Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

You, Benoît; Purdy, Christopher; Swisher, Elizabeth M.; Bookman, Michael A.; Fleming, Gini F.; Coleman, Robert L.; Randall, Leslie M.; Tewari, Krishnansu S.; Monk, Bradley J.; Walker, Joan L.; Cappuccini, Fabio; Cohn, David E.; Muzaffar, Mahvish; Mutch, David G.; Hendrickson, Andrea E. Wahner; Martin, Lainie P.; Colomban, Olivier; Burger, Robert A.

doi:10.1200/jco.22.01207

Cited by 29 publications

(24 citation statements)

References 29 publications

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“…In a subgroup analysis of GOG-0218 31 , in which cases were divided by mutation status in homologous recombination repair-related genes, there was no significant difference in the trends (Figure 5E). The results were also similar in another subgroup analysis of GOG-0218 stratified by chemosensitivity status as determined by changes in blood CA125 levels 32 (Figure 5F).…”

Section: Resultssupporting

confidence: 80%

“…Given that bevacizumab is effective for only about a year and has a rebound effect after its discontinuation, it is likely that the benefit of bevacizumab, including improved survival and quality of life, will only be seen in patients with short survival. Our findings may explain the results of previous studies that bevacizumab did not prolong overall survival (OS) in the ICON7 and GOG-0218 overall cohorts 46, 47 but did prolong OS in chemotherapy-refractory, high-risk patients 32, 48 .…”

Section: Discussionsupporting

confidence: 80%

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Bevacizumab in ovarian cancer: time-dependent changes in risk of progression

Takamatsu

Yamaguchi

Hamanishi

et al. 2023

Preprint

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Background Bevacizumab has been used in the first-line and recurrent treatment of ovarian cancer. However, the time-dependent changes in the effects of bevacizumab administration are not fully understood. Methods The ICON7-A cohort was generated from two ancillary analyses of the ICON7 trial. ICON7-A tumors were classified as homologous recombination deficient (HRD) or non-HRD based on their gene expression profiles. Kaplan-Meier curves from published phase III trials were graphically analyzed to examine changes in the risk of progression over time between groups. Results In the ICON7-A cohort, the risk of progression in the bevacizumab group (Bev+) compared to the control group (Bev-) was lowest at 6 months. Thereafter, the risk in Bev+ gradually increased and became higher than in Bev- after discontinuation of bevacizumab at 12 months, showing a 'rebound effect'. Restricted mean survival analysis showed that Bev+ had significantly better progression-free survival (PFS) than Bev- before bevacizumab discontinuation, but had significantly worse PFS after bevacizumab discontinuation. The rebound effect was observed both in HRD and non-HRD tumors of the serous subtype, but not in the non-serous subtype. In Kaplan-Meier curve image-based analysis, time-dependent changes in the risk of progression, including rebound effects, were replicated in the overall ICON7 and GOG-0218 cohorts and in their subgroups stratified by prognostic factors, presence of HR-associated mutations and chemotherapy sensitivity. In contrast, no rebound effect was observed in the studies GOG-0213, OCEANS, AURERIA and MITO16B, in which relapsed patients received bevacizumab until progression. Conclusion In ovarian cancer, bevacizumab reduces progression for approximately one year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment of ovarian cancer, bevacizumab is more beneficial in patients with a short expected survival who are unlikely to be affected by the rebound effect.

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Section: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 80%

Bevacizumab in ovarian cancer: time-dependent changes in risk of progression

Takamatsu

Yamaguchi

Hamanishi

et al. 2023

Preprint

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“…Both ICON-7 and GOG-0218 validation studies showed an association between unfavorable KELIM score and benefit from bevacizumab for progression-free survival and overall survival. 68 In clinical trials with PARP inhibitors, a favorable KELIM score may be associated with higher PARP inhibitor efficacy. In the VELIA trial, veliparib combined with carboplatinpaclitaxel, followed by maintenance veliparib was associated with improved progression-free survival compared with chemotherapy alone.…”

Section: Biomarker-based and Translational Endpointsmentioning

confidence: 99%

Outcomes and endpoints of relevance in gynecologic cancer clinical trials

Madariaga

Sánchez-Bayona

Herrera

et al. 2023

Int J Gynecol Cancer

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Drug development is paramount to improve outcomes in patients with gynecologic cancers. A randomized clinical trial should measure whether a clinically relevant improvement is detected with the new intervention compared with the standard of care, using reproductible and appropriate endpoints. Clinically meaningful improvements in overall survival and/or quality of life (QoL) are the gold standards to measure benefit of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide an earlier measure of the effect of the new therapeutic drug, and are not confounded by the effect of subsequent lines of therapy. Yet, its surrogacy with improved overall survival or QoL is unclear in gynecologic malignancies. Of relevance to studies assessing maintenance strategies are other time-to-event endpoints, such as progression-free survival two and time to second subsequent treatment, which provide valuable information on the disease control in the longer term. Translational and biomarker studies are increasingly being incorporated into gynecologic oncology clinical trials, as they may allow understanding of the biology of the disease, resistance mechanisms, and enable a better selection of patients who might benefit from the new therapeutic strategy. Globally, the endpoint selection of a clinical trial will differ according to the type of study, population, disease setting, and type of therapeutic strategy. This review provides an overview of primary and secondary endpoint selection of relevance for gynecologic oncology clinical trials.

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“…Our findings may explain the results of previous studies that bevacizumab did not prolong overall survival in the ICON7 and GOG-0218 overall cohorts 37,38 but prolonged overall survival in chemotherapy-refractory, high-risk patients. 22,39 The absence of rebound effect in the studies of recurrent ovarian cancer (eFigure 5A-C in Supplement 1) seems to be attributed to the protocol that did not stop bevacizumab until disease progression. [23][24][25] A similar result was observed in the MITO-16B trial 26 in which patients received bevacizumab in the first-line treatment and again in recurrent disease (eFigure 5D in Supplement 1).…”

Section: Relative Riskmentioning

confidence: 99%

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

Takamatsu,

Nakai,

Yamaguchi

et al. 2023

JAMA Netw Open

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ImportanceAlthough bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.ObjectiveTo investigate time-dependent changes in the outcomes of bevacizumab therapy.Design, Setting, and ParticipantsThis cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed.ExposuresBevacizumab treatment vs placebo or no treatment.Main Outcomes and MeasuresRestricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.ResultsIn the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P &lt; .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P &lt; .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P &lt; .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P &lt; .001; after, 0.71; 95% CI, 0.56-0.90; P &lt; .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P &lt; .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image–based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination–associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression.Conclusions and RelevanceIn ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.

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Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

Cited by 29 publications

References 29 publications

Bevacizumab in ovarian cancer: time-dependent changes in risk of progression

Bevacizumab in ovarian cancer: time-dependent changes in risk of progression

Outcomes and endpoints of relevance in gynecologic cancer clinical trials

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

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