-checkpoint inhibitors. Based on the available data from atezolizumab in ovarian cancer and other solid tumors, we therefore implemented PD-L1 testing using the VENTANA SP142 diagnostic assay as a stratification factor and in addition, we will explore alternative PD-L1 testing assays, aiming to best define the population, which will benefit the most from immune-checkpoint inhibitors. This major amendment was approved by the authorities in January 2020 after recruitment of 94 patients.
Methods
This is an international placebo-controlled randomized phase III trial, which is conducted as a European Network of Gynaecological Oncological Trial Groups (ENGOT) trial according to model A.10 Ethical approval was obtained by the Ethikkommission of the Medizinische Fakultät Heidelberg (AFmu-655/2017). The target population includes patients with recurrent ovarian-, fallopian tube, or primary peritoneal carcinoma with first or second relapse within 6 months after platinum-based chemotherapy or third relapse. Eligible patients undergo a biopsy for testing PD-L1 status. After obtaining the result, patients are randomized to chemotherapy + bevacizumab + placebo (standard arm) vs chemotherapy + bevacizumab + atezolizumab. Allowed chemotherapy regimen include paclitaxel and PLD according to prior treatment and investigators' decision. The allowed chemotherapy backbone is weekly paclitaxel 80 mg/m² and PLD 40 mg/m²d1 q28. Bevacizumab is dosed at 10 mg/KG d1,15 q28 and atezolizumab/placebo at 840 mg d1,15,q28. Stratification factors are: number of prior treatment lines (1–2 vs 3); planned chemotherapy (PLD vs paclitaxel); previous administration of bevacizumab (yes vs no); and tumor PD-L1 status (Figure 1).
Study design of AGO-OVAR 2.29/ENGOT-ov 34.
Participants
Major inclusion criteria are patients with histologically diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer and relapsed disease. Up to three prior therapies are allowed in patients with one or two prior treatment lines and the treatment-free interval after platinum has to be less than 6 months. In addition, patients with three prior lines of chemotherapy who are not considered for platinum-containing chemotherapy lines are also eligible. Patients must have measurable disease, evaluable disease in combination with Gynecologic Cancer Intergroup (GCIG) CA-125 criteria, or histologically proven relapse/progression. In addition, a de novo tumor biopsy (not older than 3 months) sent to the central laboratory as a formalin-fixed, paraffin-embedded sample for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria. Notably, the prior use of bevacizumab is allowed.
Outcomes
The primary objective of this study is to determine the efficacy of atezolizumab plus bevacizumab and chemotherapy compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian-, fallopian tube, or primary peritoneal cancer with first or second relapse within 6 months after platinum-based chemotherapy or third relapse. There are two co-primary endpoints. Overall survival defined as the time from randomization to death from any cause and progression-free survival defined as the time from randomization to progressive disease (PD) or death, whichever occurs earlier. Progressive disease is based on investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Secondary endpoints include Quality of Life and patient reported outcomes (PRO) measured by EORTC QLQ-C-30, QLQ-OV28, and PRO-CTCAE in the whole study population and in subgroups. Further secondary endpoints include response rate, safety, tolerability, and efficacy in biomarker defined subgroups.
To monitor patient safety and supervise the progress of the trial an independent data monitoring committee has been established. The first independent data monitoring committee (IDMC) meeting took place after 24 patients had been randomized and had completed at least cycle 1. There were no concerns to continue without any changes.
Randomization and blinding
The randomization procedure differed between the first 24 patients (run-in phase) and the rest of the patients. These first 24 patients were allocated to arm A and arm B in a 1:1 ratio balancing for the stratification factor planned chemotherapy (12 patients with paclitaxel and 12 patients with PLD). The recruitment was interrupted for the safety analysis.
Random assignment for all other patients follows a 1:1 ratio to the treatment arms with the following stratification factors: number of prior lines (1–2 vs 3); planned chemotherapy (PLD vs paclitaxel); previous administration of bevacizumab (yes vs no); and tumor PD-L1 status (positive vs negative vs non-informative). The inclusion of patients with non-informative tissue PD-L1 status will be capped to 10% of the whole study population (this additional strata was implemented by the above mentioned amendment). Randomization lists with randomly permuted block sizes were prepared by the Coordinating Center for Clinical Trials (KKS), Philipps-University of Marburg, Germany. Randomization is performed by the IWRS-system of S-CLINICA.
Sample size calculation
We assume a median overall survival of 15 months in the control arm and 20 months in the experimental arm (ie, HR of 0.75) and a median progression-free survival of 6.5 months resp. 9.3 months (HR of 0.70). Further assumptions are a 24-month accrual phase followed by an approximately 13.2-month follow-up, exponential distributions of overall survival and progression-free survival, and a drop-out rate of 5%. The analysis is planned with a power of 80% for the overall survival comparison. The sample size and power calculations were performed with ADDPLAN (v.6.1.0).
Statistical methods
Each of the co-primary endpoints overall survival and progression-free survival will be compared according to the intention to treat principle using the Wald-test for the treatment variable from a Cox model with the treatment arm and randomization stratification factors as covariables. The two-sided significance levels are 0.005 for progression-free survival and 0.045 for overall survival. Secondary endpoints will be analyzed with appropriate statistical methods.
Discussion
Treatment of patients in whom a platinum-based chemotherapy is no longer a good treatment option is still one of the most challenging treatment situations. Usual single-agent chemotherapies such as paclitaxel, PLD, topotecan, and gemcitabine show very limited activity. Therefore, best supportive care without any further tumor-directed therapy is also a standard option. So far, one of the only positive phase III trials in the past few years was the AURELIA trial which showed superiority by the addition of bevacizumab to standard chemotherapy regarding progression-free survival and Quality of Life. Therefore, single-agent non-platinum-based chemotherapy in combination with bevacizumab is a new standard. Unfortunately, this regimen is only approved by authorities in the European Union in patients without prior use of bevacizumab. The use of bevacizumab already in the first or second line setting11 12 limits it use in the resistant population due to this regulatory restriction. However, there is growing evidence regarding retreatment with bevacizumab in colorectal and ovarian cancer.13 14 As we allowed prior use of bevacizumab in this trial, we will also be able to provide data for the re-usage of bevacizumab in combination with non-platinum agents.
So far there is no phase II data regarding safety of this combination in our patient population that is characterized by more fragility, tumor symptoms, and persisting toxicities compared with patients in earlier lines of treatment. We therefore had to focus on safety issues and started a safety run-in phase with 24 patients who completed at least cycle 1 and we stopped the trial before further patients could be randomized. Safety data were monitored by IDMC, which had no concerns. Next IDMC meetings are planned after an additional 60 and 120 randomized patients complete at least cycle 1 (without stopping the trial).
Important for the conduct of this trial was the presentation of the JAVELIN 200 trial in 2019. In JAVELIN 200 a similar patient population was randomized in a 3-arm trial to PLD, avelumab, or the combination of both drugs. The trial did not meet its primary endpoint but a subgroup analysis suggested that a benefit by the addition of an immunotherapy is limited to patients with a positive PD-L1 status. Unfortunately, the full publication of JAVELIN 200 and further data regarding the predictive role of the PD-L1 status in prospective randomized trials in ovarian cancer is still missing. Considering this new evidence, we decided to add PD-L1 status as a stratification factor in our trial. In addition, it is unclear in ovarian cancer, if the PD-L1 status in the primary tumor compared with metastases, over time and multiple treatment lines remains stable. Therefore, we decided to perform PD-L1 staining on fresh biopsies to rule out uncertainty of the recent PD-L1 status before inclusion in the trial.
In conclusion, AGO-OVAR 2.29/ENGOT-ov 34 is the logical further development of the so far most efficacious regimen in platinum-resistant ovarian cancer. Because the primary endpoint includes overall survival as recommended by the Fifth Ovarian Cancer Conference,15 the trial will be able to provide a definitive answer to this new treatment option in ovarian cancer patients.
Acknowledgments
We would like to thank the participating study groups: Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Studiengruppe, AGO Austria, Belgian Gynecologic Oncology Group (BGOG), Grupo Espagnol de Investigation en Cancer de Ovario (GEICO), Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Nordic Society of Gynecologic Oncology (NSGO), and Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK). In addition, we would like to thank F. Hoffmann-La Roche Ltd for financial support and providing the study drugs. Furthermore, we would like to thank Iqbal Hügel and his team from SPS for monitoring services.
Footnotes
Contributors All co-auhtors are contributing to the trial, read and approved the manuscript.
Funding This study was funded by F. Hoffmann-La Roche.
Competing interests PH reports grants and personal fees from Astra Zeneca, grants and personal fees from Roche, personal fees from Sotio, grants and personal fees from Tesaro, personal fees from Stryker, personal fees from Zai Lab, personal fees from MSD, grants and personal fees from public funding (ASCO, DKH, DFG), personal fees from Clovis, personal fees from Immunogen, grants from GSK, grants from Boehringer Ingelheim, grants from Medac, grants from Genmab, outside the submitted work. PP reports personal fees from Roche Laboratory, other personal fees from MSD laboratory, other from Clovis Oncology, outside the submitted work. AR reports grants and personal fees from Pharmamar, personal fees from Lilly, personal fees from Novartis, personal fees from Amgen, personal fees from Astra Zeneca, personal fees from Tesaro, grants and personal fees from Roche, grants from Eisai, outside the submitted work. KL reports other personal fees from Astra Zeneca, other from GSK, outside the submitted work. CK reports personal fees and non-financial support from Roche, personal fees and non-financial support from Tessaro, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Pharmamar, personal fees from Lilly, personal fees from Genomic Health, outside the submitted work. EP reports personal fees from AGEA, personal fees from Amgen, personal fees from Astra Zeneca, personal fees from Angelini, personal fees from Celgene, personal fees from Eisai, personal fees from Eli Lilly, personal fees from GSK, personal fees from MSD, personal fees from Novartis, personal fees from Pharmamar, personal fees from Pfizer, personal fees from Roche, personal fees from Tesaro, personal fees from Clovis, personal fees from Daiichi Sankyo, outside the submitted work. FH reports non-financial support from NewOncology; personal fees from Roche, personal fees from AstraZeneca, from Clovis, personal fees from Tesaro, from PharmaMar, outside the submitted work. JS reports grants, non-financial support and other from Roche, grants, non-financial support, and other perdonal fees from PharmaMar, grants, non-financial support and other peredonal fees from Teasaro, grants, non-financial support and other personal fees from Clovis, grants, non-financial support and other peersonal fees from Astra Zeneca, grants and non-financial support from MSD, grants, non-financial support and other personal fees from Novocure, outside the submitted work. ND: Dr. de Gregorio reports personal fees from Roche, personal fees from GSK, personal fees from Pharmamar, personal fees from Astra Zeneca, personal fees from Clovis, personal fees from Ingress, from null, outside the submitted work. PW reports grants and personal fees from Amgen, personal fees from Astra Zeneca, personal fees from Clovis, personal fees from MSD, grants and personal fees from Novartis, personal fees from Pfizer, grants and personal fees from Roche, personal fees from Tesaro, personal fees from Eisai, personal fees from Pharmamar, personal fees from Teva, outside the submitted work. JL reports personal fees and other from Pfizer, grants and other from Merck/MSD, personal fees from Eisai, personal fees from Tesaro/GSK, grants and personal fees from AstraZeneca, personal fees from Artios, personal fees from Regeneron, outside the submitted work. DL reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Tesaro, grants and personal fees from Clovis, grants and personal fees from Merck, grants, personal fees and non-financial support from Pharmamar, personal fees from Immunogen, personal fees from Genmab, personal fees from Amgen, personal fees and non-financial support from Astra Zeneca, outside the submitted work. FM reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, outside the submitted work.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
Data availability statement There are no data in this work