Objective Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy.
Methods PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention.
Results There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups.
Conclusion PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.
- Ovarian Neoplasms
Data availability statement
Data are available upon reasonable request. GSK makes available anonymized individual participant data and associated documents from interventional clinical studies that evaluate medicines, upon approval of proposals submitted to https://www.gsk-studyregister.com/en/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Blinded independent centralized radiological review is often included in ovarian cancer trial designs to provide an independent, objective review of imaging data, and to help validate progression-free survival as a primary endpoint. Ovarian cancer trials have reported high concordance between local and independent review committee assessments of progression status; however, when high discordance is apparent, little has been published regarding best practices to optimize blinded independent centralized review performance.
WHAT THIS STUDY ADDS
Due to training intervention of the independent reviewers, 10 of the most essential considerations in terms of best practices for radiologists were identified, and changes were implemented to the PRIMA imaging charter; two original reviewers with high reader variability were removed.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study demonstrates the benefit of using specialized, disease-specific training for the independent reviewers in an ovarian cancer trial, and highlights the need to evaluate concordance early on in trials.
Successful clinical trials must adopt study design practices to reduce bias and ensure that appropriate endpoints are selected. While overall survival is the gold standard endpoint in oncology trials, demonstrating an effect on overall survival in front-line ovarian cancer studies is challenging, despite clear evidence of benefit to progression-free survival.1–3 Progression-free survival is regarded by the Gynecological Cancer InterGroup (GCIG) consensus as an acceptable primary endpoint in front-line ovarian cancer due to its temporal relevance in a rapidly evolving treatment landscape.4 5 Since 2014, new drug approvals by the US Food and Drug Administration (FDA) have substantially risen for ovarian cancer, with over a dozen approvals largely based on progression-free survival data;5 6 thus supporting progression-free survival as the primary endpoint for front-line ovarian cancer.7
However, methodologic flaws can compromise the validity of progression-free survival as a primary endpoint. A lack of consensus in determining disease progression between radiologists can bias the estimated treatment effect and increase the informative censoring in a trial.8 In addition to symmetry in disease assessment between trial arms, the use of either a placebo and/or disease response assessment conducted by blinded independent centralized radiological review are necessary elements of a well conducted registrational trial.5 9 Due to the unique disease characteristics of ovarian cancer, imaging ovarian cancer can be particularly challenging compared with imaging other solid tumors.5 10 Blinded independent centralized review has been implemented in ovarian cancer trials to provide an independent, objective review of imaging data by external experienced radiologists.5 Advantages of blinded independent centralized review and investigator-assessed progression-free survival are described in table 1; however, little has been published regarding best practices to optimize blinded independent centralized review performance.
PRIMA/ENGOT-OV26/GOG 3012 was a phase 3 front-line trial that resulted in FDA and European Medicines Agency (EMA) approval of niraparib maintenance therapy in patients with advanced ovarian cancer who responded to platinum-based therapy, irrespective of homologous recombination deficiency (HRD) status.11–13 The primary endpoint in PRIMA was progression-free survival as assessed by blinded independent centralized review.11 Our objective was to use this trial to illustrate the importance of conducting blinded independent centralized review assessments properly and to ensure concordance was optimized with investigators via implementation of training and imaging charter amendments.
PRIMA was a randomized, double-blind, placebo-controlled phase 3 trial in patients with newly diagnosed stage III or IV ovarian cancer, for which ethical approval was obtained by the appropriate Institutional Review Board as listed in online supplemental table 1 (eg, Western Institutional Review Board Copernicus Group covered several US sites) as well as appropriate written informed consent. Full descriptions of the patient eligibility and trial design have previously been published.11
The primary study endpoint was progression-free survival in patients with HRD-positive (tested using Myriad MyChoice® CDx) ovarian cancer and in the overall population, as determined by hierarchical testing. Progression-free survival was defined as the time from randomization after the last platinum-based chemotherapy to the earliest date of objective disease progression via imaging (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.114) or death from any cause. Tumor assessment occurred at screening and then every 12 weeks (±7 days) from the cycle 1/day 1 visit, using computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT until progression, when a final follow-up set of imaging was required. Progression was assessed by RECIST v1.1 criteria and clinical criteria using blinded independent centralized review by two independent radiologists and, if necessary, an arbiter, as well as by an independent oncologist when the radiology review did not meet the criteria for progressive disease. In total, five blinded independent centralized reviewers were assigned to PRIMA. Disease progression would also be reviewed if CA125 levels increased, per the GCIG criteria,15 in conjunction with histological proof or clinical symptoms, as specified in the protocol.
Blinded Independent Central Review Process
Upon determination of progression by the investigator or discontinuation of treatment, all imaging and supportive clinical data were submitted for blinded central review by two independent radiologists according to RECIST v1.1. Clinical data for radiology review only included information regarding prior procedures and radiotherapy, as previously irradiated regions would not be assessed by blinded independent centralized review. Whereas for a clinical review, supportive data included CA125 levels, all reported adverse events (except hematologic toxicities), and any other imaging data acquired (eg, ultrasound). Upon blinded independent centralized reviewer selection, specific experience in ovarian cancer imaging was not mandatory, assuming that reviewers were qualified to read abdominal/pelvic CT/MRI scans (for RECIST assessment of patients undergoing PET–CT scans, central reviewers interpreted the CT scans; PET scans were read by nuclear medicine physicians and results were provided as part of clinical review dossier). However, if the determination of progression differed between the two independent radiologists, a third independent radiologist completed adjudication. If central radiology review failed to determine progressive disease, the central blinded clinician then reviewed clinical information for determination of progressive disease, and the site was informed of the central progressive disease determination. If the investigator determined progressive disease, but central review did not, the patient continued study treatment provided safety and treatment criteria were met. All scheduled patient imaging was performed until radiologic or clinical progressive disease was confirmed by blinded independent centralized review, subsequent therapy initiated, or study discontinuation.
The central blinded clinician reviewed clinical and radiographic data supporting clinical progression to determine whether the patient had protocol-defined clinical progressive disease (and if so, at which time point), but did not advise on timing of radiographic progression, nor modify lesion selection performed by independent radiologists. Lesions assessed by physical examination and documented by the site were assessed qualitatively and incorporated into the central blinded clinician’s assessment. Blinded independent centralized review assessments were used for study purposes only, and were not used to inform clinical decision making for patients.
To optimize blinded independent centralized reviewer performance and reduce bias in the assessment of progressive disease, a training intervention was developed for blinded central reviewers, which was composed of live reader training and an offline review of provided materials. The reader training focused on the application of RECIST v1.1 in the context of ovarian cancer, and was provided by one of the authors (SAW), a fellowship-trained body imaging radiologist with expertise in ovarian cancer imaging. The first part consisted of a didactic presentation to provide the context for understanding the different pathways of metastatic disease spread in ovarian cancer, including direct extension and lymphatic, hematologic, and peritoneal spread. The second part included a discussion of the application of RECIST v1.1 as it specifically pertains to ovarian cancer, with an emphasis on lesion selection and assignment of progression. Details such as the importance of imaging data quality and what constitutes measurable lesions versus non-measurable lesions were emphasized. Reviewers were encouraged to identify and measure at least one lesion at baseline and to capture subtle disease as non-target lesions if they did not meet the size criteria; failing the identification of any disease, reviewers had to confirm no lesions were identified. During follow-up, any lesion considered malignant seen for the first time on follow-up, not measured, or selected at baseline for comparison were considered new lesions. Reviewers were reminded to consider all anatomy to assess the disease burden and possible new lesions at each time point. The third part of the training consisted of a mix of CT and MRI case examples to emphasize the main points discussed and key points to consider, including assessment under the diaphragm, use of the coronal plane when imaging, and presence of calcifications.
Lastly, an interactive question and answer session concluded the training. All five of the central reviewers who were originally assigned to the PRIMA study attended the initial training. Radiologists then reviewed materials, such as the system user manual v1.0 plus radiology addendum v1.0, and the reviewer communication log v3.0 offline.
Discordance rates between progressive disease and non-progressive disease were assessed routinely for investigator progression-free survival and blinded independent centralized review progression-free survival data as part of study conduct. Rates were calculated as the percentage of patients with unconfirmed blinded independent centralized review progressive disease or non-progressive disease (including censored patients). Final discordance rates were determined post-hoc for the overall patient population, and the following biomarker subgroups: HRD-positive, HRD-positive BRCA mutated (BRCAm), HRD-positive BRCA wild-type (BRCAwt), and HRD-negative populations.
Progression-Free Survival Assessments
At the primary analysis (data cut-off 17 May 2019), median progression-free survival and hazard ratios (HR) for the overall patient population, HRD-positive BRCAm, HRD-positive BRCAwt, and HRD-negative populations were assessed and compared between blinded independent centralized review and investigator.
In accordance with the journal’s guidelines, we will provide our data for independent analysis by a team selected by the editorial team for the purposes of additional data analysis or for the reproducibility of this study in other centers, if such is requested.
In a subset of 80 patients (April 2018), the average discordance rate between blinded independent centralized reviewers and investigator determination of progressive disease and non-progressive disease pre-intervention was 39% (n=31; figure 1). Among the 31 patients in whom investigators deemed progression and blinded independent centralized review reviewers did not, the most common sources of discordance were radiological findings of peritoneal carcinomatosis (n=11; 24% of all new lesions) and fluid collections (such as ascites and pleural effusion; n=8; 18% of all new lesions) arising from new non-target lesions (table 2).
Intervention Training and Post-Intervention Discordance
While these metrics were being calculated, the reviewers underwent the previously described intervention training in July 2018. As a result, 10 of the most essential considerations in terms of best practices for radiologists to reduce reader variability were identified, and are described in table 3. Crucial changes to the PRIMA imaging charter were also identified (see table 3). These changes included evaluating coronal and sagittal scan reconstructions to improve identification of disease, such as peritoneal/omental lesions, or for enhanced demarcation from nearby anatomical structures (eg, bowel). All cases reviewed before May 2018 were re-reviewed after the training intervention, and all new cases were reviewed according to the updated PRIMA imaging charter. Due to high reader variability between pre-intervention and post-intervention, two out of five reviewers were removed from the PRIMA study and replaced by one additional reviewer who was hired post-intervention, but who also underwent the intervention training separately from the other reviewers. All PRIMA scans read by these two reviewers were re-read prior to the primary data lock for the PRIMA study.
The median progression-free survival was 13.8 months with niraparib and 8.2 months with placebo in the overall patient population per blinded independent centralized reviewer assessment (HR 0.62, 95% confidence interval [CI] 0.50–0.76; p<0.001). A sensitivity analysis showed similarity with investigator-assessed progression-free survival: median progression-free survival was 13.8 months with niraparib and 8.2 months with placebo in the overall patient population (HR 0.63, 95% CI 0.51–0.76; p<0.001; figure 2). Across the overall and HRD-positive patient populations, there was a final concordance of 88% and 87%, respectively, between blinded independent centralized review and investigator-assessed progressive disease.
In the overall population, 52% (n=255/487) of niraparib treated subjects and 37% (n=91/246) of placebo-treated subjects were censored per blinded independent centralized review assessment. The number of patients censored by investigators were similar (48% [n=232/487] of niraparib patients and 33% [n=80/246] of placebo patients). Reasons for censoring included: no evaluable baseline or no evaluable post-baseline radiological assessments; patients who have not progressed or died and have not started subsequent anti-cancer therapy; patients who have progressed or died after the start of subsequent anti-cancer therapy; and patients who have progressed or died after ≥2 missed radiological assessments (25 weeks allowing for visit window). Of the patients who had investigator-assessed progressive disease, 68 patients did not have progression confirmed by blinded central review.
The majority of these patients (71%, n=48) were censored on the same day that the investigator called progression; of the remaining 20 patients (29%), 11 patients had blinded central reviewer confirmed progressive disease, and 9 patients were censored. For those 11 patients with progression confirmed by blinded central review, the median time from investigator confirmed progressive disease to blinded central reviewer confirmed progressive disease was 2.8 months (range 0.7–7.3 months) for the niraparib arm (n=7) and 3.3 months (range 0.07–7.9 months) for the placebo arm (n=4). Event observations were also comparable between blinded independent centralized reviewers and investigators: 48% (n=232/487) versus 52% (255/487) for patients receiving niraparib, respectively, and 63% (n=155/246) versus 68% (n=166/246) for patients receiving placebo. In total, 20% (n=145/733) of patients enrolled in the PRIMA trial discontinued from the study (reasons included loss of follow-up, death, and withdrawal of consent), of which 62% (n=90/145) of patients were receiving niraparib.
At the primary data cut-off (May 2019), final discordance rates in the overall population decreased from 39% to 12% post-intervention training. Discordance rates between blinded independent centralized reviewers and investigators were also determined by biomarker subgroup, and ranged from 10–15% (HRD-positive 13% [n=48/373]; HRD-positive BRCAm 15% [n=33/223]; HRD-positive BRCAwt 10% [n=15/150]; HRD-negative 13% [n=32/249]). Similar observations in progression-free survival assessments were demonstrated across all biomarker subgroups (figure 2); the largest variation between blinded independent centralized reviewers and investigators was demonstrated in the HRD-positive BRCAwt subgroup (progression-free survival 19.6 months [HR 0.50; 95% CI 0.30–0.83] and 16.6 months [HR 0.60; 95% CI 0.37–0.95], respectively). In the final PRIMA study, of the 733 patients who were randomized, 360 (49%) patients were deemed to have progressive disease by both blinded independent centralized reviewers and investigators; 27 (4%) patients (16/487 patients receiving niraparib and 11/246 patients receiving placebo) were deemed to have progressive disease by blinded independent centralized review only.
Summary of Main Results
In our study, discrepant reads were identified during an early-phase assessment of PRIMA, with an average of 39% discordance between investigator assessment and blinded independent centralized review assessment. After the intervention, an improvement in the discordance rate was noted, with a decrease from 39% to 12%. When assessed by biomarker status, discordance rates were similar across subgroups, with the HRD-positive BRCAwt population, the smallest subgroup, having the highest discordance rate of 15%.
Results in the Context of Published Literature
Other ovarian cancer trials have reported high concordance between local and independent review committee assessments of progression status.1 16 In GOG-0218, concordance levels for both progressive disease and non-progressive disease determination ranged from 74% to 79% across the three study arms assessed.1 AGO-OVAR16 reported 84% and 86% concordance for assessment of disease progression between the treatment and placebo arms of the study, respectively.16 In a meta-analysis of phase 3 oncology trials,17 the mean proportion of discord on timing or occurrence of disease progression was just over 50% across 12 contributing studies. Importantly, the GOG-0218 analysis and the meta-analysis concluded that discrepancies were likely owing to variability in the process instead of systematic bias.1 17
However, there are negative trial consequences of high discordance rates between investigator and blinded independent centralized review. When the local investigator concludes progressive disease but blinded independent centralized review does not, enrolled patients are typically removed from the study without further scans, and the patient is censored at the time of the last negative evaluation, potentially biasing endpoint estimates if unbalanced across study arms, and reducing power to detect true treatment effects.9 18
Furthermore, discordance between blinded independent centralized reviewers may be problematic, and requires an adjudicator, who is an independent radiologist used to resolve discrepant reads between blinded independent centralized reviewers. Across 79 oncology trials, the proportion of cases in which a lack of consensus between reviewers required a third adjudicator was 42% overall, but 55% in ovarian cancer, making ovarian cancer the second-most-likely cancer to require adjudication.19 Furthermore, it has been emerging that the pattern of first recurrence during or after PARP inhibitor therapy is frequently oligometastatic disease.20 In the recurrent setting, approximately 30–50% of patients receiving PARP inhibitors may recur without significant increase in CA125 serum levels.21 22 Therefore, understanding the biology of the disease and recurrence patterns with specific agents is important for evaluation of disease response, and should be performed by a team of clinicians and radiologists with expertise in their specialized areas for optimal disease assessment.20–22
Strengths and Weaknesses
Our study demonstrates the effectiveness of implementing disease-specific training for radiologists in front-line oncology trials. We identified 10 best practices to reduce reader variability; however, there are some limitations to consider. Study investigators did not participate in the intervention training, as they were typically clinicians or radiologists with expertise in ovarian cancer and had access to a patient’s clinical data. A refresher course of RECIST v1.1 guidelines and PRIMA protocol definitions of clinical progression were available to study investigators, provided by the sponsor (Tesaro/GSK). There was particular emphasis on GCIG criteria for CA125 progression components and the importance of symptoms and other imaging.
The refresher training was not obligatory for study sites’ radiologists as they were not contractually bound by Tesaro/GSK. Additionally, in cases where there was no designated study radiologist, patient imaging data would be reviewed by the on-duty radiologist, who would also typically have experience in ovarian cancer imaging. Finally, recent data demonstrates agreement between local evaluation and blinded centralized review of progression-free survival endpoints in clinical trials, and therefore may obviate the need for the costly and time-consuming blinded independent central review for all patients in trials.23 This concordance has been demonstrated in a wide variety of hematologic and solid tumors, including ovarian cancer.16 24 25
Implications for Practice and Future Research
Several factors may contribute to the difficulty of determining radiologic disease progression in ovarian cancer, for example, the presence of surgical scarring and peritoneal spread occurring in the form of discrete measurable target lesions or non-target lesions (eg, ascites, omental nodularity/caking).1 16 This is reflected in our study, as target, non-target, and new lesion discordance was most often due to the presence of peritoneal carcinomatosis (table 2). Our study demonstrates that specialized disease-specific training can improve concordance among blinded independent centralized review reviewers, and this is particularly relevant when there may be more heterogeneity in reader experience with cancers that may spread via the peritoneum, as disease-specific expertise among blinded central reviewers cannot always be guaranteed in trials. Final results from the PRIMA trial showed consistency between investigator and blinded independent centralized review results in sensitivity analyses.11 Elements of this training highlight several best practice procedures (table 3) that can be implemented during radiology review, which may be useful in optimizing blinded independent centralized review assessments and thereby improve validity of endpoint assessment.
As a result of the training, several amendments were made to the PRIMA imaging charter. These include routinely obtaining coronal and sagittal reconstructions, as previously these additional planes would not be acquired or provided to blinded independent centralized review radiologists per the original imaging charter. While all lesions visualized by CT/MRI were marked or measured in the axial plane, coronal or sagittal reconstructions aid in the identification and selection of peritoneal nodules, or more clearly delineate lesions from nearby organs such as the bowel. Per the updated imaging charter, coronal and sagittal reconstructions would be reviewed and considered by blinded independent centralized review radiologists. Additionally, blinded independent centralized radiologists reviewed patient scans regardless of whether the scan was scheduled per the study protocol or was unscheduled i.e., due to clinical symptoms such as increased CA125. CA125 levels are routinely obtained in randomized clinical trials where progression-free survival is the primary endpoint.
Previously, investigators would declare progression and initiate second-line treatment based solely on CA125 levels regardless of clinical evidence of measurable disease, potentially lowering the threshold of defining progression and skewing final progression-free survival measurements in trials. Guidelines were then published by GCIG recommending that after first-line therapy, the doubling of CA125 from the upper limit of normal, or doubling from the post-treatment nadir, would be suggestive of disease progression.26 Revisions to the definition of progression include declaring a patient to have progressive disease based on either RECIST criteria or CA125 levels, and is defined as the date of the earlier of the two events if both are documented.26
A new modality in diagnostic imaging is radiomic analysis from CT or MRI data that, when applied to ovarian cancer, has provided valuable information on tumor biology.27 28 New applications enable the use of these data to identify radiomic features that correlate with specific genotypic and phenotypic features that may enable predications of disease progression or prognosis. This modality is especially advantageous for highly heterogenous tumors by enabling the evaluation of the entire tumor or tumor burden, which is not possible through biopsy, while still allowing the characterization and quantification of disease progression and drug resistance.27–29
Overall, for clinical trials using blinded independent centralized review assessment as a primary endpoint, we have demonstrated the importance of fully optimizing blinded independent centralized review. Furthermore, we have shown in PRIMA that initial blinded independent centralized review and investigator discordance was greatly improved, indicating a benefit in using specialized, disease-specific training, and highlighting the need to evaluate concordance early on in trials.
Data availability statement
Data are available upon reasonable request. GSK makes available anonymized individual participant data and associated documents from interventional clinical studies that evaluate medicines, upon approval of proposals submitted to https://www.gsk-studyregister.com/en/.
Patient consent for publication
The authors would like to acknowledge Hasan H Jamal, MSc at GSK, for their review and coordination of the manuscript. Medical writing support was provided by Claire Kelly, PhD, of Fishawack Indicia Ltd, UK, part of Avalere Health, funded by GSK. The authors would like to acknowledge the contributions made to this publication by the teams at Paraxel and Calyx. Data from this study were previously presented, in part, as a poster presentation at the 2022 International Gynecologic Cancer Society (IGCS) annual meeting by Herzog, T.J. et al, EP224/#531 Optimization of Assessment of Disease Progression Between Blinded Central Independent Review and Investigator Assessment in the PRIMA/ENGOT-ov26/GOG-3012 Trial (abstract Herzog, T.J et al, IJGC. 2022;32: suppl 3).
AG-M and BJM are joint senior authors.
Twitter @Thomas Herzog
Contributors TJH: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing.; SAW: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; MRM: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; BP: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; IV: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; WSG: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; IAM: Conceptualization; Data curation; Validation; Data Curation; Roles/Writing - original draft; Writing - review and editing; WY: Data Curation; Roles/Writing - original draft; Writing - review and editing; JAH: Conceptualization; Data Curation; Roles/Writing - original draft; Writing - review and editing; DG: Conceptualization; Data curation; Validation; Data Curation; Roles/Writing - original draft; Writing - review and editing; AGM: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing; BJM: Conceptualization; Data curation; Roles/Writing - original draft; Writing - review and editing. TJH is guarantor for this manuscript.
Funding This study was funded by GSK (GSK study 213359). GSK contributed to study design, implementation, data collection, interpretation, and analysis.
Competing interests TJH has served on advisory boards (Aravive, AstraZeneca, Caris, Clovis Oncology, Eisai, Epsilogen, GSK, Immunogen, Johnson & Johnson, Merck, Roche Genentech, Seagen) and as a consultant for Abbvie. SAW reports consulting fees (GSK and BioClinica). MRM reports personal fees and other (Karyopharm Therapeutics, Sera Prognostics, Roche); institutional grants and no financial interest (Apexigen, AstraZeneca, Deciphera, GSK, Ultimovacs); personal fees and invited speaker (AstraZeneca, GSK); personal fees and advisory boards (AstraZeneca, Biocad, Boehringer Ingelheim, GSK, Karyopharm, Merck, Mersana, ImmunoGen, Clovis Oncology, Roche, Zailab); personal fees, stocks and a member of board of directors (Karyopharm). BP reports research funding (AstraZeneca, Celgene, Celsion, Clovis, Genentech, SeaGen, GSK, Merck, Mersana, SeaGen, Takada, Toray) and consulting fees (AstraZeneca, Celsion, Eisai, GSK, GOG Foundation, Immunogen, Inxmed, Lily, Merck, Mersana, SeaGen, Toray). IV reports consulting fees (Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncoXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis), travel grants (Karyopharm, Genmab, Novocure), and contracted research grants (Amgen, Roche, Oncoinvent AS). WSG reports advisory board and speaker fees (GSK). IAM, WY, and DG are employees of GSK. JAH is an employee of GSK and reports stocks in GSK. AGM reports personal fees for educational/advisory-related activities (Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Mersana, MSD, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Takeda). BJM reports consulting fees (Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyoparm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, GSK, US Oncology Research, VBL, Verstem, Zentalis); speakers honoraria (AstraZeneca, Clovis, Eisai, Merck, Myriad, Roche/Genentech, GSK); investigator honoraria (Gradalis).
Provenance and peer review Not commissioned; externally peer reviewed.
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