Optimal Treatment Duration of Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial

Author(s): Jacobus Pfisterer, MD¹; Florence Joly, MD, PhD²; Gunnar Kristensen, MD³; Joern Rau, MSc⁴; Sven Mahner, MD^5,6; Patricia Pautier, MD⁷; Ahmed El-Balat, MD^8,9; Jean-Emmanuel Kurtz, MD¹⁰; Ulrich Canzler, MD¹¹; Jalid Sehouli, MD¹²; Martin L. Heubner, MD^13,14; Andreas D. Hartkopf, MD^15,16; Klaus Baumann, MD^17,18; Annette Hasenburg, MD^19,20; Lars C. Hanker, MD²¹; Antje Belau, MD^22,23; Barbara Schmalfeldt, MD^24,25; Dominik Denschlag, MD²⁶; Tjoung-Won Park-Simon, MD²⁷; Frédéric Selle, MD²⁸; Christian Jackisch, MD²⁹; Alexander Burges, MD⁶; Hans-Joachim Lück, MD³⁰; Günter Emons, MD³¹; Werner Meier, MD^32,33; Martina Gropp-Meier, MD³⁴; Willibald Schröder, MD³⁵; Nikolaus de Gregorio, MD^36,37; Felix Hilpert, MD^38,39; and Philipp Harter, MD⁴⁰

Source: DOI: 10.1200/JCO.22.01010 Journal of Clinical Oncology 41, no. 4 (February 01, 2023) 893-902.

Dr. Maen Hussein's Thoughts

More is NOT better.

PURPOSE

To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer.

METHODS

In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability.

RESULTS

Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab.

CONCLUSION

Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

Author Affiliations

¹Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group and Gynecologic Oncology Center, Kiel, Germany²Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein (GINECO) and Centre François Baclesse, University Caen Normandie, Caen, France³Nordic Society of Gynaecological Oncology (NSGO) and Oslo University Hospital, Oslo, Norway⁴AGO Study Group and Coordinating Center for Clinical Trials, Philipps-University Marburg, Marburg, Germany⁵AGO Study Group and University Medical Center Hamburg-Eppendorf, Hamburg, Germany⁶Department of Obstetrics and Gynecology, University Hospital LMU Munich, Munich, Germany⁷GINECO and Gustave Roussy Cancer Center, Villejuif, France⁸AGO Study Group and University Hospital Frankfurt, Frankfurt, Germany⁹Spital Uster, Uster, Switzerland¹⁰GINECO and Institut de Cancérologie Strasbourg Europe, Strasbourg, France¹¹AGO Study Group and University Hospital Carl Gustav Carus, Technische Universität Dresden and National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany¹²AGO Study Group and Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany¹³AGO Study Group and University Hospital Essen, Essen, Germany¹⁴Cantonal Hospital Baden AG, Baden, Switzerland¹⁵AGO Study Group and University Hospital Tübingen, Tübingen, Germany¹⁶University Hospital Ulm, Ulm, Germany¹⁷AGO Study Group and University Hospital Gießen and Marburg, Site Marburg, Marburg, Germany¹⁸Hospital Ludwigshafen, Ludwigshafen, Germany¹⁹AGO Study Group and University Hospital Freiburg, Freiburg, Germany²⁰University Medical Center Mainz, Mainz, Germany²¹AGO Study Group and University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany²²AGO Study Group and University Hospital Greifswald, Greifswald, Germany²³Frauenarztpraxis Dr. Belau, Greifswald, Germany²⁴AGO Study Group and Hospital Rechts der Isar, Technical University Munich, Munich, Germany²⁵University Medical Center Hamburg-Eppendorf, Hamburg, Germany²⁶AGO Study Group and Hochtaunus-Kliniken, Hospital Bad Homburg, Bad Homburg, Germany²⁷AGO Study Group and Hannover Medical School, Hannover, Germany²⁸GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France²⁹AGO Study Group and Sana Hospital Offenbach, Offenbach, Germany³⁰AGO Study Group and Gynäkologisch-Onkologische Praxis Hannover, Hannover, Germany³¹AGO Study Group and University Medical Center Göttingen, Göttingen, Germany³²AGO Study Group and Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany³³University Hospital Düsseldorf, Düsseldorf, Germany³⁴AGO Study Group and Onkologie Ravensburg, Ravensburg, Germany³⁵AGO Study Group and GYNAEKOLOGICUM Bremen, Bremen, Germany³⁶AGO Study Group and University Hospital Ulm, Ulm, Germany³⁷SLK-Kliniken Heilbronn, Klinikum am Gesundbrunnen, Heilbronn, Germany³⁸AGO Study Group and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany³⁹Krankenhaus Jerusalem, Mammazentrum Hamburg, Hamburg, Germany⁴⁰AGO Study Group and Evangelische Kliniken Essen-Mitte, Essen, Germany

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial

Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. Adding it to nab-paclitaxel in platinum resistant ovarian cancer pateints had18-m overall survival was 46% and 27%. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16· vs 11·9 months.

Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study

Participants (who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum) regime were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Overall survival (OS) was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76
OS was significantly improved in the overall population (median 17·7 m vs 14·0 m, hazard ratio (HR) 0·82

Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial

This is another well-done study that, frankly, confirms what we’ve seen elsewhere—PDL1 inhibition does not seem to meaningfully change outcomes in platinum-resistant ovarian cancer, even when added to chemo + bev.

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201

The ENGOT-OV60/GOG-3052/RAMP 201 phase II trial evaluated avutometinib (a RAF/MEK clamp) plus defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC), showing a confirmed objective response rate (ORR) of 31% (44% in KRAS-mutant, 17% in KRAS wild-type) and a median progression-free survival (PFS) of 12.9 months (22.0 vs 12.8 months for KRAS-mutant vs wild-type). The median duration of response was notably long at 31.1 months, and the disease control rate was 88%. The most common grade ≥3 AEs were elevated creatine phosphokinase (CPK) (24%), diarrhea (8%), and anemia (5%), with a 10% discontinuation rate due to adverse events (AEs); so management of AE’s is key for using this new drug combo. This combination looks like a real contender for a new standard in recurrent LGSOC, especially for KRAS-mutant patients.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial

Adding Atezo to combination chemotherapy with bevacizumab did not meet the primary end point of PFS. Regardless of the PDL-1 status it was also more toxic. It seems that ovarian cancer is still immune to immunotherapy.